RENAL CELL CARCINOMA

Epidemiology :
Renal cell carcinoma constitutes about 1% of all malignant neoplasms in India, with a male to female ratio of 1.5:1. Its incidence has been shown to be on an increase over the last 2 decades, primarily due to enhanced detection of tumours by expanded use of imaging techniques such as ultrasound and computed tomography. It is more common in the urban than rural population.

Clinical presentation :
Renal cell carcinoma is usually seen in the middle aged or elderly individuals, with a male predominance.
Renal cell carcinoma may remain clinically occult through most of its natural course. Nearly 40% of the renal carcinomas remain asymptomatic throughout their course and are diagnosed on routine imaging studies for some other complaint or during the course of investigations for metastatic disease or systemic symptoms.
The commonest presenting symptoms are pain in the lumbar region, lump and haematuria. This classic triad of symptoms is present in about 9% of all patients and is indicative of advanced disease. Haematuria is usually secondary to involvement of the pelvicalyceal system or ureter. Backache usually signifies involvement of the posterior abdominal wall muscles or nerves by the disease. Presence of a varicocele, dilated veins on the anterior abdominal wall and oedema of the lower extremities may indicate inferior vena caval thrombus.
Nearly 45% patients with renal carcinoma present with localised disease, 25% with locally advanced disease and 30% with metastatic disease. The commonest sites of metastases are lung, bones, liver, brain, soft tissues and cutaneous elements.
Many patients with renal carcinoma develop systemic symptoms of the disease, leading to many paraneoplastic syndromes.

Investigations :
Apart from routine haematological and biochemical investigations including renal chemistry, alkaline phosphatase (for liver or bone metastases) and serum calcium (for evaluation of paraneoplastic syndromes), radiographic evaluation by imaging studies is the hallmark of preoperative evaluation of renal tumours.
Plain film radiography may show foci of renal calcification in 5-10% of cases, a focal bulge on the renal contour and osseous metastases. The calcification could be peripheral, curvilinear or central. Central calcification is associated with a malignant lesion in 87% of cases.
A number of imaging studies e.g. ultrasonography, CT scan, MRI, arteriography, inferior venacavography are available for imaging of the renal masses and their characterisation. However, no single modality is best for all patients, since each provides unique information. A judicious combination of these modalities provides optimum information about diagnosis, staging and treatment approach.

Ultrasonography and CT scans are the most useful imaging techniques for renal carcinoma. Both can provide excellent diagnostic and staging information and can define the anatomical details about the extrarenal spread of disease including extension to adjacent organs, tumour thrombus extension to renal vein or inferior vena cava; retroperitoneal lymph nodes and liver metastases. They are also very useful for planning FNAC from suspected renal cell carcinomas. CT scanning has better sensitivity and specificity than ultrasonography for detecting renal masses. Small sized masses less than 3 cm are frequently discovered on routine abdominal scanning. Before the advent of CT scan, small sized masses formed 5% of RCC. The incidence of small renal cell carcinomas is about 9-38% with CT imaging. Helical CT with its volumetric scanning ability and in the phase of optimal vascular enhancement further increases the accuracy of CT in detecting smaller lesions. The use of contrast enhancement has greatly improved the sensitivity of CT scan in characterisation of abnormal renal masses. They can detect very small changes in the renal density that might indicate the presence of a very small tumour. Inhomogeneous enhancement to a lesser degree than the normal renal parenchyma is indicative of renal cell carcinoma. CT has about 91% accuracy for pre-operative staging as compared to surgical and pathological staging.

Magnetic Resonance Imaging is the best modality currently available for staging renal carcinoma, and provides a 3-dimensional picture of the tumour, with a reported accuracy of 82-96%. Vascular involvement is best demonstrated on MRI. MRI is valuable in patients where iodinated contrast is contraindicated, in renal failure and in pregnant patients. It is used as a problem-solving tool when CT scan or ultrasound findings are equivocal.
Renal arteriography, being an invasive technique is seldom used in the evaluation of renal masses but can provide useful information in case of a small tumour of indeterminate origin and for defining the vasculature in the presence of very large tumours or when nephron-sparing surgery is planned. It is also used when angioinfarction of renal cell carcinoma is contemplated.
Inferior venacavography and Doppler have a limited complementary role to MRI for better delineation of the tumour thrombus in the IVC. Transoesophageal ultrasonography or echocardiography can also be used to accurately delineate the upper extent of the thrombus, which is of extreme importance for the surgeon to plan appropriate operative procedure.
Metastatic work up: It is mandatory to have a baseline metastatic work up before deciding primary treatment, as follows :
- X-ray chest for documenting lung metastases if present. CT thorax is not routinely indicated but may be done if the patient has chest symptoms or has suspicious findings on X-ray chest or has a solitary lung nodule on X-ray chest. CT thorax is not recommended in the presence of multiple metastases on X-ray chest.
- Ultrasonography or CT scan to rule out liver metastases
- Isotope bone scan.

Fine needle aspiration cytology for cytological diagnosis of renal carcinoma is controversial. It may be used for patients with indeterminate masses despite imaging studies where inflammatory lesions, abscesses or metastases are suspected. It may also be used in medically high-risk patients where accurate preoperative diagnosis may help in planning treatment. The relatively low diagnostic yield, suboptimal accuracy and potential risk of tumour seedling along the needle tract do not justify its routine use.

Staging :
The TNM staging system (AJCC) provides more detailed information about the extent of the disease and also provides improved stratification according to survival.

Primary tumour (T)

Management :
Surgery is the mainstay of the management of renal cell carcinoma.

Incidental Renal Tumours
With the advent and increased use of ultra-sound and CT scans for the assessment of abdominal complaints, there is an increasing number of renal masses detected incidentally. Renal tumours thus detected tend to be small and are often of lower grade and stage carrying better prognosis. Open surgical exploration with frozen section and intent of nephrectomy (total/partial) is the treatment of choice for true indeterminate masses with a possibility of malignancy in good surgical risk patients. Surveillance by regular imaging follow-up may also be considered for patients with poor surgical risks.

Treatment of localized renal cell carcinoma :

Radical Nephrectomy
The accepted standard treatment for non-metastatic renal cell carcinoma is radical nephrectomy, which entails the early ligation of renal artery, followed by the renal vein and then en bloc removal of the kidney, perirenal fat within and including the Gerota fascia as well as the upper ureter and ipsilateral adrenal, along with regional lymphadenectomy. Although traditionally adrenalectomy has been part of radical nephrectomy, recent evidences suggest that it need not routinely be part of radical nephrectomy, since adrenal involvement is uncommon and adrenalectomy does not improve survival and may actually lead to increased morbidity. There is no need to perform ipsilateral adrenalectomy if the CT films show normal adrenal glands. However, adrenalectomy is necessary if there are adrenal abnormalities on pre-operative CT films or gross extension of the renal tumour into adrenal gland seen intra-operatively. Adrenalectomy is also indicated if the renal tumour is large (> 5cm) or if it is located in the upper pole of the kidney. Adrenalectomy does not usually form part of partial and laparoscopic nephrectomy.

Lymphadenectomy : The controversy regarding the need for lymphadenectomy as an integral component of radical nephrectomy has largely been settled. Regional lymphadenectomy is routinely performed at the time of radical nephrectomy. It involves removal of all the nodal tissue from the crus of the diaphragm to the bifurcation of the aorta, including the interaortocaval tissue at the hilum. It allows correct pathological staging, provides prognostic information, is therapeutic in the presence of micrometastases, relieves pain and backache due to retroperitoneal node mass and prevents retroperitoneal nodal relapse. However, its value in prolonging survival has not yet been established in randomised trials. The proponents of lymphadenectomy argue that since there is no effective alternative treatment modality for renal cell carcinoma and since long term survival in the presence of nodal metastases has been reported, lymphadenectomy may prolong survival in presence of micrometastases. To date, there has been limited evidence to support extensive lymphadenectomy, 5-year survival improved by about 10% only. As RCC metastasise via both lymphatic and haematological routes and the lymphatic drainage of kidney is variable, extensive lymph node dissection is not recommended as a routine.
Venous tumour thrombus extension: Radical nephrectomy can be carried out despite the presence of inferior vena caval (IVC) thrombus. It is reported that RCC with venous tumour thrombus extension, even into the vena cava, do not necessarily carry an ominous prognosis if they are completely excised and are not associated with perinephric fat, contiguous visceral invasion or regional nodal or distant metastases. However, tumour infiltration into endothelial wall of IVC is an adverse prognostic factor. The surgical approach to tumour thrombus extension into the IVC depends on the upper limit of the thrombus namely infrahepatic, retrohepatic or suprahepatic. The surgical treatment for a thrombus in the renal vein or infrahepatic IVC is well established and involves control of the IVC above and below the thrombus, control of the opposite renal vein, venacavotomy and tumour thrombus extraction. The retrohepatic thrombus may be managed by one of the following approaches viz. a) venacavotomy and extraction of the thrombus with the usual controls as in the infrahepatic type. This option is suitable in patients in whom after mobilisation of the right lobe of liver anteriorly, a clear margin can be obtained between the hepatic veins and the thrombus; b) when it is not possible to get between the thrombus and the hepatic veins to apply the clamp, a bifemoroatrial partial venous bypass may be done. This shunt bypasses all the venous blood from the lower extremities directly into the right atrium, leaving the vena cava almost empty, thereby providing a bloodless field for surgery; or c) total cardiopulmonary bypass with cardioplegia and hypothermia. However, once the thrombus extends to the suprahepatic IVC with or without extension to the right atrium, total cardiopulmonary bypass with cardioplegia and hypothermia remains the only feasible approach.

Nephron Sparing Surgery : Although radical nephrectomy remains the treatment of choice for localised renal cell carcinoma, nephron sparing surgery is now indicated when preservation of functioning renal parenchyma is important. The accepted indications for nephron sparing surgery - either enucleation or partial nephrectomy, include situations wherein radical nephrectomy would render the patient anephric with subsequent immediate need for dialysis e.g., patients with bilateral synchronous renal cell carcinoma or renal cell carcinoma in a solitary functioning kidney. This procedure can also be considered in patients with associated diseases like hypertension or diabetes mellitus, which may cause chronic renal impairment. Other options for management of tumour in a solitary kidney are nephrectomy followed by dialysis and transplantation or ex-vivo partial nephrectomy with autotransplantation.

The role of nephron sparing surgery in patients with unilateral renal cell carcinoma and normal contralateral kidney is controversial. This issue has become more important since more and more cancers are being diagnosed incidentally with the use of ultrasound or CT scan as screening procedures. There are numerous recent reports of excellent 5-year cancer-specific survival results of approximately 90%, which is comparable to contemporary radical nephrectomy series. Elective nephron sparing surgery should be limited to small RCC of < 4-cm. in size. Local relapses can usually be salvaged with radical nephrectomy. Long term studies, which address the question of survival and relapse after nephron sparing surgery, are necessary to define its exact role. Till then, radical nephrectomy unquestionably remains the treatment of choice for larger unilateral renal cell carcinoma with normal contralateral kidney.

Several factors continue to be in favour of radical nephrectomy. These include the low risk of contralateral kidney renal dysfunction as defined in long-term follow-up studies of living-related donor nephrectomy patients, and the low-risk (1-2%) of development of metachronous renal tumour in the normal contralateral kidney. On the other hand, there remains a risk of local tumour recurrence after nephron-sparing surgery (overall 2% reported in the literature). In addition, there are occasional cases of unsuspected multifocal tumours that would not be removed by partial excision. It is also important to note that nephron-sparing surgery is technically more demanding and carries a higher morbidity.

Laparoscopic Radical Nephrectomy

Laparoscopic radical nephrectomy for renal tumours requires less post-operative analgesia than open surgery, with faster recovery and shorter hospitalisation period. It is a feasible operation, with reproducible operative results, but the experience has been limited to very few centres. Even amongst centres with major laparoscopic nephrectomy experiences, many are not extending their indications to malignant diseases routinely. It must be noted that complications are presently higher than open surgery. While local or port recurrence appears rare, comparative survival outcome studies are lacking. It is recommended that such surgical approach be limited to clinical research settings. Hand assisted laparoscopic nephrectomy has also been tried recently and has the advantage of preserving the tactile sensation of the hand during manipulation and removal.

Simple nephrectomy is no more considered the standard surgical treatment for renal cell carcinoma. Although there are no randomised trials in the literature comparing radical with simple nephrectomy, the results of simple nephrectomy are inferior to those achieved with radical nephrectomy in terms of local control and survival. The only indications for simple nephrectomy are in the presence of metastatic disease when there is pain or refractory haemorrhage from the tumour or prior to giving immunotherapy (adjunctive nephrectomy).

Adjuvant therapy :

The value of adjuvant radiation therapy for patients with renal cell carcinoma remains unclear. Randomised trials of adjuvant radiotherapy need to be conducted in the high-risk group of patients to carefully evaluate the role of postoperative radiotherapy in reducing the local relapse rate or improving the survival.

The value of immunotherapy and/or chemotherapy in the adjuvant setting has not been adequately evaluated in randomised trials. The current literature does not support the use of these modalities either alone or in combination in the adjuvant setting and hence these are not recommended.

Treatment of metastatic disease :

Survival in patients with metastatic renal cell carcinoma is poor, the majority of patients dying of disease within 12-24 months. The presently available nonsurgical modalities of treatment have failed to significantly improve the survival. However, there is a small subset of patients with solitary metastases, who may have a better survival than patients with multiple metastases and may be treated surgically, with intent of cure.

In the absence of any proven treatment alternatives, nephrectomy and excision of solitary metastatic lesion seems to be justified in good surgical risk patients and long-term survival can be achieved in some patients. Various centres have reported 25-35% five-year survival rates in patients who have undergone radical surgical treatment of solitary metastatic disease. Patients with a single resectable metastatic site should be considered for surgical resection. This is especially so if the patient is asymptomatic, has good performance status, and a long disease-free interval between the initial nephrectomy and subsequent development of the metastatic disease and has non-hepatic metastases.

Management of disseminated metastatic disease :

Role of cytoreductive nephrectomy : Recent evidence from 2 randomised trials and their combined analysis have shown a significant survival benefit with cytoreductive nephrectomy prior to immunotherapy in patients with metastatic renal cell carcinoma and hence cytoreductive nephrectomy should be carried out in good risk patients who have resectable renal tumours. The introduction of laparoscopic nephrectomy has provided a relatively non-invasive method of performing nephrectomy prior to immunotherapy.

Palliative nephrectomy may be performed if the patient has significant uncontrolled symptoms such as pain, intractable haematuria, hypertension or paraneoplastic syndromes. Under such conditions, angioinfarction may also be used. However, there is no survival benefit with palliative nephrectomy as the sole treatment. Delayed adjunctive nephrectomy may be considered upon demonstration of partial or complete response to immunotherapy, especially if objective response is evident within 1 month of commencement of therapy.

Patients with unresectable / multiple metastatic disease may consider participation in innovative clinical trials of immunotherapy, chemotherapy or novel drugs / approaches.

Immunotherapy : Alpha interferon may be considered as first line treatment since it has the best data so far. However, the response rate and absolute benefit from alpha-interferon is modest at best, and durable response is seen only in a minority of patients. Patient selection for immunotherapy is important. The favourable factors for response include good performance status, prior nephrectomy with long disease-free interval, non-bulky pulmonary and/or soft tissue metastasis, and lack of tumour-related symptoms.

There are some suggestion that combination therapy including use of Interleukin-2 may improve the response rate, and also the survival. This can be considered for patients with good performance status and good organ-system function.

Hormonal therapy has been used systemically in patients with recurrent or metastatic renal cell carcinoma. Progesterone depot preparations or medroxyprogesterone acetate achieve about 2-17% subjective and almost no objective response. Multiple studies have demonstrated no survival benefit with hormonal therapy. Antioestrogen tamoxifen has also yielded similar results in recent years.

Chemotherapy has been tried in the management of metastatic renal cell carcinoma, the commonest drugs being Floxuridine, vinblastine, 5-flurouracil, doxorubicin and cisplatin. However, no chemotherapeutic drug or regimen has shown a reasonable level of activity in renal cell carcinoma. With the exception of vinblastine and 5-flurouracil, none of the drugs have been shown to exert a significant effect on metastatic disease. A comprehensive review of 83 trials of chemotherapy containing all classes of drugs, demonstrated 6% cumulative response (1.3% CR, 4.7% PR). The objective responses are usually partial and short lived. The responses may be mediated through an indirect effect on the immune system, although this needs to be supported by scientific evidence. New chemotherapeutic drugs or approaches need to be investigated in prospective clinical trials and patients of metastatic renal cell carcinoma who fail immunotherapy should be encouraged to enter into such clinical trials of chemotherapy.

Radiation therapy may be tried for palliation of painful skeletal metastases. Response rates of 50-70% have been reported following local palliative radiation therapy to metastatic sites. In view of relative radioresistance of renal cell carcinoma, a higher dose of about 50Gy is often required for significant relief from. In a multivariate analysis, the likelihood of pain relief from painful bony metastases was dependent upon the radiation dose and the performance status of the patients. Metastatic osseous lesions in the weight bearing areas should be considered for surgical stabilisation first, followed by radiation therapy. Radiation therapy is also useful in the treatment of brain metastases, which are often haemorrhagic and can cause rapid neurological deterioration. Solitary metastases may be considered for surgery or radiosurgery followed by whole brain irradiation which can deliver high doses of radiotherapy essential for effective palliation. Routine short-course whole brain irradiation using conventional fractionation techniques has been shown to give disappointing results.

Palliative care (symptomatic & supportive care) is a valid option in selected groups of patients, including elderly patients and patients with unfavourable prognostic factors for response. These include bulky visceral or bony metastasis, short disease-free interval after initial nephrectomy, extensive prior treatment and unresected tumours.

Follow-up Protocols for Renal Cell Carcinoma :
Follow up of patients with renal cell carcinoma after surgical treatment is recommended to detect local recurrence and distant metastases as early as possible to permit additional treatment when indicated and if possible. Such therapy may include resection of pulmonary metastasis or local recurrences. Certain cases may also be candidates for immunotherapy. With this background in mind, a regular postoperative follow up of patients with renal cell carcinoma is recommended.
The follow up protocol of patients with renal cell carcinoma after treatment may be guided by the prognostic factors including pathological stage and the type of surgical intervention (radical nephrectomy versus nephron sparing surgery).

Regular history, physical examination, serum renal chemistry, liver function tests (especially alkaline phosphatase) and a chest X-ray to detect pulmonary metastases are indicated. Bone and brain scans are considered only when history is suggestive of metastasis or if there is a persistent elevation of serum alkaline phosphatase. Routine CT scan of abdomen is controversial. Imaging of the contralateral kidney is advocated if there is an increased risk of development of metachronous tumour in the other kidney (as in familial cases or VHL disease). Imaging of the retroperitoneum is recommended only after nephron sparing surgery or after radical nephrectomy for locally advanced disease.

1. Which is the real gold standard for small-volume renal tumors? Radical nephrectomy versus nephron-sparing surgery.
Manikandan R, Srinivasan V, Rane A.
J Endourol. 2004 Feb;18(1):39-44.

BACKGROUND AND PURPOSE : Until recently, the gold standard for treatment of localized renal-cell carcinoma with a normal contralateral unit was deemed to be a formal radical nephrectomy. Advocates of nephron-sparing surgery have recently challenged this concept; we wished to evaluate the evidence to determine which treatment is objectively superior for patients with renal tumors up to 4 cm. MATERIALS AND METHODS : MEDLINE, CANCERLIT, and EMBASE computer literature searches were performed to identify peer-reviewed papers pertaining to radical nephrectomy (RN), nephron-sparing surgery (NSS), or comparisons of these methods for tumors as large as 4 cm in maximum diameter. Review of the bibliographies of recovered articles and data in recent textbooks were used to supplement the computerized searches. There were a total of 797 cases in the RN group and 1211 in the NSS group. The parameters specifically evaluated were evidence of local recurrence, disease progression, and death within 33 months, this period being chosen primarily because it was the shortest follow-up in the studies evaluated. The data were then subjected to rigorous statistical analysis. Laparoscopic radical nephrectomy (LRN) and laparoscopic nephron-sparing surgery (LNSS) articles were also reviewed; however, current follow-up periods were considered too short to draw a statistically significant conclusion. RESULTS: Disease-specific survival rates (P=0.001; Mann-Whitney test) as well as the incidence of metastases (P<0.05; Mann-Whitney test) were significantly better in the NSS group. The incidence of local recurrence (P=0.22; Mann-Whitney test) was not significantly different. It should be borne in mind that there are different follow-up periods for each study, and this may have had an impact on the results.

CONCLUSION : Nephron-sparing surgery seems to be as effective as RN in patients with renal cell tumours up to 4 cm, although only a large randomized controlled trial with long follow-up periods would provide a definite answer.

2. Is routine ipsilateral adrenalectomy during radical nephrectomy harmful for the patient?
Hellstrom PA, Bloigu R, Ruokonen AO, Vainionpaa VA, Nuutinen LS, Kontturi MJ.
Scand J Urol Nephrol. 1997 Feb;31(1):19-25.

To investigate the effects of unilateral adrenalectomy on the postoperative course and laboratory parameters, 40 patients with a renal tumour were randomized either to undergo (n=20) or not to undergo (n=20) ipsilateral adrenalectomy. Adrenal hormone (cortisol, epinephrine, norepinephrine and aldosterone), adrenocorticotropic hormone, electrolyte, creatinine, growth hormone, glucose, insulin and free fatty acid concentrations were measured preoperatively and postoperatively. Cortisol and epinephrine concentrations were elevated immediately after the operation but returned to preoperative levels within the first 2 postoperative days. There were no significant differences between the adrenalectomy and non-adrenalectomy groups, except that the cortisol concentration was higher in the latter in the afternoon of the day of surgery. The conclusion is that no long-term shortage of adrenal hormones is caused by unilateral adrenalectomy. Other metabolic and endocrine responses were identical in the groups. Thus ipsilateral adrenalectomy does not seem to be harmful to the patient and the need for it must be resolved on the basis of local tumour factors.

