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