3. A randomized trial of postoperative radiotherapy versus observation in stage II and III renal adenocarcinoma. A study by the Copenhagen Renal Cancer Study Group.
Kjaer M, Iversen P, Hvidt V, Bruun E, Skaarup P et al.
Scand J Urol Nephrol. 1987;21(4):285-9.

Between 1979 and 1984 the Copenhagen Renal Cancer Study Group randomized 72 patients nephrectomized for stages II and III renal adenocarcinoma in a prospective study of postoperative radiotherapy versus observation. Radiotherapy was 50 Gy in 20 fractions to the kidney bed, ipsi- and contralateral lymph nodes. 7/72 were excluded from further analysis because of major protocol violations. 33/65 were in stage II, 32/65 in stage III. Relapse was found in 31/65 = 48% during the follow-up period without any difference between the two groups. 12/27 = 44% had significant complications from stomach, duodenum or liver, median 5 mo., range 1-44 mo. after radiotherapy. In 5/27 = 19% did the postirradiatory complications contribute to the death of the patients. Patients with stage II tumours survived significantly better than those with stage III tumours (p less than 0.05), but no significant differences in survival could be demonstrated between patients randomized to postoperative radiotherapy or observation. It is concluded that postoperative radiotherapy as given in the present study is without any beneficial effect on relapse rate and survival. Moreover, the treatment is associated with an unacceptable complication rate.

4. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial.
Messing EM, Manola J, Wilding G, Propert K, Fleischmann J et al
J Clin Oncol. 2003 Apr 1;21(7):1214-22.

PURPOSE : To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma. PATIENTS AND METHODS : A total of 283 eligible patients with pT3-4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate. RESULTS : At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P=.09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P=.33). Performance status (P=.003), nodal status (N2 v N0, P <.0001), and tumor stage (P=.0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P=.009) and shorter time to recurrence (P <.0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment.

CONCLUSION : Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.

5. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study.
Pizzocaro G, Piva L, Colavita M, Ferri S, Artusi R, Boracchi P, Parmiani G,Marubini E.
J Clin Oncol. 2001 Jan 15;19(2):425-31.

PURPOSE : Because interferon gave promising results in the management of metastatic renal cell carcinoma in the 1980s, a multicentric randomized controlled trial was planned to compare adjuvant recombinant interferon alfa-2b (rIFNalpha2b) with observation after radical nephrectomy in patients with Robson stages II and III renal cell carcinoma. Overall and event-free survival were to be evaluated together with prognostic factors. PATIENTS AND METHODS : Overall and event-free survival curves for 247 patients (124 controls and 123 treated) were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox’s multiple regression models were adopted to perform a joint analysis of treatment and prognostic factors. RESULTS : The 5-year overall and event-free survival probabilities were 0.665 and 0.671, respectively, for controls and 0.660 and 0.567, respectively, for the treated group; the differences were not statistically significant (2P=.861 for overall and 2P=.107 for event-free survival with the log-rank test). Regarding prognostic factors, only grade, pT, and pN demonstrated a significant prognostic role. First-order interactions of treatment with pT and pN category were investigated; a significant interaction was found between pN and treatment. A harmful effect of rIFNalpha2b in the 97 treated pN0 patients and a protective effect in the 13 treated pN2/pN3 patients were statistically significant.

CONCLUSION : Adjuvant rIFNalpha2b is not indicated after radical nephrectomy for renal cell carcinoma. The protective effect in the small group of pN2/pN3 patients requires further investigation.

6. Postoperative UFT adjuvant and the risk factors for recurrence in renal cell carcinoma: a long-term follow-up study. Kyushu University Urological Oncology Group.
Naito S, Kumazawa J, Omoto T, Iguchi A, Sagiyama K, Osada Y, Hiratsuka Y.
Int J Urol. 1997 Jan;4(1):8-12.

BACKGROUND : Radical nephrectomy is the standard therapy for low-stage renal cell carcinoma. However, recurrence sometimes develops even in patients who are considered to have undergone a curative resection of the primary tumor. The purpose of this study was to evaluate the usefulness of UFT (a 1:4 mixture of tegafur and uracil) adjuvant and the risk factors for recurrence in renal cell carcinoma. METHODS : A prospective randomized trial was conducted to compare the use of long-term oral UFT adjuvant with nonadjuvant therapy after a radical nephrectomy for Robson stage I or II renal cell carcinoma. A multivariate analysis was also performed to estimate the risk factors for recurrence. RESULTS : A total of 71 patients were entered into this study, and 66 were evaluable (33 for each group). There was no significant difference in patient characteristics between the 2 groups. The nonrecurrence rate at 5 years after a radical nephrectomy was 80.5% and 77.1% in the UFT adjuvant group and the nonadjuvant group, respectively, with a median follow-up of 112.9 months; the difference was not significant. The toxicity of UFT was generally mild and tolerable. The tumor grade was found to be an important factor influencing recurrence.

CONCLUSION : UFT cannot be universally recommended as an adjuvant therapy for radical nephrectomy in all patients with low-stage renal cell carcinoma.

7. Stratification by risk factors predicts survival on the active treatment arm in a randomized phase II study of interferon-gamma plus/minus interferon-alpha in advanced renal cell carcinoma (E6890).
Dutcher JP, Fine JP, Krigel RL, Murphy BA, Schaefer PL, Ernstoff MS, Loehrer PJ.
Med Oncol. 2003;20(3):271-81.

INTRODUCTION : Standard therapy for recurrent or metastatic renal carcinoma includes the biologic response modifiers interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). The response rate for both agents is modest and toxicity is significant. New agents are needed. Interferon-gamma (IFN-gamma) is a type II interferon that demonstrated promising activity in renal carcinoma in early clinical trials. In vitro data suggested synergistic activity when IFN-gamma was combined with IFN-alpha. The Eastern Cooperative Oncology Group conducted a randomized phase II trial to confirm the efficacy of IFN-gamma as a single agent and to evaluate the efficacy and toxicity of IFN-gamma in combination with IFN-alpha in the treatment of patients with metastatic or recurrent renal carcinomas. MATERIALS AND METHODS : Ninety-five patients with recurrent or metastatic renal carcinoma were entered on trial. Patients were stratified based on risk assessment using the Elson method. Patients were randomly assigned to receive either IFN-gamma 0.1 mg/m2 weekly (arm A) or IFN-gamma 0.3 mg/m2 iv daily x 5 every 3 wk plus IFN-alpha 10 MU/m2 daily (arm B). Treatment efficacy was evaluated every 6 weeks. RESULTS : Toxicity in the arm A was minimal. Significant toxicity was noted in arm B, with four cases of grade 4 neurotoxicity. No responses were seen with IFN-gamma alone. Five responses (two CR and three PR) were noted in the combination arm for an overall response rate of 10%. Four of five responders were classified as “good risk.” Median survival for arm A was 7.0 mo vs 10.4 mo for arm B. Risk stratification was significant in arm B.

CONCLUSION : IFN-gamma at this dose and schedule failed to demonstrate activity in metastatic/recurrent renal carcinoma. The combination of IFN-gamma and IFN-alpha demonstrated a response rate similar to IFN-alpha alone. There was no evidence of synergy between IFN-gamma and IFN-alpha.

8. Use of interleukin-2 in advanced renal carcinoma: meta-analysis and review of the literature.
Malaguarnera M, Ferlito L, Gulizia G, Di Fazio I, Pistone G.
Eur J Clin Pharmacol. 2001 Jul;57(4):267-73.

OBJECTIVE : Interleukin-2 (IL-2) is a glycoprotein that influences the immunoendocrine network by several actions. This cytokine is commonly used in the patients with renal carcinoma, both as neo-adjuvant treatment prior to surgery and as adjuvant therapy. The aims of our study were to evaluate the IL-2 efficacy on postoperative survival rate in patients with metastatic renal carcinoma, to compare the efficacy of treatment with IL-2 alone with the results achieved by conventional systemic chemotherapy or association protocols IL-2-based and to examine the toxic effects of the IL-2-based therapeutic regimens in renal cell carcinoma (RCC). DESIGN : We enrolled 7 randomised trials concerning the IL-2-based treatments of RCC and performed meta-analytic processing by the Mantel-Haenszel-Peto method in order to achieve odds ratios and 95% confidence intervals of the examined treatments. We also considered 11 non-randomised trials, evaluating them in terms of survival rate through the endpoints available. In all trials taken into account, we finally examined the toxic effects as WHO grade, specifying study by study the main site involved. RESULTS AND CONCLUSIONS : Complete or partial response rates have been obtained in 6% to 30% of treated patients in all the trials considered. Our study revealed the need for careful screening as well as a continuous adjustment of doses when an immunotherapeutic protocol is employed in order to treat a metastatic renal carcinoma. Treatment with IL-2 alone achieves better results than systemic chemotherapy, even if the two types of treatment showed an almost overlapping medium- to long-term mortality rate. IL-2 plus lymphokine-activated killer cells accomplish only a partial response. The protocol with IL-2 plus IFN alpha displayed an interesting efficacy associated with a low toxicity even if the cumulative toxic effect of the two drugs should be carefully monitored. To date, the association of tumour-infiltrating lymphocytes, IL-2 and IFN alpha provided the best results in terms of survival and toxicity.

9. Renal cell carcinoma: should radical nephrectomy be performed in the presence of metastatic disease?
Sawczuk IS, Pollard JC.
Curr Opin Urol. 1999 Sep;9(5):377-81.

Metastatic renal cell carcinoma is associated with an unfavorable prognosis and the treatment options are limited. Adjunctive radical nephrectomy, performed either before or after the administration of systemic immunotherapy, has been proposed as a means of improving outcome. The role of nephrectomy for patients with metastatic disease remains controversial. This article reviews the role of nephrectomy in metastatic renal cell carcinoma and the optimal timing for surgery relative to immunotherapy.

10. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer
Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED.
N Engl J Med. 2001 Dec 6;345(23):1655-9.

BACKGROUND : The value of nephrectomy in metastatic renal-cell cancer has long been debated. Several nonrandomized studies suggest a higher rate of response to systemic therapy and longer survival in patients who have undergone nephrectomy. METHODS : We randomly assigned patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy to undergo radical nephrectomy followed by therapy with interferon alfa-2b or to receive interferon alfa-2b therapy alone. The primary end point was survival, and the secondary end point was a response of the tumor to treatment. RESULTS : The median survival of 120 eligible patients assigned to surgery followed by interferon was 11.1 months, and among the 121 eligible patients assigned to interferon alone it was 8.1 months (P=0.05). The difference in median survival between the two groups was independent of performance status, metastatic site, and the presence or absence of a measurable metastatic lesion.

CONCLUSIONS : Nephrectomy followed by interferon therapy results in longer survival among patients with metastatic renal-cell cancer than does interferon therapy alone.

11. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.
Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R;
Lancet. 2001 Sep 22;358(9286):966-70.

BACKGROUND : Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone. METHODS : We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5x10(6) IU/m(2) subcutaneously three times per week) started 2-4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat. FINDINGS : 40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0.60, 95% CI 0.36-0.97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0.54, 0.31-0.94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects.

INTERPRETATION : Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status.

12. Cancer and Leukemia Group B 90206: A randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma.
Rini BI, Halabi S, Taylor J, Small EJ, Schilsky RL.
Clin Cancer Res. 2004 Apr 15;10(8):2584-6.

The majority of sporadic clear cell renal cell carcinoma (RCC) is characterized by loss of heterozygosity of the von Hippel-Lindau (VHL) tumor suppressor gene and somatic inactivation of the remaining VHL allele. The resulting VHL gene silencing leads to induction of hypoxia-regulated genes including vascular endothelial growth factor (VEGF). Thus, therapeutic inhibition of VEGF holds promise for treatment of this historically refractory malignancy. An antibody to VEGF (bevacizumab, Avastin) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC. Interferon-alpha (IFN-alpha) is a standard initial cytokine therapy in RCC with a modest response rate and a survival advantage demonstrated in randomized trials. We hypothesized that the addition of anti-VEGF therapy to IFN-alpha would prolong survival in untreated metastatic RCC patients. A Phase III trial is now being conducted randomizing untreated, metastatic clear cell RCC patients to IFN-alpha alone or IFN-alpha plus Avastin.

BLADDER CARCINOMA

Introduction :
Bladder cancer is the commonest urological malignancy in India. More than 90% of bladder cancers are transitional cell carcinoma (TCC). It tends to occur in two principal forms : superficial and invasive cancers. Nearly 75% of all bladder cancers initially present with superficial disease.

Diagnosis :
Painless haematuria - often episodic and intermittent and in late stages persistent. The degree of haematuria does not correlate with the extent of disease – it may be gross or microscopic. Even a single episode of haematuria needs to be investigated from the point of view of bladder cancer, even if another potential cause for haematuria is found. The impetus for investigation is increased with age, and those who carry a greater risk of bladder cancer e.g. smokers and those with exposure to industrial carcinogens for bladder cancers. Lower urinary irritative and obstructive symptoms may be the sole presenting symptoms in the absence of haematuria. Pain, backache, oedema of lower extremities, lower abdominal mass are all indicative of an advanced stage of the disease.

Investigations :
The aims of investigations in bladder cancer are diagnosis and staging to guide therapy. The main factor that decides the treatment is the presence or absence of muscle invasion. The diagnostic and staging investigations in a case of bladder cancer are as follows :

• Routine haematological & biochemical investigations including renal chemistry.
• Freshly voided urine cytology of exfoliated cancer cells is particularly useful in the presence of a high-grade malignancy or CIS. Urine specimens for cytology should not be obtained from the first voided morning specimens. Positive cytology in the absence of any lesion on imaging may indicate a lesion anywhere in the urinary tract. Negative voided cytology does not necessarily exclude the presence of a low-grade bladder tumour.
• Intravenous urogram is indicated in all patients with haematuria or cystoscopic evidence of bladder cancer. It is not a sensitive means of detecting bladder cancer alone but useful in examining the upper urinary tracts for associated urothelial tumours. Retrograde pyelogram should be performed if the upper tracts are not adequately visualized on the intravenous urogram. The necessity to perform routine IVU at initial diagnosis is now questioned because of the low incidence of important findings obtained with this method.
• Ultrasonography of the abdomen and pelvis to document status of upper tracts and for associated upper tract urothelial tumours, besides demonstrating the bladder tumour.
• Cystoscopy : The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and pathological evaluation of the resected lesion. During cystoscopy, the characteristics of bladder tumour(s) are noted and a biopsy from the bladder tumour taken. Bladder washings for cytology should be taken as studies have demonstrated superiority of bladder washing over voided urine cytology.
• Bimanual examination under anaesthesia may be done in case of invasive tumours for local staging of the tumour. It may be performed both before and after the TUR. The presence of a palpable mass after TUR implies an extravesical disease.
• Urinary markers : Various tests for bladder tumour antigen, NMP 22, FDP etc. are now available. These have a better sensitivity for detecting bladder cancer but the specificity is much lower. Higher false positive tests can lead to unnecessary imaging and bladder biopsies. It is not clear whether these tests can offer additional information, which is useful for decision making, treatment and prognosis of superficial bladder cancer.
• For invasive cancers, it is essential to document the extent of the disease by doing appropriate investigations. Computed Tomography (CT) scanning is used to assess the extent of the primary tumour. It provides information about the presence of pelvic and para-aortic lymphadenopathy and the possible presence of liver or adrenal metastases. However, it has limitations in recognizing minimal pelvic nodal disease or microscopic invasion of adjacent organs. CT guided fine needle aspiration biopsy of pelvic lymph node may be performed to document presence of lymph node metastases. Magnetic Resonance Imaging (MRI) scanning maybe as helpful as CT scanning.

Metastatic work up :

• Routine chest radiographs are performed to rule out pulmonary metastases, however, CT Thorax is the most sensitive means of detecting pulmonary metastasis.
• Bone scans are optional for metastatic evaluation to detect bony metastasis and also useful as a baseline for future reference, especially in patients with bone pains or increased alkaline phosphatase.
• USG or CT scan of liver

The first treatment decision based on tumour stage is whether the patient has a superficial or muscle invasive bladder cancer. Transurethral resection of the bladder tumour (TURBT) is the most important test for judging the depth of tumour penetration. Inclusion of muscle in biopsy is essential. The most commonly utilized staging systems are UICC System (TNM).

During resection, the following are recommended :

• resect tumour down to muscle and send superficial and deep components of the tumour separately to the pathologist
• if the cancer is muscle invasive, complete debulking is preferable
• biopsy of the base of the tumour
• random biopsies from apparently uninvolved normal areas of bladder are indicated in the presence of positive cytology, even in the absence of a tumour or in any nonpapillary tumour. Random biopsies in a patient with a solitary papillary lesion are contraindicated due to the perceived hazard of implantation of tumour cells and absence of any additional information. Biopsies from the prostatic urethra are indicated if there is suspicion of Tis of the bladder in view of the high frequency of involvement of the prostatic urethra.
• bladder washings for cytology before resection is optional
  The second treatment decision made based on staging is to identify patients with invasive tumours who may benefit from aggressive, potentially curative therapy. Ploidy, p53 status and other markers such as NMP 22, BTA and M344 are considered investigational and are not used to guide treatment decisions outside of the experimental protocol.

TNM Classification of urinary bladder cancer (2002)
Primary tumour (T)

More than 90% of bladder carcinomas are transitional cell carcinoma (TCC); the remainder are squamous cell or adenocarcinomas.

Bladder tumours are classified as superficial (Ta, T1, Tis) or invasive (T2, T3, T4) based on cystoscopy, transurethral resection, imaging studies and histopathological findings.

Management of Superficial Bladder Cancer :
Superficial bladder cancer consists of :

• Non invasive papillary tumour (Ta)
• Tumour invading the lamina propria (T1)
• High grade (G3) Carcinoma in situ(CIS)

Transurethral resection of the bladder tumour(s) is the standard of care for superficial bladder cancers. However, despite an adequate transurethral resection, nearly 70-80% of patients will have relapse within the bladder while 20-25% will progress to muscle invasion. The objective in managing superficial bladder cancer is in the prevention and detection of recurrences and progression. Bladder cancer with low risk of recurrence or progression can be managed by close surveillance and regular check cystoscopy, while those with high risk of relapse need intravesical chemo or immunoprophylaxis.

Numerous prognostic factors have been shown to be associated with recurrence and progression of superficial bladder cancer viz.:
- high grade or poorly differentiated tumours(G3)
- co-existent CIS or dysplasia in random mucosal biopsies
- multiple or multicentric tumours
- multiple recurrences within a short period of time (rapidly recurrent tumours)
- lamina propria invasion (T1)
- tumour size more than 3 cm
           - prostatic urethral involvement

Based on these prognostic factors, superficial bladder cancers can be divided into the following risk groups:
- Low risk : Single, Ta, G1, <3 cm in diameter
- High risk : T1, G3, multifocal or highly recurrent, CIS
- Intermediate risk : All other tumours, Ta-T1, G1-G2, >3 cm in diameter

One single chemotherapeutic instillation of epirubicin or mitomycin C within 6 hours of TUR is able to reduce the disease recurrence rate by about 50% and is therefore advocated in all patients of superficial bladder cancer, except when bladder perforation is suspected. Intravesical BCG is contraindicated in the presence of open wounds in the bladder.

Low risk group patients with papillary tumours require no further treatment as the recurrence rate in this group is very low after single instillation immediately after TUR.

Intermediate and high-risk patients require a 4-8 weeks course of intravesical therapy.

Intravesical therapy[1,2,3] is indicated in patients who are at high risk for tumour recurrence and progression and can be given as prophylactically or therapeutically. Instillations can be done with chemotherapeutic agents (e.g. mitomycin C, doxorubicin, thiotepa) or immunotherapeutic agents (e.g. BCG, interferon). However, studies have not clearly demonstrated advantage of one chemotherapeutic agent over the rest. Early instillation is generally recommended, although there are various regimes for dosage and instillation course for intravesical chemotherapy. Current data suggests the superiority of BCG over intravesical chemotherapeutic agents for prevention of recurrence and progression in the high-risk group in randomized clinical trials. The chemotherapeutic agents have been shown to have the potential to reduce local recurrence but do not affect the progression to muscle invasion. Intravesical BCG is the gold standard and has been shown to be effective in reducing tumour recurrence rate and presently is the only agent, which has been shown to reduce the progression rate to muscle invasion, reduce the need for cystectomy, increase the time to cystectomy and improve survival.

Role of maintenance therapy : The usefulness of maintenance chemotherapy or immunotherapy is not clearly defined. In rapidly recurrent tumours and in those with a high risk of progression, continuation of monthly instillation after the first induction course is advocated. It has been shown that continuation of maintenance therapy beyond 6 months did not improve the reduction in the recurrence and progression rates.

Treatment of disease recurrence : For a non muscle invasive recurrence, either the initial instillation schedule is restarted or cross over therapy with chemo or immunotherapeutic agents is considered. Other immunomodulating agents which have shown activity in the prevention of disease recurrence and which are at least as active as the chemotherapeutic agents eg interferon, interleukin, KLH etc may be tried in this setting. Muscle invasive recurrences should be treated as per the standard guidelines for these tumours.

Treatment of Tis : Intravesical BCG is the standard of care for therapy of carcinoma-in-situ without associated muscle invasive tumour. A complete response is achieved in 70% patients with a single 6-week instillation course of BCG. If the cytology and biopsies remain positive, another 6 weeks cycle of intravesical BCG may produce an additional 15% complete remission. Maintenance 3 monthly therapy is advocated to prevent recurrence. Nonresponders to 2 complete cycles of BCG instillations or recurrent disease is treated with cystectomy plus urethrectomy. However, bladder can be preserved in more than 70% patients with the use of BCG instillations.
Treatment of T1G3 tumours : These tumours have a high tendency to progress to muscle invasion and hence some advise early cystectomy in these patients with excellent cure rates. However, with intravesical BCG immunoprophylaxis, nearly 50% patients can survive with an intact bladder. The subset of patients with T1G3 tumours, which requires early cystectomy is not clearly defined, but certain factors such as solid appearance of the tumour, high recurrence rate, multiplicity of tumours and presence of concomitant Tis may indicate the need for early cystectomy in these patients.

BCG therapy is given as a standard induction course of 6 weeks with one instillation a week. Monthly maintenance therapy is not superior to standard therapy. The 6 + 3 schedule may be superior to standard induction therapy for CIS.
Follow-up testing is to detect recurrences and progression. Cystoscopy is recommended as the gold standard of follow up after TUR. The first cystoscopy should be done at 3 months to detect incomplete resection, implantation at biopsy sites or rapidly recurrent tumour. The frequency of subsequent cystoscopies should be adapted to the prognostic group of the patient.

In low risk patients with no recurrence at 3 months, a follow up cystoscopy can be delayed upto 6 months and then carried out annually for upto 5 years due to the very low recurrence rates. In patients with high risk tumours, cystoscopy every 3-months for the first 2 years, every 4 months for the 3rd year, 6-monthly thereafter upto 5 years and annually thereafter is recommended. The schedule for the intermediate group should be between these two groups of patients. With any recurrence, the schedule of cystoscopies is restarted from the beginning. It seems reasonable to stop the follow up in low risk group after 5 years while for the high-risk group, it needs to be continued for minimum 10 years and preferably lifelong.

Cytological surveillance should accompany every cystoscopic examination. During cystoscopy, directed biopsy should be taken if there is any suspicious area. The risk of upper tract urothelial cancer in bladder cancer is 4%. Intravenous urogram is therefore recommended at least once in two years, or in the presence of positive cytology and negative cystscopy. Ultrasonography is recommended once a year.

The role of urinary markers like NMP22, urine cytology or multitarget FISH study on exfoliated urine cells to replace cystoscopic evaluation or to postpone it is under evaluation but till the time the results of these studies are available, cystoscopic evaluation remains the gold standard for follow up in a patient with superficial bladder cancer.

Management of Muscle-Invasive Tumour
Approximately 40% of newly diagnosed bladder cancers have muscle invasion. Besides, 20-25% of superficial bladder cancers will progress to muscle invasion some time during their natural history.

Standard of care for muscle invasive disease includes radical cystectomy with pelvic lymphadenectomy[4]. Radical surgery appears to have some survival advantage over radiotherapy in organ-confined disease. It should be offered only to surgically fit patients. Low volume nodal disease with organ-confined primary tumour may have survival benefit from radical cystectomy with regional lymphadenectomy. In the presence of gross nodal disease, 5-year survival rates are poor. Some authors have reported that extended lymphadenectomy improved survival in patients with tumours confined to the bladder. However, since no controlled studies exist to date supporting the curative value of extended lymph node dissection, only limited or regional lymph node dissection is advocated. Before proceeding to cystectomy, pelvic nodal status should be established. Radical cystectomy is mandatory for non-transitional cell carcinomas, which generally respond less to chemotherapy and radiation therapy. However, despite an adequate surgery, approximately 50% patients will develop metastatic disease within 2 years, emphasizing the need for systemic treatment in these patients.

The indications for urethrectomy have reduced considerably due to the advent of orthotopic bladder substitution surgery. Currently, urethrectomy has been recommended if the tumour involves the bladder neck in women or the prostatic urethra in men. A positive urethral cut margin at the end of cystectomy also signifies the need for urethrectomy. Urethrectomy may be done at the time of cystectomy or subsequently as a separate procedure.

The 5-year survival rates after radical cystectomy alone are as follows:

The mode of urinary reconstruction has little impact on disease control. Orthotopic neobladder reconstruction [5,6,7] does not compromise survival. The morbidity of orthotopic neobladder reconstruction is appreciable in terms of major complications and reoperation rates. The contra-indications to orthotopic neobladder include prostatic urethral involvement, positive urethral margins, multiple bladder tumours or multicentric involvement of the urinary tract. Basically, it is not advisable in the presence of significant risk of urethral recurrence. Orthotopic neobladder reconstruction should be advised to suitable patients after cystectomy for organ-confined muscle-invasive bladder tumour. While discussing this option with the patient, the morbidity must be addressed. The longer recovery period after orthotopic neobladder may delay the subsequent adjuvant therapy in patients with locally advanced disease and in these patients, this option may not be advisable.

Radiotherapy
Radiation therapy may be used with a curative intent in patients with T2-T3 N0 M0 tumours with a potential for bladder preservation [8]. It has not been compared with radical surgery in controlled randomized trials. From historical series, 5 years control rate of 24-45% with a 5 years overall survival of 26-40% is achieved with radiotherapy for muscle invasive bladder cancer. External beam radiation therapy may be delivered in 30-35 fractions to the dose of 60-70 Gy. Use of altered fractionation has been reported to induce a higher local control rate but this modality is still investigational [9]. There is no evidence of benefit observed in randomized trials for preoperative radiotherapy before cystectomy and hence it is not recommended. Data suggests that the proportion of complete responders may be improved by accelerated fractionation schemes – this is presently being addressed in prospective trials. Presently there is increasing evidence that the addition of concurrent cisplatin chemotherapy to radiation therapy leads to higher response rates in T2-T3 tumours but it is not clear whether these higher response rates translate into better survival [10]. Randomized trials of concurrent chemoradiation therapy versus conventional radiation therapy are lacking.

The favourable prognostic factors for success of radiation therapy are low T-category, a solitary tumour, absence of hydronephrosis, complete resection of all visible tumour, small tumour size of <5 cm and absence of concomitant Tis. Although the 5-year survival rate is acceptable, local recurrences will occur in about half the number of patients who may benefit from a prompt salvage cystectomy. Non-invasive relapses may be treated with TUR followed by intravesical therapy. In view of the high local recurrence rate, a long-term follow up with cystoscopy, exfoliative urine cytology and other investigations to rule out disseminated disease is warranted.

Chemotherapy
Nearly 50% of patients with muscle invasive bladder cancer develop metastatic disease within 2 years despite adequate surgery. This stresses the need for incorporation of systemic therapy [11,12] in the treatment of muscle invasive bladder cancer. Chemotherapy may be used in neoadjuvant, adjuvant or palliative setting [13,14].

Neoadjuvant chemotherapy : The advantages of neoadjuvant chemotherapy include early treatment of micrometastases, ability to evaluate response to chemotherapy, possibility of downstaging and bladder preservation, better drug delivery etc. However, it can delay the potentially curable local treatment and hence must be advised judiciously. Response rates of 60-70% with CR rates of about 30% with neoadjuvant chemotherapy have been reported from various centers. Most series have reported significant downstaging of the disease with a higher chance of resectability. Numerous randomized trials have not yet proven a survival benefit with neoadjuvant chemotherapy till recently [11,12].

Neoadjuvant chemotherapy and bladder preservation :
Although radical cystectomy is generally accepted as the gold standard treatment for muscle invasive bladder cancer, a renewed interest in the quality of life issues has increased the interest in bladder preservation protocols. With incorporation of effective chemotherapy in the treatment paradigms of bladder cancer, there is a subset of patients who is likely to respond well to chemotherapy and who may have a potential for bladder preservation. Bladder sparing surgery together with neoadjuvant or adjuvant chemotherapy and/or radiation therapy may be a reasonable alternative to radical cystectomy in well selected patients. The general treatment schema for bladder preservation protocols is as follows :

The combination of chemotherapy and radiation therapy is capable of producing 5-year survival rates of 42-63% with bladder preservation in about 40% patients [10,11,12]. However, there are no randomized trials comparing radical cystectomy with bladder preservation protocols and there has always been a selection of patients with a good prognosis (low stage low-grade disease), which are likely to have an equivalent survival along with bladder preservation. Hence this approach may be used only in properly selected patients after explaining the whole treatment schema to them. Consideration may be given to patients with low-volume (T2) disease without hydronephrosis or co-existing CIS, who have had a complete transurethral resection of the bladder tumour and/or complete response to induction chemotherapy, who are committed to preserving bladder function and can comply with regular close follow-up examinations. There is a need to await the follow-up and publication of ongoing large multicenter trials to determine overall benefit, i.e. survival advantage and bladder preservation.

Adjuvant Chemotherapy
The randomized trials addressing the question of whether adjuvant chemotherapy after radical cystectomy or radical radiation therapy in high-risk patients can improve survival have small numbers of patients and the data is insufficient, confusing and flawed. Although some of these trials do show a marginal survival benefit especially in patients with more than 3 metastatic nodes, the evidence is not strong enough to support its routine recommendation in clinical practice. Results of large multicentre trial are imperative to provide convincing data. Adjuvant chemotherapy may be selectively given to patients at a high risk of systemic relapse (T3b, T4 & N+) disease, as there is a suggestion of improved survival in these patients with adjuvant chemotherapy. The most commonly used chemotherapy regimens are M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) or CMV (cisplatin, methotrexate, vinblastine). Recently published results of the trial comparing M-VAC with Gemcitabine-cisplatin combination in metastatic bladder cancer have shown clinical equivalence of the two regimens with a better toxicity profile in the Gemcitabine-cisplatin arm [13,14]. Although it seems logical to extrapolate these results to the adjuvant setting, there is no evidence that Gemcitabine-cisplatin regimen is equivalent to the standard M-VAC / CMV regimens in this setting.

Systemic Therapy of Metastatic Bladder Cancer
Approximately 40% of patients will develop metastatic disease during their clinical course, typically appearing in lymph nodes, lung, liver or bone. Majority of these patients will succumb to their disease despite treatment.
Chemotherapy is the standard therapy for patients with metastatic bladder cancer. Combination M-VAC chemotherapy has been shown to be superior to single agent chemotherapy in 2 randomized trials. Based on evidence from randomized trials, either MVAC or CMV can be considered standard combination for metastatic bladder cancer. Combination chemotherapy may achieve durable response and long-term survival in a small subgroup of patients (<15%). Quality of life issues are very important considerations.
Novel chemotherapeutic agents such as gemcitabine and taxanes have been the most exciting therapeutic options currently available. In an international randomized trial, M-VAC was compared with gemcitabine & cisplatin (GC) [13]. Both the arms were found to be equivalent in terms of response rates, time to treatment failure, time to progressive disease and overall survival. GC appeared to have reduced toxicity profile as compared to M-VAC, making GC a new standard chemotherapeutic option in patients with metastatic bladder cancer.

1. Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer.
Shelley MD, Court JB, Kynaston H, Wilt TJ, Coles B, Mason M.
Cochrane Database Syst Rev. 2003;(3):CD003231.

BACKGROUND : Tumour recurrence following transurethral resection (TUR) for Ta and T1 bladder cancer is a major clinical problem. Intravesical administration of mitomycin C (MMC) or bacillus Calmette-Guerin (BCG) has proven prophylactic activity but both are associated with local and systemic side-effects. A systematic review was carried out to compare the efficacy of these two agents. OBJECTIVES : To undertake a systematic review and meta-analysis comparing intravesical mitomycin C and Bacillus Calmette-Guerin in terms of tumour recurrence, disease progression and overall survival in Ta and T1 bladder cancer. Treatment-related toxicities would also be evaluated. SEARCH STRATEGY : A comprehensive search of MEDLINE, EMBASE, Healthstar, Cochrane Controlled Trials Register, Cancerlit, and DARE was performed, and hand searching of relevant journals undertaken. SELECTION CRITERIA : Trials in any language were included in the meta-analysis if they were properly randomised, included medium to high risk patients with Ta or T1 bladder cancer and compared intravesical MMC versus BCG. DATA COLLECTION AND ANALYSIS : Trial eligibility, methodological quality and data extraction were assessed independently by two reviewers. Time to event analysis was evaluated using log hazard ratios, with a sensitivity analysis for subgroups according to patient’s risk of recurrence. MAIN RESULTS : Twenty-five articles were identified but only seven were considered eligible. This represented 1901 evaluable patients in total, 820 randomised to MMC and 1081 to BCG. Six trials had sufficient data for meta-analysis and included 1527 patients, 693 in the mitomycin arm and 834 in the BCG arm. The weighted mean log hazard ratio (variance) for tumour recurrence for the six trials was - 0.022 (0.005). This indicated no significant difference between MMC and BCG (p=0.76). However, the meta-analysis indicated evidence of significant heterogeneity between trials (p=0.001). A subgroup analysis of three trials that included only high risk Ta and T1 patients indicated no heterogeneity (p=0.25) and a log hazard ratio (variance) for recurrence of -0.371 ( 0.012). With MMC used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, is highly significant (p=0.0008). The seventh trial, in abstract form only, used BCG in low doses for two arms of the trial (27 mg and 13.5mg) compared to a standard dose of mitomycin C (30mg), and reported a significantly reduced recurrent rate with BCG (27mg) compared to mitomycin C (p=0.001). Only two trials included sufficient data to analyse disease progression and survival, representing a total of 681 patients; 338 randomised to BCG and 343 to MMC. There was no significant difference between MMC and BCG for disease progression (log hazard ratio + variance: 0.044 + 0.04, p=0.16) or survival (-0.112 + 0.03, p=0.50). Local toxicities (dysuria, cystitis, frequency, and haematuria) were associated with both MMC (30%) and BCG (44%). Systemic toxicities, such as chills, fever and malaise, were observed with both MMC and BCG (12% and 19%, respectively) although skin rash was more common with MMC. REVIEWER’S CONCLUSIONS : The data from the present meta-analysis indicate that tumour recurrence was significantly reduced with intravesical BCG compared to MMC only in the subgroup of patients at high risk of tumour recurrence. However, there was no difference in terms of disease progression or survival, and the decision to use either agent might be based on adverse events and cost.

2. Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette-Guerin therapy.
Cookson MS, Sarosdy MF.
J.Urol. 1992;148(3):797-801.

Abstract : We reviewed our results with 86 patients who had a pretreatment history of a stage T1 tumor. All patients were treated with transurethral resection of all visible tumor followed by intravesical bacillus Calmette-Guerin (BCG) and many patients received additional maintenance therapy. Local recurrences were treated with repeat transurethral resection followed by additional BCG. Median followup was 59 months, with a range of 9 to 149 months. Overall, 78 of 86 patients (91%) were free of tumor recurrence with BCG therapy. This result includes 69% of the patients who responded to the initial transurethral resection and intravesical BCG, and 22% who ceased having tumors after additional treatments for local recurrences. Only 7% of the patients had progression to stage T2 tumors after BCG therapy. Grade of the stage T1 tumor, concurrent carcinoma in situ and tumor multiplicity before BCG did not predict tumor recurrence or progression. Of patients with recurrences after BCG therapy, those with stage T1 tumors had a higher rate of progression compared to those with stage Ta tumors but the difference was not statistically significant (p=0.086). These data clearly support the efficacy of transurethral resection plus intravesical BCG immunotherapy in the treatment of stage T1 tumors as well as in the prevention of disease progression.

3. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group.
Bouffioux C, Kurth KH, Bono A, Oosterlinck W, Kruger CB, de Pauw M, Sylvester R.
J.Urol. 1995;153(3 Pt 2):934-41.

Abstract : The European Organization for Research and Treatment of Cancer genitourinary group has completed 2 parallel prospective randomized studies, one with 30 mg. mitomycin C and the other with 50 mg. doxorubicin as adjuvant intravesical treatment after transurethral resection of superficial transitional cell bladder carcinoma. These studies were designed to compare early (the day of resection) versus delayed (between 7 and 15 days after resection) instillations and short-term (6 months) versus long-term (12 months) treatment. The results indicate that in regard to recurrence rate patients having a delayed and short-term treatment do worse than those having early instillations (for 6 or 12 months) or those having prolonged treatment (either immediate or delayed). With an average followup of 4 years survival, progression beyond T1 disease, development of distant metastases and appearance of a second primary were not influenced by the therapeutic regimen. A multivariate analysis of prognostic factors is presented, which indicates that after adjustment for these factors, patients in the delay, no maintenance arm have a significantly higher recurrence rate than the other patients.

4. The surgical management of muscle invasive bladder cancer : a contemporary review.
Cookson MS.
Semin Radiat Oncol. 2005 Jan;15(1):10-8.

Muscle-invasive bladder cancer is a potentially lethal disease with a high rate of cure if timely and effective therapy is applied while the disease is confined to the bladder or regional lymph nodes. Radical cystectomy is the gold standard to which all other local therapies including multimodality bladder-preserving strategies should be compared. Contemporary cystectomy combined with regional lymphadectomy may be performed with an acceptably low morbidity, provides unparalleled local control, and may result in durable disease-free survival even among patients with locoregional lymph node metastases. Refinements in surgical technique coupled with the expanded application of continent urinary diversion have resulted in excellent functional outcomes without compromising cancer control in properly selected patients. An increasing awareness of the importance of quality-of-life issues combined with an enhanced understanding of tumor biology have resulted in the surgical modifications which include an expanded role for lymphadectomy and preservation of uninvolved adjacent organs.

5. Continent diversions: the new gold standards of ileoanal reservoir and neobladder.
Beitz JM.
Ostomy Wound Manage. 2004 Sep;50(9):26-35

In recent decades, surgical treatment of familial adenomatous polyposis, chronic ulcerative colitis, and muscle-invasive bladder cancer has undergone a revolution. Specifically, ileoanal reservoir and neobladder have become the new “gold standard” of definitive surgical therapy for these disorders. This article discusses issues in surgical construction, indications, contraindications, perioperative care concepts, and nursing and health professional implications related to these two procedures. These interventions include screening candidates for ileoanal reservoir or neobladder to rule out Crohn’s disease or metastatic cancer and educating candidates for continent diversions about the proposed procedure(s) and associated events, potential complications, postoperative exercise, sexual health and function issues, and the benefits of support group participation so they can gain a realistic understanding of ultimate functional outcomes. Questions for future research are addressed.

6. Laparoscopic radical cystectomy with ileal conduit diversion.
van Velthoven RF, Piechaud T.
Curr Urol Rep. 2005 Mar;6(2):93-100.

Remaining the gold standard treatment of muscle-invasive bladder cancer and high-risk superficial tumors, the radical cystectomy has been translated into a fully laparoscopic protocol, actually gaining more and more acceptance worldwide. In this article, a transperitoneal antegrade laparoscopic protocol is described for radical cystectomy performed in both genders. After removal of the specimen, generally through a mini-laparotomy, most of the teams perform the maneuvers for urinary diversion through an ileal conduit as an open procedure, although a completely laparoscopic procedure has been successfully achieved. Laparoscopic cystectomy will face the proof of time if oncologic rules about surgical management of transitional cell carcinoma are carefully respected to avoid any cell spillage. When obvious laparoscopic advantages for the patients are encountered with laparoscopic cystectomy, it seems unlikely that a full laparoscopic protocol, including the diversion, may gain wide acceptance; in that case, the true laparoscopic benefits would be wasted by unjustified lengthening of operative time and by compromising the quality of uretero-ileal anastomoses.

7. The ileal neobladder : complications and functional results in 363 patients after 11 years of followup
Hautmann RE, de Petriconi R, Gottfried HW et al.
J.Urol. 1999;161(2):422-7.

Abstract : PURPOSE : Since 1986 orthotopic lower urinary tract reconstruction using the ileal neobladder has been our diversion of choice in patients of both sexes undergoing cystectomy. We report on experience and functional results of the first 363 men 11 years after this procedure. MATERIALS AND METHODS : Complications were assessed, tabulated, subdivided into early (3 months or less postoperatively) and late types, and further categorized with respect to relationship to neobladder construction. Continence and voiding pattern were individually evaluated via a detailed patient questionnaire. RESULTS : Perioperative death occurred in 11 patients (3%). Neobladder related early and late complications occurred in 56 (15.4%) and 85 (23.4%) of the 363 patients, respectively. Neobladder related early and late abdominal reoperation rates were 0.3 and 4.4%, respectively. Perioperative neobladder unrelated early complications were observed in 122 patients (33.6% ) and 44 (12.1%) required operative treatment. Late postoperative complications unrelated to the neobladder occurred in 45 patients (12.4%) and 19 required open surgical revision. Of 290 evaluable patients 96.1% void spontaneously, 3.9% perform clean intermittent catheterization in some form and 1.7% perform regular intermittent catheterization. Daytime and nighttime continence was reported as good by 95.9% and satisfactory by 95% of the patients. Unacceptable daytime continence requiring more than 1 pad per day occurred in only 4.1% of the patients and only 5% are wetting more than 1 pad a night. CONCLUSIONS : The ileal neobladder produces good functional results and can be constructed with acceptable complications. Our data suggest that although it is not a complication-free procedure, we advocate its use when possible.

8. Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy.
Cowan RA, McBain CA, Ryder WD et al.
Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):197-207.

PURPOSE : To investigate whether delivering an increased radiation dose to the tumor-bearing region of the bladder alone would improve local disease control without increasing treatment toxicity. METHODS AND MATERIALS: A total of 149 patients with unifocal T2-T3N0M0 bladder carcinoma were randomized between whole bladder conformal radiotherapy (WBRT, 52.5 Gy in 20 fractions, n=60) and partial bladder conformal RT (PBRT) to tumor alone with 1.5-cm margins within either 4 weeks (PBRT4, 57.5 Gy in 20 fractions, n=44) or 3 weeks (PBRT3, 55 Gy in 16 fractions, n=45). The response was assessed cystoscopically after 4 months. RESULTS : The 5-year overall and CFS rate was 58% and 47%, respectively, for the whole population. The CR rate was 75% for WBRT, 80% for PBRT4, and 71% for PBRT3 (p=0.6), with a 5-year local control rate of 58%, 59%, and 34%, respectively (p=0.18). Solitary new tumors arose within the bladder, outside the irradiated volume, in 6 (7%) of 89 patients who underwent PBRT. The 5-year overall survival and cystectomy-free survival rate was 61% and 49% for WBRT, 60% and 50% for PBRT4, and 51% and 41% for PBRT3 (p=0.81 and p=0.59). The treatment toxicity was mild and equivalent across the three trial arms. CONCLUSION : The reduction in treatment volume allowed delivery of an increased radiation dose without a reduction in local tumor control or the development of excess toxicity. However, this dose-escalated partial bladder approach did not result in significantly improved overall survival.

9. RTOG 97-06 : initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy.
Hagan MP, Winter KA, Kaufman DS et al.
Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72.

To examine combination cisplatin and twice-daily accelerated irradiation (RT) after aggressive transurethral resection of bladder tumor (TURBT) in an attempt to preserve the bladder and to determine the likelihood that patients who complete this regimen could then complete three cycles of methotrexate, cisplatin, vinblastine (MCV) chemotherapy.Between 1998 and 2000, 52 patients with Stage T2-T4aN0M0 disease, from 17 institutions, were entered into the trial. Forty-seven patients were deemed eligible; the planned accrual was 40. Of the 46 patients, 68% were >60 years old, 70% were men, and 96% had a Karnofsky score >/=90. The clinical T stage was T2 in 66%, T3a in 25%, and T3b in 9%. The median follow-up at the time of analysis was 26 months. The protocol required TURBT within 6 weeks of the initiation of induction therapy. Induction treatment involved 13 days of concomitant boost RT, 1.8 Gy to the pelvis in the morning followed by 1.6 Gy to the tumor 4-6 h later. For sensitization, cisplatin (20 mg/m(2)) was given on the first 3 days of each treatment week. Three to four weeks after induction, patients were evaluated cystoscopically for residual disease. Patients whose biopsies and cytologic evaluations showed no disease completed consolidation chemoirradiation. Patients with residual tumor went on to cystectomy. After either consolidation or cystectomy, patients were to complete three cycles of MCV chemotherapy.Of the 47 patients, 45% completed all phases of the protocol treatment with minor, or no, deviations. Five patients refused either the postinduction evaluation or cystectomy and 6 refused adjuvant chemotherapy. The CR rate after induction therapy was 74%. For 2 patients, residual disease after induction was limited to positive cytologic findings, and for 8 patients, biopsy of the primary site revealed persistence. Of the 8 cystectomy patients, 2 had no evidence of disease in the bladder at pathologic review of the surgery specimen. Grade 3 toxicity related to chemotherapy was observed in 11% of patients during both induction and consolidation, and in 41% during adjuvant chemotherapy. A total of 8 patients (36% of those receiving adjuvant chemotherapy) went on to develop Grade 4 neutropenia or thrombocytopenia during additional adjuvant chemotherapy. Grade 3 toxicity due to RT was seen in 4% and 0% of patients during induction and consolidation, respectively. One patient developed Grade 4 hydronephrosis during consolidation. The projected 36-month value for locoregional failure, distant metastasis, overall survival, and bladder-intact survival was 27%, 29%, 61%, and 48%, respectively.After aggressive TURBT, twice-daily accelerated RT initiated in concomitant-boost format is well tolerated and results in a rate of complete response (74%) similar to that in previous bladder-sparing trials. The projected 2-year values for locoregional control, bladder-intact survival, and overall survival were also consistent with previously reported trials of bladder-sparing treatment. With only 45% of patients completing three cycles of MCV, this form of adjuvant chemotherapy appears to be poorly tolerated by most patients.

10. Selective bladder preservation by trimodality therapy for patients with muscularis propria-invasive bladder cancer and who are cystectomy candidates.
Shipley WU, Zietman AL, Kaufman DS, Coen JJ, Sandler HM.
Semin Radiat Oncol. 2005 Jan;15(1):36-41.

The Massachusetts General Hospital and the Radiation Therapy Oncology Group have been leading the charge for organ conservation in bladder cancer in North America for over two decades. In a series of six successive studies the group has refined the techniques and is now moving toward a translational future in which novel biologic agents will be combined with the best current strategies. The North American approach is characterized by its selective nature, in that it preselects patients likely to do well with a trimodality approach and then further selects according to the response to an induction course of chemotherapy and radiation. Only those who are complete responders move onto full dose. This “check point” allows salvage cystectomy to be performed on incomplete responders before they have had full-dose radiation. This preserves the urinary diversion options open to the surgeon as well as brings forward the time to a salvage procedure should it be needed.

11. A meta-analysis of randomised trials suggests a survival benefit for combined radiotherapy and radical cystectomy compared with radical radiotherapy for invasive bladder cancer: are these data relevant to modern practice?
Shelley MD, Wilt TJ, Barber J, Mason MD.
Clin Oncol (R Coll Radiol). 2004 May;16(3):166-71.

OBJECTIVE : Treatment options for muscle-invasive bladder cancer include radical cystectomy or radical radiotherapy, and the prevailing choice varies by country. The ideal treatment would be a bladder-preserving therapy without compromising survival. The objective of this review was to compare the overall survival after radical surgery (cystectomy) with radical radiotherapy in patients with muscle-invasive cancer. MATERIALS AND METHODS : We searched the Cochrane Controlled Trials Register, Medline, EMBASE, Cancerlit, Healthstar and the Database of Abstracts of Reviews of Effectiveness. Authors of unpublished data were contacted. Randomised trials comparing surgery (alone or with preoperative radiotherapy) with radiotherapy were eligible for assessment. Three reviewers assessed trial quality based on the Cochrane Guidelines. Data were extracted from the text of the article or extrapolated from the Kaplan-Meier plot. The Peto odds ratio was determined to compare the overall survival and disease-specific survival. Analysis was performed on an intention-to-treat basis and treatment actually received. RESULTS : No randomised trials comparing surgery alone with radiotherapy alone were identified. Three randomised trials comparing preoperative radiotherapy followed by radical cystectomy (surgery) versus radical radiotherapy with salvage cystectomy (radical radiotherapy) were eligible for assessment. These trials represented a total of 439 patients, 221 randomised to surgery and 218 to radical radiotherapy. Three trials were combined for the overall survival results, and one was evaluable for the disease-specific survival analysis. The mean overall survival (intention-to-treat analysis) at 3 and 5 years were 45% and 36% for surgery, and 28% and 20% for radiotherapy, respectively. Peto odds ratio (95% confidence interval [CI]) analysis consistently favoured surgery in terms of overall survival. The results were significantly in favour of surgery at 3 years (OR=1.91, 95% CI 1.30-2.82) and at 5 years (OR=1.85, 95% CI 1.22 -2.82). On a treatment-received basis, the results were significantly in favour of surgery at 3 years (OR 1.84, 95% CI 1.17-2.90) and 5 years (OR 2.17, 95% CI 1.39-3.38) for overall survival, and at 3 years (OR 1.96, 95% CI 1.06-3.65) for disease-specific survival. CONCLUSIONS : The analysis of this review suggests that there is an overall survival benefit with combined preoperative radiotherapy plus radical surgery compared with radical radiotherapy plus salvage cystectomy in patients with muscle-invasive bladder cancer. However, it must be considered that only three trials were included for analysis, the patient numbers were small and that many patients did not receive the treatment they were randomised to. It must also be noted that many improvements in radiotherapy and surgery have taken place since the initiation of these trials; therefore, the data may not be readily extrapolated to modern practice. Ideally, a new trial comparing modern bladder-sparing therapy with the latest surgical approach to this disease is required.

12. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis.
Winquist E, Kirchner TS, Segal R, Chin J, Lukka H;
J Urol. 2004 Feb;171(2 Pt 1):561-9.

PURPOSE : Despite local therapy most patients with muscle invasive transitional cell carcinoma (TCC) of the bladder die of systemic relapse, indicating a need for effective adjunctive systemic treatment. We determined whether neoadjuvant chemotherapy improved overall survival. MATERIALS AND METHODS : A systematic review and meta-analysis were performed of all known randomized controlled trials (RCTs) of neoadjuvant chemotherapy for stages II and III TCC conducted between 1984 and 2002. RESULTS : A total of 16 eligible RCTs (3,315 patients) were identified. Of these trials 11 (2,605 patients) provided data suitable for a meta-analysis of overall survival and the pooled HR was 0.90 (95% CI 0.82 to 0.99, p=0.02). Eight trials used cisplatin based combination chemotherapy and the pooled HR was 0.87 (95% CI 0.78 to 0.96, p=0.006), consistent with an absolute overall survival benefit of 6.5% (95% CI 2 to 11%) from 50% to 56.5%. Reported progression-free survival data were insufficient for meta-analysis but they appeared concordant with overall survival results. Mortality due to combination chemotherapy was 1.1%. A major pathological response was associated with improved overall survival in 4 trials.CONCLUSIONS Neoadjuvant cisplatin based chemotherapy improves overall survival in muscle invasive TCC. The size of the effect is modest and combination chemotherapy can be administered safely without adverse outcomes resulting in delayed local therapy. An optimal chemotherapy regimen was not identified and newer regimens have not been tested in RCTs in this setting. Further efforts to identify the patients most likely to benefit from neoadjuvant therapy are necessary to optimize its use.

13. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.
von der Maase H, Hansen SW, Roberts JT et al.
J Clin Oncol. 2000 Sep;18(17):3068-77.

PURPOSE : Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS : Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS : Four hundred five patients were randomized (GC, n=203; MVAC, n=202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P=.75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

14. Role of gemcitabine/cisplatin in the treatment of advanced and metastatic bladder cancer.
Bodrogi I.
Magy Onkol. 2003;47(2):198-203.

M-VAC combination chemotherapy was considered as the “gold standard” of the treatment of advanced and metastatic bladder cancers. Arrival of gemcitabine or taxanes in the 90s attracted attention since their efficacy was combined with low toxicity profiles. Gemcitabine/cisplatin combination became the most frequently studied treatment modality in the past 3 years. Multicentric, multinational randomized phase-III study indicated that in bladder cancer the gemcitabine/cisplatin combination is equal to M-VAC while in the case of the former the risk to benefit ratio is lower. Accordingly, gemcitabine/cisplatin combination is a safer treatment option in advanced and metastatic bladder cancer and is a real alternative to M-VAC. In the case of patients where cisplatin cannot be administered due to poor renal function, the new drugs with better toxicity profiles provide further treatment options.

TESTICULAR GERM CELL TUMOURS

Incidence :
Testicular cancer forms about 1% of all malignancies in males in India. Although uncommon, they affect young males in the prime of their life. Besides, the disease as well as the treatment can affect the fertility of these patients and affect their quality of life. Testicular tumours are the models of the success of multimodality treatment of cancer, boasting of high cure rates even in the presence of metastatic disease. About 40% of all testicular tumours are pure seminomas. 2-3% present as bilateral tumours. Other histological varieties like yolk sac tumour (endodermal sinus tumour), teratoma, embryonal carcinoma etc are considered together for management due to similar biological behaviour and natural history and are collectively called “nonseminomatous germ cell tumours of testis” (NSGCT)

Histological classification : is carried out using either the WHO international classification or the Armed Forces Institute of Pathology classification of Dixon and Moore. The former is more elaborate and also recognizes yolk sac tumors and spermatocytic seminomas as separate subtypes.

Patterns of spread :
The pattern of spread in NSGCT is distinct from that seen in Seminomas. In NSGCT, 60% of cases will present with extensive disease. The spread is usually to the retroperitoneal lymph nodes first and then hematogenously to other parts. The exception is pure choriocarcinoma – which rapidly spreads to lungs, brain and other soft tissues early in the disease. Pattern of retroperitoneal lymph nodal involvement in germ cell tumors has important treatment implications. Donohue et al have shown that a right sided primary will usually involve the interaortocaval, precaval and preaortic nodes. The left testicular mass will involve the left paraaortic, preaortic and interaortocaval nodes. Suprahilar LN involvement is uncommon and external iliac/ obturator nodes are only rarely the sites of metastasis.

Diagnosis :
The majority of patients shall present with a testicular swelling (more than 70% of cases). Contrary to common belief, pain is a presenting feature in as many as 46% of cases (due to torsion, infection, bleeding or infarction).

Other less common features include gynaecomastia, backache (due to metastasis), dyspnoea, chest pain, hemoptysis and infertility.

Pretreatment Evaluation:

• CBC, Biochemistry including renal chemistry and liver function tests
• Tumor Markers : AFP, beta HCG, LDH. Pure seminomas do not produce any tumor markers (90% cases, 10% may have mildly raised b-hCG). Pure choriocarcinomas produce only b-HCG. Embryonal and yolk sac tumors usually have elevated AFP alone. NSGCTs will usually show elevation of both b-HCG and AFP. Elevated tumors markers are used to support the diagnosis, indicate residual tumor following orchiectomy, trace response to chemotherapy and detecting early relapse.
• X-ray chest
• Ultrasound of the testicular mass
• FDG-PET has limited application. In our country, its specificity is diminished since inflammatory lesions and tuberculosis will give false positivity.

Testicular mass with Suspicion of Germ Cell Tumor (GCT)

Primary (Initial) Treatment :
High Inguinal Radical Orchidectomy. Biopsy of contralateral testis if :

• Abnormal ultrasound
• Cryptorchid Testis
• Marked Atrophy

Diagnosis is based on the histology of the testicular mass removed by inguinal orchidectomy. A thorough histopathological review including histological subtype, tumor size and extent, presence or absence of lymphatic or vascular emboli, tumour necrosis etc. is essential.

Orchiectomy is not required in patients with extragonadal GCT with normal testicular examination (clinical and sonographical). Patients sometimes present with scrotal orchiectomy being done if malignancy is not suspected and especially if a patient presents to a non-oncological centre. In such circumstances, aggressive local therapy (resection of inguinal portion of spermatic cord and hemi-scrotectomy) will ensure that the survival of the patient is not compromised.

Post Primary Treatment Work-up :

• Post primary treatment markers : AFP, beta HCG.
• CT Scan (Abdomen + Pelvis) : for demonstrating retroperitoneal lymphadenopathy and status of liver.
• X-ray chest.
• CT thorax only if the X-ray is suspicious for lung metastases or to demonstrate mediastinal lymphadenopathy in the presence of enlarged nodes on CT abdomen.
• CT / MRI of Brain (optional) : if CNS involvement suspected.
• Bone scan if there is a clinical suspicion of bone metatstases.

Staging : (Post Primary Surgery) AJCC Staging of Testis Tumors
Staging shall be done by the TNM system and the prognostic group assignment is done as per the International Germ Cell Consensus Classification.

N = upper limit of normal for the LDH assay
†HCG = human chorionic gonadotropin

International Germ Cell Consensus Classification for Seminoma :

Good Prognosis : (All of the following)

• Normal alpha fetoprotein, any b-hCG, any LDH and
• Any primary site and
• No non-pulmonary visceral metastases present
  Intermediate Prognosis :
• Non-pulmonary visceral metastases present

International Consensus Advanced Germ Cell Tumor Prognosis Classification Scheme (NSGCT)

Good Prognosis (All of the following) :

• AFP <1000 ng/ml and b-hCG <5000 IU/l and
• LDH <1.5 X upper limit of normal (ULN) and
• Non mediastinal primary and
• No non-pulmonary visceral metastases present

Intermediate Prognosis (All of the following) :

• AFP 1000-10000 ng/ml or b-hCG 5000-50000 IU/l or LDH 1.5-10 X ULN and
• Non mediastinal primary site and
• No non-pulmonary visceral metastases present

Poor prognosis (Any of the following) :

• AFP >10000 ng/ml or b-hCG >50000 IU/l or LDH 10 X ULN or
• Mediastinal primary site or
• Non-pulmonary visceral metastases present

Management : of Seminoma :
Stage I :

The DFS and OAS for Stage I seminoma testis is 95-99% at 10 years with excellent salvage rates even at relapses[1].

Post orchidectomy treatment options are :
- Prophylactic Para-aortic +/-Pelvic Nodes Radiation
- Surveillance

Prophylactic Para-aortic +/-Pelvic Nodes Radiation : External beam radiation therapy to para-aortic with or with out ipsilateral pelvic nodal region to a dose of 20-25Gy with 6-15 MV photons @1.5 -1.8 Gy/# in 2-3 weeks, from lower border of D10 vertebra (retrocrural nodes) to lower border of L5 vertebra [1-6]. If previous scrotal surgery, field of radiation therapy to be extended to include ipsilateral inguinal nodes (dog-leg radiotherapy).

Surveillance : Considered in select cases T1, T2 with committed for long-term follow up. Strict follow up is must, every 3 months with serial tumour markers and CT scan abdomen + pelvis, for first 2 years, then every 6 months for 3-7 years, then annually. Although the relapse rates with surveillance are 16-18%, they can be salvaged with radiation &/or chemotherapy.

Surveillance for seminoma needs to be continued for a long time since late relapses are seen occasionally.

Stage II : Para-aortic nodes detected on imaging (CT)
IIA –IIB :
Treatment options :

• Radical Radiation Therapy
• Chemotherapy

Radical Radiation Therapy : Radical radiation therapy to Para-aortic and ipsilateral pelvic region (dog-leg) to a dose of 35-40 Gy @1.5-1.8 Gy/# in 3-4 weeks with reducing fields, with a boost to the involved site [7,8]. The role of prophylactic mediastinal irradiation is not clear

Chemotherapy : As per the stage IIC protocol

Stage IIC-IIIC :

Chemotherapy +/- Involved Field Radiation :

Chemotherapy with 3 cycles of cisplatin, bleomycin and etoposide combination chemotherapy is the gold standard regimen for germ cell tumours of the testis.

Following chemotherapy, imaging studies are repeated to assess the response. If complete response, no further treatment required. If there is a residual mass more than 3 cm in the retroperitoneum, consolidation therapy by local radiation therapy is advised. The role of retroperitoneal lymph node dissection in this setting is questionable due to difficulty in removing post-chemotherapy seminoma at surgery. However, if residual disease less than 3 cm, patient can be closely observed with serial imaging and if disease progression noted, treatment should be advocated. A core biopsy may also be obtained from the residual mass to document presence or absence of viable disease in the residual mass.

Involved Field Radiation : Involved or Residual Paraaortic nodal disease >3 cm can be treated with radiation to a dose of 30 – 40 Gy @1.8 Gy / # in 3-4 weeks [9,10].

Relapse after radiation therapy :

Chemotherapy with 3 cycles of BEP is recommended.

Management of nonseminomatous germ cell tumours :

Stage I NSGCT :

Following high orchiectomy, the treatment options include :

• Nerve sparing retroperitoneal lymph node dissection : This is usually the preferred option since it identifies the patients with occult retroperitoneal lymph node metastases who will need chemotherapy, has a very low (<2%) chance of relapse in the retroperitoneum and a very high cure rate. It preserves antegrade ejaculation in more than 90% of patients. Extensive follow up with CT scan as in surveillance is not mandatory and patient anxiety is allayed.
• Chemotherapy
• Surveillance : Although has the potential to avoid major surgery with its morbidity, it requires a very extensive follow up with tumour markers, X-ray chest and CT scan abdomen at very frequent intervals. Thus it requires excellent compliance from the patients which may not be possible in India. Besides, there is an anxiety about the nearly 30% chance of relapse, some of which may be advanced and unsalvageable if the patient does not comply with the surveillance schedule.

Stage I NSGCT patients are divided into those with a low risk of relapse and those with a high risk of relapse. Those with a high risk of relapse (upto 50%) include those with a higher than T1 stage, presence of lymphatic or vascular emboli, predominance of embryonal carcinoma &/or absence of yolk sac elements, those with raised biomarkers without any obvious metastatic disease on imaging studies (CSIM+) or with Ki-67 staining. These patients may be treated with nerve sparing RPLND or 2-3 cycles of BEP chemotherapy. The low risk patients (relapse rate of <20%) may be kept under active surveillance.

Surveillance requires an intelligent and motivated patient as well as strict adherence to frequent evaluation protocol (physical examination, radiological imaging and tumor markers estimation), which may not be practical in India and other developing countries.

Stage II NSGCT :
Therapy after high orchiectomy will depend on the tumor burden.
For stage IIA and IIB patients, the appropriate therapy is RPLND followed by adjuvant chemotherapy (2 cycles of BEP). Controversy exists on whether the systemic chemotherapy should be given immediately or at the time of relapse (OS remains 97% in both instances).

Stage IIC-IIIC NSGCT :

• Good prognosis : Primary chemotherapy with 3 cycles of BEP is recommended [11,12]. This group can be expected to have more than 90% chance of responding to chemotherapy and more than 85% will be long term survivors. Hence the focus in this subset is to reduce toxicity.
• Intermediate and poor prognosis : These patients usually have only a 40-60 % chance of complete response. Hence the emphasis here is to improve treatment efficacy. The standard treatment still remains four cycles of BEP13. Attempts to use dose escalation of cisplatin, using etoposide in place of bleomycin (PEV regimen), using VeIP upfront and combination of BEP alternating with PVB (alternating non cross resistant approach) have failed to demonstrate superiority in randomized trials. The only regimen that has shown promise in poor prognosis advanced NSGCT patients is the use of high dose chemotherapy followed by autologous PBSC rescue, with a potential for survival benefit.

BEP (given at three weekly intervals) :

Bleomycin 30 units day 1,8,15
Etoposide 100 mg/m2 IV days 1 to 5
Cisplatinum 20 mg/m2 IV days 1 to 5

Certain sites of metastasis confer a distinct disadvantage in patients with NSGCT. These include liver, bone and brain. Metastasis to any of these sites reduces the 3-year OS rates significantly.

Response to primary chemotherapy is assessed 2-3 weeks after completion of the planned course of chemotherapy. Clinical evaluation, CT scan of the abdomen + pelvis, X-ray or CT scan of chest and serum biomarkers evaluation are advised for evaluation of response.

In patients with complete response (clinical, radiological and serological), only close observation is necessary. In patients with residual masses, decision regarding adjuvant surgery is based on whether the tumor markers remain elevated or have normalized. In patients with normal post-chemotherapy markers and residual mass > 1 cm in size, complete surgical resection is warranted to document the histology of the residual mass and for disease control. Methods to identify patients in whom post-chemotherapy surgery can be avoided remain controversial [14,15]. Resections should be done aggressively for retroperitoneal and pulmonary masses. In patients in whom markers remain elevated despite primary chemotherapy, salvage chemotherapy or desperation RPLND is advocated. VIP and VeIP (for patients previously treated with bleomycin) are considered standard and will yield a disease free survival in one third of the cases. Addition of Paclitaxel in the TIP combination has shown promise that is currently being studied in a prospective manner. The role of HDCT followed by PBSC rescue is established as potentially curative therapy in the salvage setting – with 25 to 50% of patients achieving durable remissions [16]. The conditioning is usually with high dose carboplatin, etoposide, ifosfamide, thiotepa and/or paclitaxel. There is also an emerging role of surgical resection, in highly selected cases with residual chemo-refractory masses with elevated serum tumor markers (especially a retroperitoneal mass with only AFP elevation). In patients with relapsed or refractory NSGCT, factors that indicate poor outcome include incomplete response to initial therapy, extra-gonadal tumors, elevated tumor markers (AFP > 1000 ng/ml and/ or b-HCG > 10,000 IU/l) and lung metastasis.

Follow up schedule :
For patients on surveillance : Clinical evaluation, chest X-ray, tumour markers monthly for 1 year, 2 monthly for second year, 4 monthly in 3rd year, then 6 monthly to 5 years. CT scans after 3, 6, 9, 12 and 24 months.
Post-chemotherapy patients : Clinical evaluation, chest X-ray, tumour markers 2 monthly for 1 year, 3 monthly for second year, then 6 monthly to 5 years and annually thereafter. CT scans only when clinically indicated.

1 Prognostic Factors for Relapse in Stage I Seminoma Managed by Surveillance: A Pooled Analysis
Padraig Warde, Lena Specht, Alan Horwich, Tim Oliver, Tony Panzarella, Mary Gospodarowicz, and Hans von der Maase
J Clin Oncol 2002;20:4448-4452.

Purpose : Several management options are available to patients with stage I seminoma, including adjuvant radiotherapy,surveillance, and adjuvant chemotherapy. We performed a pooled analysis of patients from the four largest surveillance studies to better delineate prognostic factors associated with disease progression. Patients and Methods : Individual patient data were obtained from each center (Princess Margaret Hospital, Danish Testicular Cancer Study Group, Royal Marsden Hospital, and Royal London Hospital) for 638 patients. Tumor characteristics (size, histologic subtype, invasion of rete testis, and tumor invasion into small vessels [SVI]) as well as age at diagnosis were analyzed for prognostic importance for relapse. Results: With a median follow-up of 7.0 years (range, 0.02 to 17.5 years), 121 relapses were observed for an actuarial 5-year relapse-free rate (RFR) of 82.3%. On univariate analysis, tumor size (RFR: < 4 cm, 87%; > 4 cm, 76%; P_.003), rete testis invasion (RFR: 86% [absent] v 77% [present], P_.003), and the presence of SVI (RFR: 86% [absent] v 77% [present], P_.038) were predictive of relapse. On multivariate analysis, tumor size (< 4 cmv > 4 cm, hazard ratio 2.0; 95% confidence interval [CI], 1.3 to 3.2) and invasion of the rete testis (hazard ratio 1.7; 95% CI,1.1 to 2.6) remained as important predictors for relapse. Conclusion : We have identified size of primary tumor and rete testis invasion as important prognostic factors for relapse in patients with stage I seminoma managed with surveillance. This information will allow patients and clinicians to choose management based on a more accurate assessment of an individual patient’s risk of relapse. In addition, it will allow clinicians to tailor follow-up protocols based on risk of occult disease.

2. Short course para-aortic radiation for Stage I Seminoma of the testis.
John P. Logue, Margaret A. Harris, Jacqueline E. Livsey et al.
Int. J Radiat Oncol Biol Phys. 2003;57:1304-1309.

Purpose : To determine the outcome in men with Stage I seminoma treated with low-dose para-aortic radiation. Methods and Materials: Between January 1988 and December 2000, 431 men with Stage I seminoma were treated with para-aortic radiation to a midplane dose of 20 Gy in 8 fractions over 10 days. Results: At a median follow-up of 62 months, 15 patients (3.5%) had relapsed, with a median time to relapse of 13 months (range: 9 to 39 months). Nine patients had pelvic nodal relapse; in addition, 1 patient had para-aortic involvement, and 2 had distant disease. Four had metastatic disease only (mediastinum 2, lung 2). One patient had scrotal recurrence, and 1 was treated for progressive rise in human chorionic gonadotrophin without identifiable disease. Initial treatment at relapse was chemotherapy (12), radiation (2), and surgery (1). One patient died from progressive disease. Thirteen men (3%) have developed second malignancies, including 7 contralateral testicular tumors, 5 solid malignancies, and 1 leukemia. The overall 5-year survival was 98%, and the estimated recurrence-free survival at 5 years was 96.3%. On log–rank univariate analysis, lymphovascular invasion, involvement of the tunica, and a preoperative human chorionic gonadotrophin level of greater than 5 were found to be of prognostic significance for recurrence. Conclusions : These data support short-duration, limited-field radiation as an optimal safe and effective protocol in the management of Stage I seminoma patients.

3. Optimal Planning Target Volume for Stage I Testicular Seminoma: A Medical Research Council Randomized Trial
Fossa S.D., Horwich A., Russell J.M. et al.
J Clin Oncol. 1999;17;1146 - 1154.

Purpose : To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. Patients and Methods: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). Results: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, 23.4%, 14.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. Conclusion: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.

4. Randomized Trial of 30 Versus 20 Gy in the Adjuvant Treatment of Stage I Testicular Seminoma: A Report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328).
Jones WG, Fossa SD, Mead GM, Roberts JT et al.
J Clin Oncol. 2005 Feb 20;23(6):1200-8.

PURPOSE To assess the possibility of reducing radiotherapy doses without compromising efficacy in the management of patients with stage I seminoma. PATIENTS AND METHODS Patients were randomly assigned 20 Gy/10 fractions over 2 weeks or 30 Gy/15 fractions during 3 weeks after orchidectomy. They completed a symptom diary card during treatment and quality-of-life forms pre- and post-treatment. The trial was powered to exclude absolute differences in 2-year relapse rates of 3% to 4% (alpha=.05 [one sided]; 90% power). Results From 1995 to 1998, 625 patients were randomly assigned to treatment. Four weeks after starting radiotherapy, significantly more patients receiving 30 Gy reported moderate or severe lethargy (20% v 5%) and an inability to carry out their normal work (46% v 28%). However, by 12 weeks, levels in both groups were similar. With a median follow-up of 61 months, 10 and 11 relapses, respectively, have been reported in the 30- and 20-Gy groups (hazard ratio, 1.11; 90% CI, 0.54 to 2.28). The absolute difference in 2-year relapse rates is 0.7%; the lower 90% confidence limit is 2.9%. Only one patient has died from seminoma (allocated to the 20-Gy treatment group). CONCLUSION Treatment with 20 Gy in 10 fractions is unlikely to produce relapse rates more than 3% higher than for standard 30 Gy radiation therapy, and data on an additional 469 patients randomly assigned in a subsequent trial support and strengthen these results. Reductions in morbidity enable patients to return to work more rapidly. Prolonged follow-up is required before any inference can be made about any impact of allocated treatment on new primary cancer diagnoses.

5. External beam abdominal radiotherapy in patients with seminoma Stage I : Field type, testicular dose, and spermatogenesis.
Kari Dolven Jacobsen, Dag Rune Olsen, Kristian Foosa et al.
Int. J Radiat Oncol Biol Phys. 1997;Vol.38. No.I. pp. 102.

Purpose : To establish a predictive model for the estimation of the gonadal dose during adjuvant para-aortic (PA) or dog leg (DL: PA plus ipsilateral iliac) field radiotherapy in patients with testicular seminoma. Methods and Materials: The surface gonadal dose was measured in patients with seminoma Stage I receiving PA or DL radiotherapy. Sperm cell analysis was performed before and 1 year after irradiation. PA and DL radiotherapy were simulated in the Alderson phantom while we measured the dose to the surface and middle of an artificial testicle, varying its position within realistic anatomical constraints. The symphysis-to-testicle distance (STD), field length, and thickness of the patient were experimental variables. The developed mathematical model was validated in subsequent patients. Results: The mean gonadal dose in patients was 0.09 and 0.32 Gy after PA and DL irradiation, respectively p<0.001). DL radiotherapy, but not PA irradiation led to significant reduction of the sperm count 1 year after irradiation. The gonadal dose-reducing effect of PA irradiation was confirmed in the Alderson phantom. A significant correlation was found between the STD and the gonadal dose during DL irradiation. A mathematical model was established for calculation of the gonadal dose and confirmed by measurements in patients. Conclusions: During radiotherapy of seminoma, the gonadal dose decreases with increasing STD. It is possible to predict the individual gonadal dose based on delivered midplane dose and STD.

6. Patterns of Relapse Following Radiotherapy for Stage I Seminoma of the Testis: Implications for Follow-up.
J.E. Livsey, B. Taylor, N. Mobarek et al.
Clinical Oncol. 2001;13;296-300.

Abstract. A retrospective review was undertaken of 409 consecutive patients treated with adjuvant radiotherapy for Stage I seminoma between 1988 and 1997. A total of 339 men were treated to a volume encompassing the para-aortic nodes and 70 were treated with extended field radiotherapy. The patients were followed up within oncology clinics adhering to a standard protocol of clinical examination, chest radiography and measurement of serum marker levels. No routine computed tomographic (CT) scans were carried out. At a median follow-up of 57 months, 13 patients have relapsed, giving a recurrence-free rate of 97.2% at 3 years and 96.8% at 5 years. Of these, eight (62%) were detected at routine appointments and five (38%) requested early appointments. Chest radiography (2/5) and serum marker levels (3/5) identified disease in asymptomatic patients. Eight patients (62%) had raised markers at relapse, including two with normal serum markers at original presentation. The median size of pelvic node recurrences in the para-aortic-treated group was 7.3 cm (2.8–13 cm). Four patients have developed second testicular primaries: three were detected at routine appointments and one patient had requested an early appointment. We conclude that regular follow-up with serum marker estimations and chest radiography is sufficient to detect recurrence at an early stage and that our policy of no routine CT scanning has been shown to give acceptable results.

7. Treatment options in early-stage testicular seminoma. Review of the literature with initial results of a prospective multicenter study on radiotherapy of clinical-stage I, IIA and IIB seminomas.
Schmidberger H, Bamberg M.
Strahlenther Onkol. 1995 Mar;171(3):125 39.

BACKGROUND : Testicular seminoma in the early stages is treated with orchiectomy and radiotherapy to the retroperitoneal nodes. Despite the high cure rates of this treatment, there is an ongoing controversy concerning the extent of the radiation fields and the radiation doses to be given in the clinical stages I, IIA and IIB. In the following literature review, these controversial issues are discussed. Recent reports emphasize, that the irradiation of the paraaortic nodes seems to be adequate in stage I disease. The “wait and see” strategy avoids an overtreatment in 80% of the patients in stage I. The application of 1 or 2 cycles of carboplatinum chemotherapy induced comparable results to adjuvant radiotherapy. In the stages IIA and IIB radiotherapy to the paraaortal and ipsilateral iliacal nodes, with a prescribed dose of 30 Gy and 36 Gy respectively, has been the standard treatment. The treatment of the upper contralateral iliacal nodes has been a matter of controversy. PATIENTS AND METHODS : Four hundred and ninety-one patients in stage I testicular seminoma received adjuvant paraaortic irradiation with a total dose of 26 Gy. Forty-one patients in stage IIA, and 19 patients in stage IIB received 30 Gy or 36 Gy respectively to the paraaortic and ipsilateral iliacal nodes. RESULTS : Paraaortic radiotherapy in stage I disease was associated with low acute side effects and a disease-free survival in 97.1% of the patients after a median observation of 13 months. In stage IIA the disease-free survival was 100%, in stage IIB 94.7%. CONCLUSIONS : The literature review and preliminary results of the reported ongoing trial are indicating that paraaortic irradiation in stage I and paraaortic with ipsilateral iliacal irradiation in stages IIA and IIB seem to be a sufficient treatment in early stage testicular seminoma with low treatment associated morbidity.

8. Management of stage II seminoma
P Warde, M Gospodarowicz, T Panzarella et al.
J Clin Oncol. 1998;16:290-294.

PURPOSE : To assess the results of treatment, patterns of failure, and prognostic factors for relapse in a contemporary cohort of patients with stage II seminoma. MATERIALS AND METHODS : From January 1981 and December 1993, 99 patients (median age, 35 years) with stage II seminoma (IIA, 41; IIB, 28; IIC, 24; IID, six) were managed at our institution. Eighty were treated with radiation therapy (RT) and 19 with chemotherapy (ChT). RESULTS : With a median follow-up of 6.7 years, the five-year overall actuarial survival was 94%, the 5-year cause-specific survival was 94%, and the 5-year relapse-free rate was 83%. Sixteen (20%) of the 80 patients treated with RT relapsed (median time to relapse, 9 months). Relapse occurred outside the irradiated area in all but two patients. Distant relapse sites included the supraclavicular fossa, bone (four patients, three with spinal cord compression), and lung/mediastinum. All 19 patients treated primarily with ChT achieved disease control and none has relapsed. The relapse rate at 5 years for patients with stage IIA to IIB was 11% (seven of 64), and 56% (nine of 16) for those with stage IIC to IID disease (P<.0001). No patient with IIC or IID disease treated with ChT relapsed as compared with 56% of patients treated with RT (0 of 14 v nine of 16, P=.002). CONCLUSION : Radiation therapy is highly effective in patients with stage IIA or IIB seminoma (89% were relapse free). In stage IIC or IID disease, although local control with RT is excellent, a 50% risk of distant relapse is unacceptable, and not all patients who relapse can be salvaged. Chemotherapy should clearly be the primary treatment in patients with stage IIC or IID seminoma.

9. Management of residual mass in advanced seminoma: results and recommendations from the Memorial Sloan-Kettering Cancer Center
HS Puc, R Heelan, M Mazumdar, H Herr et al.
J Clin Oncol. 1998;14:454-460.

PURPOSE : Guidelines for management of postchemotherapy residual mass in patients with advanced seminoma remain controversial. We sought to characterize independent prognostic factor(s) for persistence of tumor to identify patients with a high risk of residual carcinoma. PATIENTS AND METHODS : One hundred four patients with advanced seminoma were assessed. All had achieved a complete response or partial response with normal markers to induction cisplatin-based chemotherapy and had radiographs available for review. Selected prechemotherapy and postchemotherapy characteristics were compared for patients who had either germ cell tumor histology at surgery or relapsed at the assessed site (defined as site failure) versus those who had only necrosis or fibrosis found at surgery and did not relapse at the assessed site (defined as site nonfailure). RESULTS : At a median follow-up time of 47 months (range, 5 to 153), 94 patients (90%) were designated as site nonfailures and 10 (10%) as site failures. Site failure correlated only with size of the residual mass (< 3 cm or normal v > or = 3 cm; P=.0006). Two of 74 patients (3%) with residual masses less than 3 cm were considered site failures, compared with eight of 30 (27%) with residual masses > or = 3 cm. CONCLUSION : Patients with advanced seminoma who have normal radiographs or residual masses less than 3 cm after chemotherapy can be observed without further intervention. The following three options exist for patients with a residual mass > or = 3 cm: observation, radiotherapy, or surgical intervention. We prefer the latter to define response, resect viable tumor when possible, and direct further treatment.

10. Radiotherapy for stage II testicular seminoma: the prognostic influence of tumor bulk
BR Mason and JH Kearsley
J Clin Oncol. 1988;6(12):1856-62

Forty-nine consecutive patients with stage 2 testicular seminoma were treated with primary radiotherapy from 1968 to 1985. Overall diseases- free survival (DFS) for patients with 36 months minimum follow-up was 82% at 3 years. This figure did not decline further with time. Infradiaphragmatic bulk disease was found to be a significant prognostic factor for local and distant relapse as well as for ultimate survival. Patients with either stage 2A or 2B disease (infradiaphragmatic bulk less than or equal to 10 cm size) had a 3-year DFS of 89% compared with a 64% 3-year DFS rate for patients with stage 2C disease (infradiaphragmatic bulk greater than or equal to 10 cm size). The (local plus distant) relapse rate was 4.0% for patients with stage 2A disease, 16.7% for patients with stage 2B disease, and 33.3% for patients with stage 2C disease. The majority of distant relapses were multifocal and prophylactic mediastinal irradiation did not appear to influence either relapse rate nor overall survival. Of seven patients who relapsed, four died of progressive malignancy, two deaths were related to salvage chemotherapy, and only one patient is alive and well following successful chemotherapeutic salvage. On the basis of our experience, we recommend radiotherapy with the use of modern imaging techniques as initial treatment for patients with retroperitoneal masses less than 10 cm size. Aggressive cisplatin-based chemotherapy should be seriously considered for patients with retroperitoneal masses greater than or equal to 10 cm size, or for patients who relapse following radiotherapy.

11. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer : a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial.
Horwich A, Sleijfer DT, Fossa SD, et al.
J Clin Oncol. 1997 May;15(5):1844-52.

PURPOSE : This prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors. PATIENTS AND METHODS : Between September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles. RESULTS : Of patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response, compared with 227 of 260 (87.3%) allocated to receive CEB (P=.009). There were 30 treatment failures in the 300 patients allocated to BEP and 79 in the 298 allocated to CEB (log-rank chi 2=26.9; P<.001), which led to failure-free rates at 1 year of 91% (95% confidence interval [CI], 88% to 94%) and 77% (95% CI, 72% to 82%), respectively. There were 10 deaths in patients allocated to BEP and 27 in patients allocated to CEB (log-rank chi 2=8.77; P=.003), which led to 3-year survival rates of 97% (95% CI, 95% to 99%) and 90% (95% CI, 86% to 94%), respectively. CONCLUSION : With these drug doses and schedules, combination chemotherapy based on carboplatin was inferior to that based on cisplatin. This BEP regimen that contains moderate doses of etoposide and bleomycin is effective in the treatment of patients with good-prognosis metastatic nonseminoma.

12. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.
J Clin Oncol. 1997 Feb;15(2):594-603.

PURPOSE : Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. MATERIALS : Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. RESULTS : Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. CONCLUSION : An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.

13. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer : a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council.
de Wit R, Roberts JT, Wilkinson PM et al.
J Clin Oncol. 2001 Mar 15;19(6):1629-40.

PURPOSE : To test the equivalence of three versus four cycles of bleomycin, etoposide, and cisplatin (BEP) and of the 5-day schedule versus 3 days per cycle in good-prognosis germ cell cancer. PATIENTS AND METHODS : The study was designed as a 2 x 2 factorial trial. The aim was to rule out a 5% decrease in the 2-year progression-free survival (PFS) rate. The study included the assessment of patient quality of life. A cycle of BEP consisted of etoposide 500 mg/m(2), administered at either 100 mg/m(2) days 1 through 5 or 165 mg/m(2) days 1 through 3, cisplatin 100 mg/m(2), administered at either 20 mg/m(2) days 1 through 5 or 50 mg/m(2) days 1 and 2. Bleomycin 30 mg was administered on days 1, 8, and 15 during cycles 1 through 3. The randomization procedure allowed some investigators to participate only in the comparison of three versus four cycles. RESULTS : From March 1995 until April 1998, 812 patients were randomly assigned to receive three or four cycles : of these, 681 were also randomly assigned to the 5-day or the 3-day schedule. Histology, marker values, and disease extent are well balanced in the treatment arms of the two comparisons. The projected 2-year PFS is 90.4% on three cycles and 89.4% on four cycles. The difference in PFS between three and four cycles is -1.0% (80% confidence limit [CL], -3.8%, +1.8%). Equivalence for three versus four cycles is claimed because both the upper and lower bounds of the 80% CL are less than 5%. In the 5- versus 3-day comparison, the projected 2-year PFS is 88.8% and 89.7%, respectively (difference, -0.9%, (80% CL, -4.1%, +2.2%). Hence, equivalence is claimed in this comparison also. Frequencies of hematologic and nonhematologic toxicities were essentially similar. Quality of life was maintained better in patients receiving three cycles; no differences were detected between 3 and 5 days of treatment. CONCLUSION : We conclude that three cycles of BEP, with etoposide at 500 mg/m(2), is sufficient therapy in good-prognosis germ cell cancer and that the administration of the chemotherapy in 3 days has no detrimental effect on the effectiveness of the BEP regimen.

14. Viable malignant cells after primary chemotherapy for disseminated nonseminomatous germ cell tumors: prognostic factors and role of postsurgery chemotherapy—results from an international study group.
Fizazi K, Tjulandin S, Salvioni R, et al
J Clin Oncol. 2001 May 15;19(10):2647-57.

PURPOSE : To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. PATIENTS AND METHODS : The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. RESULTS: The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P<.001), < 10% of viable malignant cells (P=.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P=.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P<.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P<.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P<.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P<.001) and OS (P=.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. CONCLUSION : A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

15. Predicting outcome to chemotherapy in patients with germ cell tumors : the value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy.
Mazumdar M, Bajorin DF, Bacik J, Higgins G, Motzer RJ, Bosl GJ.
J Clin Oncol. 2001 May 1;19(9):2534-41

PURPOSE : The prognostic significance of the rate of decline of the serum tumor marker alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) during the first two cycles of chemotherapy in germ cell tumor (GCT) patients was initially reported by us, but its value has been debated. We re-examined this issue in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system and investigated the role of including in the analysis patients whose markers normalized early. PATIENTS AND METHODS : One hundred eighty-nine GCT patients with elevated AFP/HCG marker values treated with platinum-based chemotherapy between 1986 and 1998 were included in this analysis. Patients were classified as good, intermediate, or poor risk by the IGCCCG criteria and as having satisfactory or unsatisfactory marker decline. Risk and marker decline were correlated with response, event-free survival, and overall survival. RESULTS : Satisfactory marker decline predicted improved complete response (CR) proportion and event-free and overall survival (P<.0001). The CR proportion, 2-year event-free, and 2-year overall survival rates for patients with a satisfactory and unsatisfactory marker decline were 92% versus 62%, 91% versus 69%, and 95% versus 72%, respectively. Marker decline remained a significant variable for all three end points when adjusted for risk (P<.01) with the outcome differences most pronounced in the poor-risk group. CONCLUSION : The rate of marker decline during chemotherapy has prognostic value independent of risk and may play a significant role in the management of poor-risk patients. It is appropriate to include patients whose markers normalized early.

16. High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.
Bhatia S, Abonour R, Porcu P et al.
J Clin Oncol. 2000 Oct 1;18(19):3346-51.

PURPOSE : To assess the role of high-dose chemotherapy as initial salvage hemotherapy in patients with relapsed testicular cancer. PATIENTS AND METHODS : From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months). RESULTS : Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality. CONCLUSION: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.

CARCINOMA PENIS

Aetiology & risk factors :

Certain geographical regions show increased relative incidence of penile cancer, including India. In contrast to United states where the disease is rare penile carcinoma makes up to 10% of male malignancy in African, South American and south Asian countries [1,2].

Certain risk factors have been identified to be associated with penile cancer and its precursors viz. tobacco use, phimosis, balanitis and sexual habits. In addition, the relationship of human papilloma virus remains to be clearly defined3.

Neonatal circumcision is a well-established protective factor against penile cancer [3].

Diagnosis :
An adequate biopsy is mandatory for diagnosis of penile cancer, determination of its invasiveness and other histological features. Phimosis may obscure the lesion, necessitating a dorsal slit prior to taking a biopsy.

Staging: (UICC TNM Classification 2002)
There is a disparity between clinical and pathological staging of the primary tumour in about 25% of cases [4]. This disparity is even greater in the case of status of the inguinal nodes. Nearly 20% of patients with clinically negative groins have lymph node metastases on pathological examination [5] whereas nearly 50% patients with clinically palpable groin nodes have no evidence of metastatic disease on pathological examination [6].

In case of palpable inguinal nodes, fine needle aspiration cytology of the nodes is recommended. However, clinical suspicion of metastases should override a negative result on FNAC.
No clinical or pathological factor, or any imaging modality has been shown to have significant accuracy especially negative predictive value as to warrant their routine use for ruling out metastatic disease in the nodes. In view of this, it is not mandatory to do any of these imaging techniques but may be used as optional investigations depending on the characteristics of the tumour, the personal experience of the clinician and the availability of these tests4.

Treatment :
The management principles in penile cancer include accurate assessment of the disease extent followed by adequate treatment for the primary lesion and for the metastatic lymph nodes. With a variety of available treatment options for various stages of the disease there is no evidence based consensus regarding the best therapeutic approach, especially for early cancers. While the relative rarity of the disease in the developed countries where most randomized trials are conducted is partly responsible, an equally important reason for the lack of evidence based consensus is the strong bias among specialists treating this disease. A recent national survey in UK revealed that irrespective of the extent of cancer, majority of urologist preferred penectomy while clinical oncologist preferred radiotherapy [7].
It is important to define which procedure is best suited for an individual patient. Various factors need to be considered while planning optimum treatment viz. Location, extent, size and type of lesion, its relation with the external urethral meatus, status of the inguinal lymph nodes, age of the patient and the desire to retain an intact penis.

A) Penile Conservative Therapy (PCT)
Since amputative surgery for penile cancer may lead to major psycho-sexual dysfunction, various attempts have been made to devise conservative treatment modalities based on careful oncological, anatomical and technical considerations. Judicious use of conventional or micrographic surgery, laser ablation or radiotherapy can allow preservation of a functioning phallus in appropriately selected patients with early cancers. However there are no comparative studies and no consensus regarding the best modality for PCT. In contrast to 97-100% local control rates with partial penectomy for early penile cancer, penile control rate with all these PCT modalities is in the range of 80-90% even in appropriately selected cases. Fortunately almost all penile failures after PCT can be successfully salvaged with a penectomy, thereby allowing preservation of the phallus and better sexual functioning in the vast majority of patients.

Surgery : Adequate surgical excision of the primary lesion is essential to ensure local control and cure from penile cancer. The excision should involve adequate surgical margins in order to minimise the risk of local recurrence. The surgical procedures can vary in their extent according to the characteristics of the primary lesion and have to be tailored to the needs of an individual patient. With the selection of a proper surgical procedure, local relapses should be virtually unknown [8].

Conservative surgical procedures like circumcision or wide excision should be adequate for lesions involving the prepuce or for small, non-invasive or minimally invasive lesions away from the urethra. The disease-free margins of excision must be confirmed by intra-operative frozen section examination. Improper selection of patients for conservative procedures may lead to high local recurrence rates [9].

Partial penectomy is indicated for lesions involving the glans, corona and distal shaft, where after adequate surgical excision [10], the residual penile stump should be serviceable for upright micturition without scrotal soiling and for sexual function without compromising the radicality of the procedure. Penile augmentation surgery using reconstructive techniques may be done at a later date in patients who are cured and desire to have normal length of penis restored. Total penectomy with perineal urethrostomy is indicated when the lesion extends more proximally to involve the proximal shaft or the base of the penis [8]. Limited extension to scrotum or skin overlying the pubis may also be included in the surgical excision if involved by the disease.

Moh's Micrographic Surgery (MMS) represents a penile tissue sparing surgical technique which essentially employs removal of diseased tissue in thin layers, accurate construction and mapping of excised tissue and confirmation of negative margins by frozen section examination of horizontal tissue sections [9]. This technique offers cure rates equivalent to more radical surgical procedures, allowing at the same time preservation of maximum normal penile tissue. This procedure is best suited for small lesions involving the distal portion of the glans.
Laser therapy has been tried in the treatment of penile cancer - in the preinvasive and small invasive lesions. Although it has the potential for preservation of normal penile tissue and function, it should be used judiciously to achieve local control rates comparable with more radical procedures [11].

Radiation Therapy : External beam radiotherapy (EBRT) using megavoltage telecobalt gamma rays or 6MV photons from Linear accelerators or interstitial implantation [12] has been used successfully in the treatment of early penile cancers for more than fifty years. The type of radiotherapy best suited for a patient depends upon the tumour location, size, thickness and its proximity to the urethra. Small, superficial tumours anywhere over the glans can be treated with surface mould therapy, localised small tumours away from the urethra can be treated with interstitial implant and any tumour can be adequately treated with EBRT. While EBRT has universal applicability and can be successfully delivered in all radiotherapy departments, excellent tumour control without severe complications with brachytherapy mandates strict case selection and expertise with the specialized procedure12. Thus even for small localised tumours, external radiation may be preferable if the requisite expertise and facilities for penile brachytherapy is not available.

A variety of fractionation schedules have been described in the literature with variable results At the Tata Memorial Hospital we traditionally used a hypofractionated accelerated regimen of 54Gy in 18 daily fractions over 3 weeks. This provided excellent local control in early cancers without any symptomatic late sequelae. However, the acute radiation muco-cutaneous reaction over the glans and penile shaft healed after a median period of 6 weeksThe main advantage of the accelerated 3-4 weeks regimen over the more protracted 6 weeks regimen is that it allows the completion of radiotherapy before the onset of the inevitable brisk radiation reaction.
The European board of urology has endorsed this treatment strategy of organ conserving therapy and watchful waiting for early-stage disease [13]. Since the results of radiotherapy alone are poor in more advanced tumours [14], initial penectomy is the treatment of choice for such tumours.

Management of ilioinguinal nodes :
The controversial issues concerning the treatment of regional lymph nodes mainly involve the indication, timing and extent of lymphadenectomy. This is primarily due to paucity of randomised clinical trials concerning these issues. There is, however, no controversy that surgical treatment is recommended for patients who have positive nodes at presentation.

Treatment Of Inguinal Lymphadenopathy In Penile Carcinoma
Lymphadenectomy in node-positive disease results in a 20-50% 5-year disease-free survival. However not all enlarged inguinal lymph nodes are metastatic nodes. Subjecting all patients with palpable inguinal lymph nodes to lymphadenectomy may result in over-treatment and unnecessary morbidity.

In T1-T2 lesions if the inguinal lymph nodes are enlarged at presentation, a course of antibiotics should be given with the intention that inflammatory changes will resolve. The inguinal nodes are reassessed four to six weeks later by clinical palpation which has been noted to be practical and acceptably accurate. By then the pathological stage and grade would have been known also and this information may help in deciding on further surgery.

In patients with clinically negative inguinal examinations on presentation, there is the controversy of whether a lymphadenectomy should be performed on a prophylactic basis. The following recommendations for individualisation of treatment can be made :

• In patients with stage T1-T2 disease, although the incidence of false negative nodes is about15-20%, metachronous inguinal node metastasis after adequate treatment of the primary lesion occurs in only about 5-11% patients. This incidence is still lower for verrucous lesions. It is very difficult to justify routine lymphadenectomy with its consequent morbidity in these patients considering their low metastatic potential. It seems reasonable to offer them close surveillance and appearance of palpable nodes during surveillance should be treated with lymphadenectomy after histological confirmation of metastatic disease. Delayed lymphadenectomy for clinically positive nodes detected during active surveillance does not seem to jeopardise long term survival when compared with patients who never develop lymph node metastases. Because most inguinal node metastases occur within 2-3 years following initial therapy, the surveillance must cover this period with repeated examinations at 2-3 monthly intervals. Poorly differentiated T1-T2 tumours may have marginally higher incidence of inguinal node metastases and may be considered for early prophylactic lymphadenectomy.
• In patients with stage T3-T4 disease, the incidence of occult nodal metastasis in clinically negative nodes increases, approaching as high as 65% in some series. In these patients, a prophylactic lymph node dissection may result in improved survival and this approach is advocated notwithstanding the morbidity of the surgical procedure.

Extent of lymphadenectomy :
Whether the palpable nodes are unilateral or bilateral, it is advocated that a bilateral lympadenectomy be done due to the fact that 50 % of the lymphatics have cross-over drainage. In patients who develop unilateral lymph node metastasis while on surveillance, it may be adequate to perform a bilateral lymph node dissection especially if the metastasis-free interval is longer than one year. The radical lymphadenectomy entails the removal of both the superficial and deep inguinal lymphatic chains. However, the surgery carries a high morbidity and a mortality rate of 3%. Major complications include disabling lymphadema (20- 50%), seroma (15- 20%), skin flap necrosis (14- 60%) and wound infection (10- 15%).

The modified inguinal lymphadenectomy is designed to reduce complication rates, but is not recommended because published data on this method involves small numbers of patients, and the results have been conflicting. The contralateral side node dissection may be limited to superficial node dissection if no histological evidence of metastasis is found in the contralateral superficial nodes. This is especially so because the patients selected for surveillance have anyway a very low rate (approximately 10%) rate of metachronous metastasis and the chance of developing contralateral node metastasis subsequently is extremely low.

There is currently no proven advantage in removing the pelvic nodes. The presence of metastatic pelvic lymph nodes usually denote a grave prognosis.Iliac lymph node metastases are found in approximately 15-30% of patients with metastatic inguinal lymph nodes the frequency of nodal metastasis being dependent on the number of positive inguinal lymph nodes, presence of perinodal extension and bilaterality of disease Moreover, improved survival in these patients has been documented after iliac node dissection (Hardner 1972). In view of this, it seems reasonable to extend the lymph node dissection to include the iliac nodes in selected cases.

At the Tata Memorial Hospital, we practise routine excision of the skin overlying the inguinal nodal area in all patients undergoing radical ilioinguinal lymphadenectomy even when the skin is not infiltrated by the nodal disease and perform immediate reconstruction using a tensor fascia lata myocutaneous flap or anterolateral thigh flap. We have had no problems of skin loss or wound breakdown since the time we began employing this procedure. In addition, the incidence of lower extremity lymphoedema has also significantly reduced with a long follow up in these patients. With the majority of patients having no significant physical impairment and with preservation of a good quality of life, this may represent a significant advance in the reduction of morbidity of ilioinguinal lymphadenectomy.

References

1. Tomatis L, Aitio A, Day NE et al. In “Cancer: Causes, Occurrence and control”. IARC Scientific publications. 1990;100 Lyon : 76-77.
2. Indian Council of Medical Research (ICMR), National Cancer Registry Programme. Consolidated Report of the Population based cancer registries 1990–1996, New Delhi: ICMR Publication, 2001: 114–224.
3. Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;(205):189-93.
4. Horenblas S, Van Tinteren H, Delemarre JFM, Moonen LMF, Lustig V & Kroger R. Squamous cell carcinoma of the penis: Accuracy of tumour, node and metastases classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J of Urol 1991; 146: 1279-1283.
5. Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. Br. J of Urol. 1993; 72: 817-819.
6. Ayappan K, Ananthakrishnan N and Sankaran V. Can regional lymph node involvement be predicted in patients with carcinoma of the penis? Br. J of Urol. 1994; 73: 549-553.
7. Harden SV, Tan LT. Treatment of localized carcinoma of the penis: a survey of current practice in the UK. Clinical Oncology (R Coll Radiol). 2001; 13(4): 284-7.
8. Horenblas S, Van Tinteren H, Delemare JFM : Squamous cell carcinoma of the penis : Treatment of the primary tumour. J Urol 1992; 147: 1533-1538
9. Mohs FE, Snow SN, Messing EM and Kuglitsch ME : Microscopically controlled surgery in the treatment of carcinoma of the penis. J Urol 1985; 133: 961-966
10. Hoffman MA, Renshaw AA, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure? Cancer. 1999 Apr 1;85(7):1565-8.
11. van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW. Laser therapy for carcinoma in situ of the penis.J Urol. 2001 Nov;166(5):1670-1.
12. Rozan R, Albuisson E, Giraud B et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiotherapy and Oncology 1995; 36: 83-93.
13. Lindegaard JC, Nielsen OS, Lundbeck FA, Mamsen A, Studstrup HN, von der Maase H. A retrospective analysis of 82 cases of cancer of the penis. Br J Urol. 1996; 77:883-890.
14. Sarin R, Norman AR, Steel GG, Horwich A. Treatment results and prognostic factors in101 men treated for squamous carcinoma of the penis. Int. J. Radiation Oncology Biol. Phys. 1997; 38, (4):713-722.

1. Squamous cell carcinoma of the penis : accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology.
Horenblas S, Van Tinteren H, Delemarre JF, Moonen LM et al.
J Urol. 1991 Nov;146(5):1279-83.

Among 118 patients with squamous cell carcinoma of the penis treated at our cancer institute between 1956 and 1989, we analyzed the accuracy of classification, using the tumor, nodes and metastasis system. We analyzed the role of lymphography, computerized tomography and fine needle aspiration cytology as additional staging procedures. The primary tumor (T category) was classified incorrectly in 26% of the cases. Overstaging was noted in 10% of the cases because of unsuspected infiltration and overstaging was noted in 16%. Overstaging occurred because of edema and infection masking the actual size and giving a misconception of infiltration, and also because of primary presentation as large exophytic tumors with no or minimal histopathological infiltration. When the regional lymph nodes were categorized simply as positive or negative 80% of the tumors were classified correctly and 20% incorrectly (13% were false positive and 7% were false negative). Regional lymph node invasion that escaped clinical examination was not detected by any imaging examination or fine needle aspiration cytology study. Positive findings were found only in patients with clinically suspected nodes. The classification of regional nodes by clinical examination only is hardly improved by additional imaging studies. Clinical decisions with respect to the management of regional lymph nodes should not be based on negative findings of lymphangiography, computerized tomography or fine needle aspiration cytology. In patients with proved metastasis additional imaging may be of some help in the detection of pelvic node invasion and the determination of the extent of involvement. We recommend lymphangiography as the examination of choice.

2. Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis.
Sarin R, Norman AR, Steel GG, Horwich A.
Int J Radiat Oncol Biol Phys. 1997 Jul 1;38(4):713-22.

PURPOSE : This retrospective study was performed to assess the treatment outcome and prognostic factors in 101 men with invasive squamous carcinoma of the penis treated at the Royal Marsden Hospital between 1960-1990. METHODS AND MATERIALS : The tumor was confined to the glans penis (T1) in 79 patients, 82 were node negative (N0), and two patients had distant metastases at presentation. The histology was Grade 1 (G1) in 36, Grade 2 (G2) in 18, Grade 3 (G3) in 28, and unknown in 19 patients. Node-positive disease was commoner in patients with G3 (p=0.02) or T2/3/4 tumors (p=0.007). Treatment for the primary tumor was external beam radiotherapy (EBRT) in 59, interstitial brachytherapy in 13, and partial or total penectomy in 29 patients. The median dose, dose/fraction, and treatment time for EBRT was 60 Gy, 2 Gy/fraction, and 46 days, respectively. Eighty patients received no inguinal node treatment, 13 had EBRT (4 with chemotherapy), and 8 underwent groin dissection at presentation. RESULTS : During a median follow-up of 5.2 years (2 months-22 years), 56 patients died (penile cancer 31, intercurrent illness 23 and unknown cause 2), giving 10 year overall and cause-specific survival (CSS) of 39 and 57%, respectively. Adverse prognostic factors for CSS on univariate analysis were G3, ulcerative/fungating or T2/3/ 4 tumors, node positive, Jackson’s Stage 2/3/4, and surgical treatment for the primary. All but the last two were significant independent prognostic factors for CSS on multivariate analysis. Penile or perineal recurrence or residual disease after initial treatment was seen in 36 out of 98 evaluable patients, giving a 10-year local failure rate (LFR) of 45%. Local failure after initial treatment was successfully salvaged in the majority (26 out of 36) of patients with further surgery or radiotherapy, and local control was achieved ultimately in 74 out of 77 T1, 7 out of 12 T2; 3 out of 3 T3, and 3 out of 5 T4 tumors. In the 44 evaluable patients with T1 tumors treated by EBRT the only adverse RT parameter approaching prognostic significance (p=0.052) was a BED value corrected for recovery of <60 Gy (alpha/beta 10, K=0.5 Gy/day, mean=21 days). CONCLUSION : Invasive squamous carcinomas of the penis carry a significant risk of loco-regional recurrence after initial radiotherapy and this can be successfully salvaged in most patients with further treatment. This mandates close follow-up to detect loco regional recurrence early.

3. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients).
Rozan R, Albuisson E, Giraud B, Donnarieix D, et al
Radiother Oncol. 1995 Aug;36(2):83-93.

Although cancer of the penis is a rare disease, we have collected 506 cases through a multicentric study. In the present study we analyse the results obtained from 259 patients treated by interstitial brachytherapy from 1959 to 1989. Among the 259 patients, 184 males had exclusive brachytherapy (group A) while 75 received a combination of surgery and brachytherapy and/or external beam irradiation (EBI) (group B). Five- and 10-year survival rates are, respectively: overall survival, 66 and 52%; cause-specific survival, 88 and 88%; disease-free survival, 78 and 67%. One hundred and forty-three patients in group A (78%) and 48 (64%) in group B avoided mutilation of the penis while late side effects occurred in 137/259 patients (53%). Survival depends on the volume of the tumor and the presence of involved nodes; systematic groin dissection does not however seem advisable.

4. A retrospective analysis of 82 cases of cancer of the penis.
Lindegaard JC, Nielsen OS, Lundbeck FA et al.
Br J Urol. 1996 Jun;77(6):883-90.

OBJECTIVE : To identify prognostic factors for penile cancer and to evaluate thetreatment strategy for early-stage disease, proposed recently by the European Board of Urology (EBU). PATIENT AND METHODS : The records of 82 patients consecutively referred to the uro-oncological centre at Aarhus University Hospital between 1965 and 1993 were reviewed. The importance of tumour stage, differentiation, patient age, local control and regional lymph node control were assessed using univariate and multivariate analyses. RESULTS : Cox multivariate analysis identified differentiation (odds ratio [OR]=6.04), UJCC-1978 T-stage (OR=1.88) and age (OR=1.04) as independent prognostic variables for survival. Penile amputation in tumours < 4 cm in diameter improved local control but not survival. Regional control and survival were not significantly improved by prophylactic adenectomy. CONCLUSION : Differentiation, T-stage and age were prognostic factors for survival. The results support the EBU treatment strategy involving penis-conserving therapy and watchful waiting for early-stage disease.

5. Squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure?
Hoffman MA, Renshaw AA, Loughlin KR.
Cancer. 1999 Apr 1;85(7):1565-8.

BACKGROUND : Total or partial penile amputation is an effective treatment for invasive squamous cell carcinoma of the penis. The authors evaluated the relation between paraffin section microscopic pathologic margins and local recurrence. METHODS : Seventeen cases of biopsy proven squamous cell carcinoma of the penis treated with partial or total penectomy were reviewed retrospectively. All resections were performed by one surgeon (K.R.L.). Permanent microscopic pathologic margins and pathologic classification were determined by one pathologist (A.A.R.) using the American Joint Committee on Cancer TNM classification of 1997. RESULTS: Seven of the 10 patients who underwent a partial penectomy were followed for a mean duration of 33.1 months (range, 3-75 months). The average microscopic pathologic margin was 14.4 mm (range, 0-40 mm) for lesions classified as T1 or greater. Three patients had a microscopic margin < or=10 mm. There were no local or regional recurrences in this group of patients. The 7 patients who underwent a total penectomy were followed for a mean duration of 25.2 months (range, 5-76 months). There were no local recurrences and only one inguinal recurrence. The average microscopic pathologic margin was 14.8 mm (range, 0-50 mm) for all stages. There were 4 patients who had microscopic pathologic margins < or=10 mm, and all were free of local disease at the last follow-up. CONCLUSIONS: None of the 14 patients followed developed local recurrence. Also, no recurrence occurred in 7 patients who had microscopic margins of <or=10 mm. This suggests that local control can be obtained with margins measuring less than the standard 15-25 mm.

6. Squamous cell carcinoma of the penis. II. Treatment of the primary tumor.
Horenblas S, van Tinteren H, Delemarre JF, Boon TA, Moonen LM et al.
J Urol. 1992 Jun;147(6):1533-8.

The treatment of the primary tumor in 110 patients with squamous cell carcinoma of the penis seen between 1956 and 1989 was reviewed. Small tumors had generally been treated by penis conserving methods, such as circumcision, local excision and external radiotherapy alone or after circumcision or local excision. Since 1982 we have used the neodymium:YAG laser as a penis conserving method. In 51 patients (46%) penis conserving treatment had been performed and 59 (54%) had undergone some form of amputation. Overall, 16 of 110 patients (15%) had local recurrence. The risk of local recurrence after penis conserving therapy was significantly related to T category, with 10% local recurrences in stage T1 tumors in contrast to 32% and 100% in stages T2 and T3 tumors, respectively. All of the recurrences in patients with stage T1 tumors were strictly local and all were salvaged. In our view penis conserving therapy is a safe procedure in patients with stage T1 tumors and should always be attempted first. Amputation is considered to be overtreatment in these cases. Of 6 recurrences in the conservatively treated stage T2 disease group 4 were strictly local. These were all well or moderately differentiated tumors, not exceeding 3.5 cm. in diameter. We suggest penile conservation for this subgroup of T2 tumors. However, partial amputation is recommended for poorly differentiated stage T2 tumors. Local failure was observed in all stage T3 tumors treated with external radiation. In general, penis conservation in stage T3 tumors should not be attempted with the treatment modalities available to date. Comparing the different methods of penis conservation, used in 49 stages T1 and T2 tumors, no difference in local recurrence rate (18%) was observed among surgery, laser and external beam radiation. In view of the low morbidity, cutting and coagulation properties and minimal tissue changes, use of the neodymium:YAG laser would be our first choice of treatment modality. Penile conservation should be attempted only when frequent and long lasting followup is guaranteed, since local recurrences can appear as late as 8 years after primary treatment.

CARCINOMA PROSTATE

Introduction :

Prostate cancer is the commonest malignancy in males in the western world, comprising also one third of their cancer burden. However it is much less common in the developing countries including India. At the Tata Memorial Hospital, it constitutes only 2.4% of all cancers in males.

Investigations for local evaluation of prostate cancer :
Factors governing choice of imaging include serum PSA level, tumour grade, anticipated treatment and availability of imaging modalities. When radical treatment is contemplated, it is reasonable to perform radiological staging, which has been shown to be superior to clinical staging.

Diagnostic and staging methods :
The main purpose of investigations is to get histological confirmation of prostate cancer and to stage the disease. The local stage of the disease (organ confined vs. non-organ confined) is the most important factor which decides therapy as well as prognosis.
1. Digital rectal Examination (DRE) : It is a simple and cost effective method having a positive predictive value (from 21% to 53%). It is a good staging method with a sensitivity of 52% and specificity of 80%. It can, however, underestimate (common) or overestimate the actual pathological stage.
2. Prostate Specific Antigen (PSA) : The normal values of PSA are <4 ng/ml. The appropriate threshold PSA level for detection of cancer of the prostate is 4.0 ng/ml. Clinically significant cancers are detected by PSA testing. If the PSA level is high, biopsy of the prostate may be recommended. Some men with prostate cancer have PSA results less than 10. About 25% of men with cancer will have a normal or low PSA. Therefore a combination of PSA & DRE as complementary investigations to guide biopsy is recommended.

<4 : Normal (1 in 50 may still harbour cancer)
4-10 : Intermediate (1 in 4 will have cancer)
>10 : Abnormal (2 in 3 will have cancer)

PSA estimation can also help as a guide to stage of prostate cancer. Serum PSA <10 ng/ml indicates a low risk of periprostatic spread and metastases. An increased risk of periprostatic spread, seminal vesicle involvement and even distant metastases exists when serum PSA >20 ng/ml. As a general guide, PSA >10 ng/ml indicates capsular penetration in more than 50% patients while PSA >50 ng/ml is usually associated with metastatic disease.
PSA is prostate specific and not cancer specific and may be raised in noncancerous conditions like BPH, prostatitis, tuberculosis etc, especially when the PSA is in the normal or borderline zone of 4-10 ng/ml.

3. Transrectal Ultrasound (TRUS) gives excellent resolution for detection of prostatic nodules and aids in biopsy. It gives about 60% sensitivity for differentiation between organ confined disease and extraprostatic extension. In the absence of MRI, it can be used for local staging of prostate cancer.

4. Computed Tomography is done mainly to document the retroperitoneal lymphadenopathy, especially in patients with high risk of nodal metastasis i. e. T3, T4 disease, PSA > 20 ng/ml, high Gleason score etc and may identify advanced disease.

5. MRI currently offers the most accurate and complete assessment of local disease and its spread. MRI with endorectal coil and MR spectroscopy can give an excellent delineation of the prostate gland. It has a reported accuracy of 85-90% for differentiating between organ-confined disease and extraprostatic spread. It gives excellent information about seminal vesicles involvement and retroperitoneal lymphadenopathy.

6. Isotope Bone Scan may be done in all patients to document presence or absence of skeletal metastases. The present evidence suggests that it may not be mandatory to perform an isotope bone scan if the PSA is less than 20 ng/ml and there is absence of bone pain, since the positive yield in such cases is extremely low.

7. Prostatic biopsy : A biopsy is the only way prostate cancer can be diagnosed. Patients with abnormal PSA results and/or suspicious DRE are recommended to undergo prostate biopsy. The standard sextant technique of needle biopsy uses a transrectal approach under ultrasound guidance (TRUS). More number of cores may be needed if hypoechoeic and/or suspicious lesions are present especially in large prostates. Prostatic biopsy should be repeated in patients with normal histology but suspicious DRE or persistently elevated/rising serum PSA. Biopsy at additional sites including lesion directed biopsies, lateral peripheral zone biopsies and mid zone biopsies etc. may also increase the diagnostic yield. Biopsy finding of high-grade prostatic intraepithelial neoplasia (PIN grades 2 and 3) and invasive prostate cancer necessitates further investigations in patients who are candidates for radical treatment of localized prostate cancer.

8. Pelvic lymph node dissection : This remains the most accurate method of assessing nodal metastasis. However, patients with low risk disease (PSA < 10ng/ml, Gleason’s score < 7 and stage T1c disease) have less than 5% chance of having positive lymph nodes. As such, only high-risk patients with stage T3c or node-positive disease should be recommended for pelvic lymph nodes dissection before definitive treatment for localized prostate cancer. Laparoscopic pelvic node dissection is equally effective.

9. Seminal Vesicle Biopsy : This is not routinely recommended, as it does not add significantly to the combination of clinical staging, PSA and Gleason score, which predicts the incidence of seminal vesicle involvement to an acceptable degree.

10. PET scan : PET scanning is being increasingly used to detect recurrences post treatment. Methionine PET of the prostate with short dynamic scanning and multicore biopsy is a useful method to ensure a high detection rate of prostate cancer in patients with increased PSA and repeat negative biopsies.

Pathology :
Histological diagnosis of prostate cancer is mandatory before starting therapy, even if there is overriding evidence of advanced carcinoma of the prostate. Targeted, sextant or extended biopsies may be done, usually by the transrectal route and the biopsies should be separately labeled and sent to the pathologist. The biopsy specimens should be reported as per the published standard reporting guidelines for reporting prostatic specimens. Extensive sampling of all biopsy cores or TUR chips will yield a higher proportion of unsuspected cancers than restricted sampling. The number of cores involved by tumour and the percentage of each core involved may influence treatment and should be carefully recorded.

In the radical prostatectomy specimen, the following factors need to be reported:

• Presence of adenocarcinoma
• Tumour grading
• Gleason score
• Volume and mapping of the cancer
• Capsular infiltration
• Margin positivity especially at apex, bladder neck and limits
• Seminal vesicle involvement
• Presence of concomitant PIN
• Vascular, lymphatic or perineural invasion
• Lymph node metastases

Staging of prostate cancer
Primary tumor (T)

* [Note : Tumor found in 1 or both lobes by needle biopsy, but not palpable or reliably visible by imaging is classified as T1c.]
** [Note : Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.]

Regional lymph nodes (N)

Treatment Guidelines :

Management of high grade prostatic intraepithelial neoplasia (PIN)
The presence of high grade PIN on biopsy is in itself not an indication for treatment but requires careful follow-up and early re-biopsy to rule out invasive cancer. With the increase in prostatic biopsies in recent years, the presence of PIN is being more frequently reported. Although high grade PIN indicates a higher predisposition to the development of invasive cancer, the natural history of PIN is uncertain and hence the evidence at the present time does not warrant early treatment of high grade PIN.

Management of invasive prostatic cancer
Invasive prostate carcinoma can be divided into :
1) Organ confined disease (early prostate cancer)
2) Locally advanced disease
3) Loco-regionally advanced disease
4) Metastatic disease

Options for Organ confined prostate cancer :

• Surveillance/ Watchful waiting
• Radical prostatectomy
• Radical radiotherapy
         * External beam / 3D Conformal / IMRT
         * Brachytherapy

All patients considered fit for radical therapy must be counseled regarding the options. The data from the available literature does not allow us to draw any valid conclusions regarding the optimum treatment for localized prostate cancer. A recent SEER database analysis has confirmed the need for a randomized trial to compare the three options. The only fact that is known is that patients of poorly differentiated tumours have better survival when treated with radical prostatectomy or radical radiotherapy as compared to surveillance. The choice of treatment should be made on the basis of clinical efficacy (there is no evidence of superiority of one modality over the other), biological potential of the cancer, the morbidity of treatment, the age and life expectancy of the patient and the patient’s own perceptions and wishes.

In a patient with localized prostate cancer with a life expectancy more than 10 years, it appears reasonable to offer radical prostatectomy or radical radiation therapy. However, these patients who are young are the ones in whom the complications of treatment may lead to impaired quality of life and hence in these patients too, surveillance remains a justifiable approach in some. The patients need to be counseled regarding the early and late sequelae and complications of treatment prior to therapy.

Surveillance
Ideal candidate for surveillance are patients with low-volume, low-grade prostatic carcinoma and elderly patients with limited life expectancy. The absence of complications related to radical local therapy and the minimal costs involved are the potential benefits of surveillance in these patients. Overall survival of patients with clinically localized prostatic carcinoma were not statistically different from the life-table probability for men of similar age group. Of those under expectant management for more than 10 years of follow-up, the cause of deaths was not prostatic carcinoma. Surveillance alone has been shown to achieve comparable results with other treatment modalities namely conventional external beam radiotherapy and radical surgery. Most series achieve 80-90% 10-year survival rates after excluding deaths from intercurrent diseases. The absence of complications compared to conventional radiotherapy or radical surgery and the minimal costs involved are the potential benefits of surveillance. Follow-up assessment includes 6 monthly consultation with routine DRE and serum PSA. Prostatic biopsy and bone scans may be done as indicated. In patients with low grade tumours selected for surveillance, the rate of development of metastases during surveillance is 2.1%/year as opposed to 14% with high grade tumours. PSA surveillance is recommended as post-primary treatment follow-up of localized disease. The doubling time of PSA of less than 6 months post-treatment may suggest systemic progression.

Radical prostatectomy (RP) :
Surgical removal of the prostate is recommended at most centres for the management of organ confined prostate cancer in men with a good life expectancy. Besides being curative due to complete removal of cancer, it gives a more accurate pathological staging and allows better planning for adjuvant therapy. The results of non-randomized retrospective reviews showed that 10 and 15 years actuarial survivals are 10-15% better after surgery than radiation or surveillance, particularly for the high-risk group. The risk of incontinence should be less than 5% in specialized centres and impotence may be prevented by the technique of nerve sparing radical prostatectomy in suitable patients.

Neoadjuvant hormone therapy prior to radical prostatectomy or adjuvant radiation therapy &/or hormone therapy has not made an impact on survival in patients with low risk early prostate cancer.

Post radical prostatectomy follow up :
- Serum PSA estimation: 4-6 weeks post RP, 6 monthly for 10 years, then every year.
- DRE : every visit.
- Bone scans, CT scans and prostate bed biopsy : options for salvage work up.

Radiation therapy (RT) :
RT can be used as a curative modality of treatment in patients with early stage prostate cancer. There are no significant randomized trials comparing the efficacy of radical radiation therapy with radical surgery and the published comparisons are flawed in terms of patient selection criteria, differences in staging and variation in the radiation techniques. However, recent data suggests that progression free and overall survival rates are similar to those of radical prostatectomy when more comparable patients are studied. Although the long-term results of radiation therapy are similar to radical prostatectomy, the true incidence of local control may be lower in patients undergoing radiation therapy. Routine inclusion of the pelvic nodes in the radiation field has not shown any significant benefit in terms of local control or survival.

Data from published literature shows that dose escalation can be safely carried out with 3D-CRT and IMRT with possible improvement in freedom from progression in patients with high grade clinically localized carcinoma of the prostate. Androgen deprivation prior to radiation therapy may have a role in improving results of radiation therapy but the type of androgen deprivation and its duration remains to be established.

Adjuvant therapy : The Early Prostate Cancer Program randomised trial of adjuvant bicalutamide vs no adjuvant treatment in patients with localised prostate cancer managed by radical prostatectomy, radiation therapy or surveillance demonstrated a significant reduction in the risk of recurrence and progression. These results need to be confirmed in other trials before incorporating into routine clinical practice.
Interstitial brachytherapy : Tumors, which can be completely encompassed by the implant high-dose volume may be treated with brachytherapy alone. It is not recommended for patients with locally advanced disease, PSA>10 and high Gleason score. There are no randomized trials or large prospective studies comparing the clinical effectiveness of brachytheapy with radical prostatectomy or radiation therapy. The limited data available in the literature suggests that it may be a reasonable alternative in patients with low risk low volume T2 disease, especially in elderly patients (freedom from biochemical relapse of 60 to 70%). It may also be used in conjunction with external beam radiation therapy in patients with intermediate and high-risk patients with localized prostate cancer. Usually ultrasound guided seed implantation with 125 I or Au seeds is done. Recent trials has shown fractionated HDR brachytherapy to be comparable to permanent implants.

Options for loco-regionally advanced prostate cancer :
1) Watchful waiting- Elderly patients with limited life expectancy
2) Neoadjuvant hormone therapy followed by Radiation therapy
3) Neoadjuvant hormone therapy followed by Radical prostatectomy
4) Hormonal therapy alone

Neoadjuvant or adjuvant hormone therapy should be considered for patients with locally advanced disease who are to be treated with a local therapy.

Radiation therapy related treatment approaches appear to be best suited for this group of patients. Radiation therapy will produce long-term clinical control in many patients but long-term biochemical control is poor and a high proportion of patients will go on to develop metastatic disease. The introduction of neoadjuvant hormonal therapy has been shown, in randomized studies, to improve clinically and biopsy judged local control of disease but no impact on survival has yet been observed. Adjuvant hormone therapy starting at the beginning or end of radiotherapy and continuing for three years or more has been reported to give a significant advantage in local and biochemical disease control with a reduction in the risk of development of metastatic disease at 5 years. Survival advantage has been reported in 2 randomized trials (EORTC & RTOG) and this approach is generally recommended.

Neoadjuvant hormone therapy followed by radical prostatectomy has been advised by some. This approach, though technically feasible in patients with minimal periprostatic spread, causes downsizing of the tumour, higher resectability and reduction in positive surgical margins, but has not been shown to have any impact on survival. In view of this, this approach remains largely experimental.

Recent MRC trial has shown a significant survival advantage for patients treated with immediate versus delayed hormonal therapy.

Management of biochemical relapse after radical local therapy :
Patients with biochemical relapse after radical local therapy need to undergo DRE, PSADT, TRUS, isotope bone scan and CT scan of abdomen+pelvis to document the site of relapse (local or systemic), if possible.

PSA relapse after radical radiation therapy: Biochemical failure after radiation therapy is defined as 3 consecutive rises in PSA, with levels obtained at 3 monthly intervals for the first two years after radiation and 6 monthly thereafter (ASTRO guidelines). Clinical relapse will eventually follow PSA failure, sometimes after many years. There is evidence that the timing of PSA failure after radiation and the PSA doubling time (PSADT) may be particularly useful in planning further treatment. Symptomatic clinical relapse typically occurs about 40 months after PSA failure. PSA failure within a year of radiation, with PSADT <8 months, there is 50% chance of metastatic disease at 3 years. The pattern of recurrence after biochemical failure correlates with PSADT – if PSADT of <6 months is associated with metastatic disease while longer PSADT is associated with local relapse.

Options of treatment after PSA failure :

• Wait and watch
• Immediate hormone therapy
• Salvage radical prostatectomy in a small group of patients with stage T1-2 cancers prior to radiation therapy, life expectancy >10 years, PSA <20 ng/ml, PSADT >1 year and PSA failure more than 1 year after radiation therapy
• Experimental therapies : Cryotherapy, PDT, brachytherapy etc.

Biochemical failure after radical prostatectomy: Biochemical failure after radical prostatectomy is defined as 0.04 ng/ml. The role of radiation therapy in patients with biochemical relapse is unclear. Although response is noted in some patients, there is no evidence as yet of survival benefit.

Guidelines for N+ Prostate Cancer: Patients who are diagnosed as having metastatic lymph nodes at radical prostatectomy may benefit from radical prostatectomy in addition to hormone therapy – either orchiectomy or medical castration. Survival benefit has been demonstrated by proceeding with radical prostatectomy with micrometastases in pelvic nodes in non-randomised trials. Patients with gross nodal metastases are treated as per the guidelines for metastatic disease.

Treatment of metastatic prostate cancer :
Hormone therapy is indicated in all patients with metastatic prostate cancer and should be offered early to all patients with symptomatic metastatic disease. The response rate to hormone therapy in patients with metastatic disease is 85%, with median duration of response of 18 months and median survival of 36 months. Patients starting hormone therapy should be offered a choice between orchiectomy or LH-RH analogues (monthly injections or 3 monthly depot preparation + antiandrogen for at least 3 days before and 2 months after the initiation of treatment to block flare) as the first line therapy.

Subcapsular or total orchiectomy are therapeutically equivalent although the former may be more acceptable to patients. There is no difference in efficacy between orchiectomy and LH-RH analogues nor between different preparations of LH-RH analogues. In patients who wish to preserve their potency, monotherapy flutamide, although not as effective as castration or LH-RH analogues may be prescribed.

Combined androgen blockade : The data regarding the use of CAB are conflicting. The meta-analysis of 22 randomised published trials suggests that CAB confers no significant survival benefit over and above that produced by monotherapy. The benefits of CAB are unlikely to be greater than 1-2% improvement in survival. It may be indicated to prevent flare phenomenon in the first month of LH-RH agonist therapy, in patients with severe symptoms and as second line therapy.

Intermittent androgen suppression is currently experimental and investigational, although encouraging results have been reported in phase II trials.

Timing of hormonal therapy (early vs. delayed): When the patients have symptoms secondary to metastatic disease, hormonal manipulation should be commenced immediately. In patients with asymptomatic metastatic disease, there is no consensus regarding the initiation of hormonal therapy. Most clinicians would consider immediate treatment appropriate but the MRC trial showed no clear survival advantage for patients with M1 disease receiving immediate treatment. Deferred treatment should only be considered after careful assessment of the patient. It is an option for elderly patients with low volume disease. These patients should be kept under close surveillance. The relative contraindications for deferred therapy are:

a. Patients with substantial metastases which predispose to pathological fracture or spinal cord compression
b. Patients without specific symptoms
c. Systemic manifestations of the disease
d. Poor patient compliance

The recently published NCI trial reported that early androgen deprivation improves local and distant disease control with no survival benefit. Another large MRC randomized study on early vs deferred hormonal therapy reported improvement in the local and distant disease control in stage M0 and M1 cases with survival benefit seen only in stage M0 group. However, patients with early hormonal deprivation exposes patients to longer duration of hormone associated toxicity including osteoporosis.

Second line therapy in patients who progress after adequate initial hormone therapy. The criteria of progression are :

• Increase in the size of measurable lesions or the appearance of new measurable lesions
• Increase in PSA levels of at least 50% on 2 consecutive measurements at least 2 weeks apart
• Increase in pain associated with new bony lesions
• Combination of above

Second line therapy is not curative and has not shown survival benefit. The median survival of patients is less than 1 year following relapse.The end point of treatment is palliation of symptoms. The selection of second line treatment depends on prior treatment, site of recurrence, co-existent illness, toxicity of therapy and patient preference.

For patients who are using only LH-RH agonist or oestrogen as primary therapy, whose plasma testosterone level is not below castration level, adding an antiandrogen is useful. If the testosterone levels are in the castrate range, indefinite use of LH-RH agonist may be beneficial. For patients who are using antiandrogens or CAB, antiandrogen withdrawl is the preferred approach and in 25% of patients, PSA levels reduce to normal or near normal range. Whether continuation of LH-RH analogues in the presence of relapse is beneficial or not is not proved by evidence.

Other treatment options like addition of a second antiandrogen, adrenal androgen inhibitors, ketoconazole, prednisolone, oestrogens, chemohormonal therapy like estramustine or chemotherapy like mitoxantrone, doxorubicin, paclitaxel, docetaxel etc., growth factor inhibitors like suramin etc. Ketoconazole produces durable response in more than 25% patients with hormone refractory prostate cancer. Recent trials of chemotherapy have shown a survival benefit of docetaxel based chemotherapy and this has now been accepted as the new standard of care.

Treatment of osseous metastases :
1. Surgical Intervention

• Pathological fracture of weight bearing bones in patients with reasonable life-expectancy
• Decompressive surgery in spinal cord compression

2. Radiation therapy

• External beam radiation therapy for painful or unstable skeletal metastases : A single fraction of 8 Gy will relieve pain in over 70% of patients. Fractionated RT for bone metastases may be considered in patients with spinal cord compression or bone-only disease.
• Hemibody radiation in patients with multiple symptomatic skeletal metastases (8 Gy for UHBI & 6 Gy for LHBI).
• Systemic radionuclide therapy : Radioisotopes like Strontium89 and Samarium153 may improve bone pains in upto 70% patients

3. Bisphosphonates (Zoledronic Acid) : Has been shown to reduce bone pains and skeletal-related events including fractures in randomized trials.

1. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men.
Catalona WJ, Richie JP, Ahmann FR, et al.
J Urol. 1994 May;151(5):1283-90.

To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandem-E or Tandem-R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 micrograms/l or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 micrograms/l, 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p=0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p=0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 micrograms/l or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings.

2. Bone scan and prostate cancer
Letaief B, Boughattas S, Hassine H, Essabbah H.
Ann Urol (Paris). 2000 Aug;34(4):254-65.

Prostatic cancer has a great predilection for bone. The evaluation of its extension towards the skeleton is based on the bone scan, which has a better sensitivity than radiological examinations and clinical evaluation. Bone scan evaluation of the osseous extension, allowed a better comprehension of the mechanism of dissemination, the assumption of Batson appearing currently not very plausible. The importance of the osseous extension on the bone scan has a prognostic value; it constitutes one of the significant parameters of stratification in clinical trials. The indications of bone scan have been greatly modified since the introduction of prostate-specific antigen (PSA). At the initial assessment, the of bone scan should be indicated only if the rate of PSA exceeds 10-20 ng/mL, in the event of low grade tumor and pain. In the follow-up, the evolution of the PSA constitutes the major element of monitoring. After radical therapy, a rise in the PSA indicates bone scan, particularly if the level exceeds 10 ng/mL. In stage D2, routine bone scan is no longer indicated, except in phases II and III of the clinical trials.

3. The positive yield of imaging studies in the evaluation of men with newly diagnosed prostate cancer: a population based analysis.
Albertsen PC, Hanley JA, Harlan LC, et al.
J Urol. 2000 Apr;163(4):1138-43.

PURPOSE : We determine the positive yield of imaging studies performed on men with newly diagnosed prostate cancer. MATERIALS AND METHODS : A prospective, population based survey was conducted on 3,690 men with prostate cancer diagnosed between October 1, 1994 and October 31, 1995. Cases were identified by the rapid case ascertainment systems used in 6 geographic regions participating in the Surveillance, Epidemiology and End Results Program. Based on information captured in primary medical record reviews we estimated the positive yield of bone scans, computerized tomography (CT) and magnetic resonance imaging. RESULTS: The positive yield of bone scan and CT was less than 5% and 12%, respectively, for all men with prostate specific antigen (PSA) 4 to 20 ng./ml., and less than 2% and 9%, respectively, for those who also had a Gleason score of 6 or less. Only men with PSA greater than 50 ng./ml. and those with Gleason scores 8 to 10 and PSA greater than 20 ng./ml. had positive yields greater than 10% and 20% for bone scan and CT, respectively. CONCLUSIONS : Imaging studies designed to identify metastases and/or extracapsular extension in men with newly diagnosed prostate cancer frequently have a low positive yield. Wide variations exist in the use of imaging studies and are associated with tumor factors, such as Gleason score and serum PSA, and nontumor factors, such as state of residence. More extensive cost-effectiveness analyses are needed to define appropriate guidelines for ordering imaging studies to optimize the positive yield among men with newly diagnosed prostate cancer.

4. Detection of prostate cancer with 11C-methionine positron emission tomography.
Toth G, et al
J Urol. 2005 Jan;173(1):66-9.

We studied the detection of primary prostate cancer with positron emission tomography (PET) using C-labeled methionine (MET) in patients withincreased prostate specific antigen (PSA) levels and repeatedly negativebiopsies. A total of 20 consecutive patients with increased serum PSA and negative repeat biopsies were included in the study. Patient age ranged from 52 to 75 years (average 65). PSA levels ranged from 3.49to 28.6 ng/ml (average 9.36). Dynamic PET images were obtained from the prostate region using C-labeled MET. Suspicious accumulations of the tracer were anatomically localized using magnetic resonance images and were used as guidance during the next biopsy. PET was positive in 15 (75%) patients, in 7 of whom (46.7%) the next repeat biopsy verified carcinoma. The overall detection rate was 35% (7 of 20) and 46.7% (7 of 15) in the whole group and in the positive PET group, respectively. All 5 of 5 patients with negative MET PET had negative biopsies. MET PET of the prostate with short dynamic scanning and multicore biopsy is a useful method to ensure a high detection rate of prostate cancer in patients with increased PSA and repeat negative biopsies.

5. Effect of peripheral biopsies in maximising early prostate cancer detection in 8-, 10- or 12-core biopsy regimens.
Philip J, Ragavan N, Desouza J, Foster CS, Javle P.
BJU Int. 2004 Jun;93(9):1218-20.

OBJECTIVE : To assess the cancer detection rate per individual core biopsy in a 12-core protocol and develop an optimal biopsy regimen for detecting early prostate cancer. PATIENTS AND METHODS : The study included 445 new patients who had a 12-core transrectal ultrasonography (TRUS)-guided prostatic biopsy over a 40-month period. The 12- core biopsy protocol included parasagittal sextant and six peripheral biopsies. The cancer detection rate per individual core was evaluated to give an optimal biopsy protocol. RESULTS : Prostate cancer was detected in 142 patients (31.9%). Parasagittal sextant biopsy would have failed to detect 40 (28.2%) of the cancers. Among the various possible biopsy protocols, the optimum 10-core biopsy strategy excluding the parasagittal mid-zone biopsies from the 12-core protocol achieved a cancer detection rate of 98.6%. CONCLUSION: The cancer detection rate increased from 71.8% for parasagittal sextant biopsies to 88.7% by adding peripheral basal biopsies (8-biopsy protocol); 98.6% of cancers in the series would have been detected with a 10-biopsy strategy omitting the parasagittal mid-zone biopsies. Thus we recommend a 10-core protocol incorporating six peripheral biopsies in patients with elevated age- specific prostate-specific antigen levels (2.6-10.0 ng/mL) for maximising cancer detection.

6. Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer.
Peschel RE, Colberg JW.
Lancet Oncol. 2003 Apr;4(4):204-5.

Patients diagnosed with early prostate cancer after 2000 can expect better outcomes from treatment than patients who were diagnosed in the 1980s and early 1990s. These improved outcomes are the result of stage migration, new technologies such as three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated external-beam radiotherapy (IMRT), better implant techniques, and optimum use of hormone therapy. We review the outcomes for radical prostatectomy, permanent seed implant, 3DCRT, and IMRT. For patients with clinical stage T1c or T2 disease and a Gleason score of less than 8, 5-year biochemical disease-free survival is remarkably similar for all the above treatments. Furthermore, complication rates are acceptable for all these modalities. For patients with bulky T2-3 disease or a Gleason score of 8-10, hormone therapy plus 3DCRT or IMRT is an excellent treatment choice. Studies of radical prostatectomy show the most reliable long-term results, and the studies of external-beam radiotherapy have used the best scientific methods to assess efficacy. On the basis of current data, we recommend specific treatment options.

7. Long-term results of a randomized trial for the treatment of Stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities.
Akakura K, Isaka S, Akimoto S, et al
Urology. 1999 Aug;54(2):313-8.

OBJECTIVES : To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. METHODS : One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. RESULTS : The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression-free and cause-specific survival rates (P=0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. CONCLUSIONS : Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity.

8. Immediate treatment with bicalutamide 150mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer.
See W, Iversen P, Wirth M, McLeod D, Garside L, Morris T.
Eur Urol. 2003 Nov;44(5):512-7

OBJECTIVE : To evaluate the effect of bicalutamide (‘Casodex’) 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer. METHODS : The bicalutamide 150mg Early Prostate Cancer (EPC) programme is the largest clinical trial programme in the treatment of prostate cancer to date. This paper reports the PSA progression data from the EPC programme at a median of 3years’ follow-up, for the overall study population, and across the radical prostatectomy and radiotherapy primary therapy strategies. PSA progression was predefined as the earliest occurrence of PSA doubling from baseline, objective progression, or death from any cause. RESULT : Overall, bicalutamide 150 mg in addition to standard care significantly reduced the risk of PSA progression by 59% compared with standard care alone (HR 0.41; 95% CI 0.38, 0.45; p<<0.0001). Significant reductions were observed following radical prostatectomy (51%; HR 0.49; 95% CI 0.43, 0.56; p<<0.0001) and radiotherapy (58%; HR 0.42; 95% CI 0.33, 0.53; p<<0.0001). Further exploration of the data by disease stage, nodal status, Gleason score and pre-treatment PSA level revealed significant reductions in the risk of PSA progression across most prognostic risk factor subgroups. CONCLUSIONS : Bicalutamide 150mg significantly reduces the risk of PSA progression, irrespective of whether patients received radical prostatectomy or radiotherapy as standard care. The EPC programme is ongoing and further progression and survival data are awaited.

9. Brachytherapy for prostate cancer: summary of American Brachytherapy Society recommendations.
Nag S.
Semin Urol Oncol. 2000 May;18(2):133-6.

This article summarizes recent American Brachytherapy Society (ABS)recommendations for permanent prostate brachytherapy. The ABS recommends treating patients with high probability of organ-confined disease with brachytherapy alone. Brachytherapy candidates with a significant risk of extraprostatic extension should be treated with supplemental external beam radiation therapy (EBRT). The recommended prescription doses for monotherapy are 145 Gy for (125)I and 125 Gy for (103)Pd. The corresponding boost doses (after 40 to 50 Gy EBRT) are 110 Gy and 100 Gy, respectively. The ABS recommends that post-implant dosimetry should be performed on all patients undergoing permanent prostate brachytherapy for optimal patient care. A dose-volume histogram (DVH)of the prostate should be performed and the D(90) (dose to 90% of the prostate gland) reported by all centers. Additionally, the D(80) D(100), the fractional V(80), V(90), V(100), V(150), V(200) (ie, the percentage of prostate volume receiving 80%, 90%, 100%, 150%, and 200% of the prescribed dose, respectively), the rectal and urethral doses should be reported and ultimately correlated with clinical outcome in the research environment. On-line, real-time dosimetry, the effects of dose heterogeneity, and the effects of tissue heterogeneity need further investigation.

10. Treatment margins predict biochemical outcomes after prostate brachytherapy.
Choi S, Wallner KE, Merrick GS, Cavanagh W, Butler WM.
Cancer J. 2004 May-Jun;10(3):175-80

PURPOSE : Due to the theoretical role of treatment margins (TMs) in cancer, we have correlated biochemical outcomes with post-implant TMs in patients treated with brachytherapy for early stage prostate cancer. METHODS : From November 1998 through September 2003, 492 of a planned total of 600 patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma (Gleason score 5 or 6, PSA 4 to 10 ng/mL) have been randomized to implantation with (125)I (144 Gy, TG-43) versus (103)Pd (125 Gy, NIST-99). This preliminary analysis included only the first 122 analyzable patients, while accrual to the trial finishes. Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. Axial CT images at 3 mm intervals were acquired within four hours postoperatively for post-implant dosimetry. The contoured images and sources were entered into Varian Variseed system 7.1 (Charlottesville, VA). After completion of standard dosimetric calculations, the 100% prescription dose TMs were measured and tabulated around the prostate periphery at the 0.0, 1.0, 2.0 and 3.0 cm planes, going distal from the bladder-prostate interface. Measurements were limited to the transverse planes. Freedom from biochemical failure was defined as a serum PSA < or=0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Patients whose serum PSA nadired at a value >0.5 ng/mL were scored as failures at the time at which their PSA nadired. The follow-up period for non-failing patients ranged from 2.1-5.0 years (median: 3.3 years). RESULTS : The average 100% prescription dose treatment margin (for individual patients) ranged from -5.0 to 8.7 mm, with an overall average of 2.6 mm (+/-3.1). In univariate analysis, the D(90) was the best predictor of biochemical control for (125)I, while the average TM was the best predictor for (103)Pd. Similarly, in multivariate analysis using the D(90), V(100), and average TM as the independent variables and biochemical control as the dependent variable, the D(90) was most closely related to biochemical control for (125)I patients, while average TM was most closely related for (103)Pd patients. In separate analysis of TM by site, the anterior TMs were the best predictors of biochemical outcomes. CONCLUSION : V(100), D(90), and TMs all appear to have a bearing on biochemical freedom from relapse after prostate brachytherapy. Efforts to better identify and test geographic dosimetric parameters are theoretically appealing, and supported by the clinical data summarized here.

11. Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer.
Zelefsky MJ, Fuks Z, Happersett L, Lee HJ et al.
Radiother Oncol. 2000 Jun;55(3):241-9.

PURPOSE : To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS : Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale. RESULTS : Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001). CONCLUSIONS : The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.

12. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial.
D’Amico AV, Manola J, Loffredo M et al.
JAMA. 2004 Aug 18;292(7):821-7

CONTEXT : Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events. OBJECTIVE : To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer. DESIGN, SETTING, AND PATIENTS : A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n=104) or in combination with 6 months of AST (n=102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease. MAIN OUTCOME MEASURES : Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival. RESULTS: After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P=.04), lower prostate cancer-specific mortality (P=.02), and higher survival free of salvage AST (P=.002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survivalfree of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group. CONCLUSION : The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.

13. Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel.
Cox JD, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF.
J Clin Oncol. 1999 Apr;17(4):1155.

PURPOSE : To develop evidence-based guidelines for (1) prostate re-biopsy after radiation and (2) radiation therapy with rising prostate-specific antigen (PSA)levels after radical prostatectomy in the management of patients with localized prostatic cancer. DESIGN : The American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in each of the two topics. Four well-analyzed patient data sets were presented for review and questioning by the panel. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. Subsequent to an executive session that followed these presentations, the panel presented its consensus guidelines. RESULTS AND CONCLUSIONS : Based on the data presented, the prostate re-biopsy negative rates ranged from 62% to 80% for patients with stage T1-2 tumors. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Further, the panel judged that re-biopsy may be an important research tool. Based on the data presented, the long-term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%. The panel requested results from prospective randomized trials to evaluate optimally this information. The panel judged that the total dose of radiation should be 64 Gy or slightly higher and that, in patients with or without radiation therapy, there is no standard role for androgen suppressant therapy for rising PSA values after prostatectomy.

14. The GETUG 70 Gy vs. 80 Gy randomized trial for localized prostate cancer: feasibility and acute toxicity.
Beckendorf V, Guerif S, Le Prise E, et al
Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1056-65.

PURPOSE : To describe treatments and acute tolerance in a randomized trial comparing 70 Gy and 80 Gy to the prostate in patients with localized prostate cancer. METHODS AND MATERIALS : Between September 1999 and February 2002, 306 patients were randomized to receive 70 Gy (153 patients) or 80 Gy (153 patients) in 17 institutions. Patients exhibited intermediate-prognosis tumors. If the risk of node involvement was greater than 10%, surgical staging was required. Previous prostatectomy was excluded, and androgen deprivation was not admitted. The treatment was delivered in two steps. PTV1-including seminal vesicles, prostate, and a 1-0.5-cm margin-received 46 Gy given with a 4-field conformal technique. PTV2, reduced to prostate with the same margins, irradiated with at least 5 fields. Dose was prescribed according to ICRU recommendations in the 70 Gy group, but adapted at the 80 Gy level. RESULTS : All patients but one in the 80 Gy arm completed the treatment. In the 70 Gy arm, the mean dose to the PTV2 was 69.5 Gy. In the 80 Gy arm, the mean dose in the PTV2 was 78.5 Gy. Acute toxicity according to Radiation Therapy Oncology Group scale during treatment was reported in 306 patients. There was no statistically significant difference between the two arms: 12% had no toxicity, 80% complained of bladder toxicity, and 70% complained of rectal symptoms. Two months after the end of treatment, 43% of the 70 Gy level and 48% of the 80 Gy level complained of side effects, including 24% and 20% of sexual disorders. There was 6% and 2% of Grade 3 urinary and rectal toxicity. Five patients required a 10-29-day suspension of the treatment. Acute Grade 2 and 3 side effects were related to PTV and CTV1 size, which was the only independent predictive factor in multivariate analysis. Toxicity was not related to the center, age, arm of treatment, or selected data from dose-volume histogram of organ at risk. CONCLUSION: Treatments were completed in respect to constraints. Acute toxicity was acceptable. Intensity of toxicity depended on target volumes.

15. A systematic overview of radiation therapy effects in prostate cancer.
Nilsson S, Norlen BJ, Widmark A.
Acta Oncol. 2004;43(4):316-81.

A systematic review of radiation therapy trials in prostate cancer has been performed according to principles adopted by the Swedish Council of Technology Assessment in Health Care (SBU). This synthesis of the literature is based on data from one meta-analysis, 30 randomized trials, many dealing with hormonal therapy, 55 prospective trials, and 210 retrospective studies. Totally the studies included 152,614 patients. There is a lack of properly controlled clinical trials in most important aspects of radiation therapy in prostate cancer. The conclusions reached can be summarized as follows :* There are no randomized studies that compare the outcome of surgery (radical prostatectomy) with either external beam radiotherapy or brachytherapy for patients with clinically localized low-risk prostate cancer. However, with the advent of widely accepted prognostic markers for prostate cancer (pre-treatment PSA, Gleason score, and T-stage), such comparisons have been made possible. There is substantial documentation from large single-institutional and multi-institutional series on patients with this disease category (PSA < 10, GS < or=6, < or=T2b) showing that the outcome of external beam radiotherapy and brachytherapy is similar to those of surgery.* There is fairly strong evidence that patients with localized, intermediate risk, and high risk (pre-treatment PSA > or = 10 and/or GS > or=7 and/or > T2) disease, i.e. patients normally not suited for surgery, benefit from higher than conventional total dose. No overall survival benefit has yet been shown.* Dose escalation to patients with intermediate-risk or high-risk disease can be performed with 3D conformal radiotherapy (photon or proton) boost, with Ir-192 high dose rate brachytherapy boost, or brachytherapy boost with permanent seed implantation. Despite an increased risk of urinary tract and/or rectal side effects, dose-escalated therapy can generally be safely delivered with all three techniques.* There is some evidence that 3D conformal radiotherapy results in reduced late rectal toxicity and acute anal toxicity compared with radiotherapy administered with non-conformal treatment volumes.* There is some evidence that postoperative external beam radiotherapy after radical prostatectomy in patients with pT3 disease prolongs biochemical disease-free survival and that the likelihood of achieving long-term DFS is higher when treatment is given in an adjuvant rather than a salvage setting. A breakpoint seems to exist around a PSA level of 1.0 ng/mL, above which the likelihood for eradication of the recurrence of cancer diminishes.* After prostatectomy, endocrine therapy prior to and during adjuvant radiotherapy may result in longer biochemical disease-free survival than if only adjuvant radiotherapy is given. No impact on overall survival has been shown.* There is fairly strong evidence that short-term endocrine therapy prior to and during radiotherapy results in increased disease-free survival, increased local control, reduced incidence of distant metastases, and reduced cause-specific mortality in patients with locally advanced disease.* There is some evidence that short-term endocrine therapy prior to and during radiotherapy results in increased overall survival in a subset (GS 2-6) of patients with locally advanced disease.* There is strong evidence that adjuvant endocrine treatment after curative radiotherapy results in improved local control, increased freedom from distant metastases, and increased disease-free survival in patients with loco-regionally advanced and/or high-risk disease.* There is moderately strong evidence that adjuvant endocrine treatment after radiotherapy results in longer overall survival compared with radiotherapy alone in patients with loco-regionally advanced disease.

16. The use of hormonal therapy with radiotherapy for prostate cancer: analysis ofprospective randomised trials.
Gottschalk AR, Roach M
Br J Cancer. 2004 Mar 8;90(5):950-4.

In 1901, Wilhelm Conrad Rontgen won the Nobel prize in Physics for his discovery of the Rontgen rays or, as he himself called them, X-rays. In 1966, Dr Charles Brenton Higgins won the Nobel Prize in Medicine for his breakthroughs concerning hormonal treatment of prostatic cancer. After 31 years, in 1997, the first prospective randomised trials of the combination of hormonal therapy and radiation therapy were published, showing increased survival when compared to radiation therapy alone for patients with prostate cancer. Since 1997, many investigators have published trials combining hormonal and radiation therapy for prostate cancer. This minireview will address the largest and most influential of these trials, and attempt to guide physicians in selecting the appropriate patients for this combined approach.

17. American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer.
Loblaw DA, Mendelson DS, Talcott JA, et al
J Clin Oncol. 2004 Jul 15;22(14):2927-41

PURPOSE : To develop a clinical practice guideline for the management of men with metastatic, recurrent, or progressive carcinoma of the prostate. The focus of this document is on the use, combinations, and timing of various forms of androgen deprivation therapy (ADT) for the palliation of men with androgen-sensitive disease. METHODS : An expert panel and writing committee were formed. The questions to be addressed by the guideline were determined, and a systematic review of the literature was performed, which included a search of online databases, bibliographic review, and consultation with content experts. A priori criteria were used to select studies for analysis and study authors were contacted when necessary. RESULTS : There were 10 randomized controlled trials, six systematic reviews, and one Markov model available to inform the guidelines. CONCLUSION : A full discussion between practitioner and patient should occur to determine which therapy is best for the patient. Bilateral orchiectomy or luteinizing hormone releasing hormone agonists are the recommended initial treatments. Nonsteroidal antiandrogen therapy may be discussed as an alternative, but steroidal antiandrogens should not be offered as monotherapy. Patients willing to accept the increased toxicity of combined androgen blockage for a small benefit in survival should be offered nonsteroidal antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.

18. Society of Urologic Oncology position statement: redefining the management of hormone-refractory prostate carcinoma.
Chang SS, Benson MC, Campbell SC, et al
Cancer. 2005 Jan 1;103(1):11-21.

Because patients with hormone-refractory prostate carcinoma are a very diverse group, management of these patients represents a unique challenge. Despite much research, to the authors’ knowledge few studies published to date have provided definitive treatment answers. The Society of Urologic Oncology (SUO) convened a multidisciplinary panel of urologists, oncologists, and radiation oncologists to develop a treatment algorithm for patients with hormone-refractory prostate carcinoma. The resulting treatment outline was based on a review of the literature review and on the expert opinions of the panelists. The current article provided a logical progression of treatment choices that included hormonal manipulations, chemotherapeutic options, and adjunctive therapies. Future clinical trials and therapies were also discussed by the authors. Management strategies should be targeted toward the individual patient. Although significant progress has been made in understanding and treating hormone-refractory prostate carcinoma, earlier interventions would be ideal and better therapeutic approaches to prolong survival are necessary.