• Gynaecological Cancers Guidelines
• Gynaecological Cancers Abstracts

Gynaecological Cancers Guidelines

EVIDENCE-BASED MANAGEMENT FOR GYNAECOLOGICAL CANCERS
[Cervix and Ovary]

CERVICAL CANCER

Pretreatment evaluation
1. Complete physical and gynecological examination.
2. CBC, Biochemistry and urine analysis, Chest X ray
3. Ultrasonography or CT Scan / MRI of abdomen and pelvis.
4. Biopsy- punch, knife, colposcopy guided or conization
5. Cystoscopy / Barium enema / sigmoidoscopy / IVU - if bladder, rectal or ureteric involvement is suspected

FIGO Staging of Carcinoma of cervix (1994)
(To be done jointly by Gynaecologic Surgical and Radiation Oncologists and may have to be supplemented by EUA)

Stage 0 Preinvasive carcinoma/ carcinoma in situ
Stage I Tumour confined to cervix.
IA1          Micro-invasive (diagnosed only under microscopy), no greater than 3 mm                depth and no wider than 7 mm.
IA2          <5mm below the basement membrane (BM) and <7mm in transverse                          dimension.
IB           >5mm below BM and >7mm wide invasive lesion but limited to cervix only.
IB1         <4 cm in size.
IB2         > 4 cm in size.

Stage II Tumour beyond uterus but not the lower 1/3 of vagina or
              up to the pelvic side walls.
IIA          without Parametrial invasion.
IIB          with Parametrial invasion.

Stage III Tumour extending upto pelvic wall, lower 1/3 vagina,
              hydro-nephrosis or non-functioning kidney.
IIIA          No extension to pelvic wall but involved lower 3rd vagina.
IIIB          Extension to pelvic side wall, hydronephrosis or non-functioning kidney.

Stage IV
IVA         Invasion of bladder and/or rectum.
IVB         Disease outside pelvis. Para-aortic nodes are regarded as distant                         metastasis.

TREATMENT OPTIONS

Stage 0 cervical cancer (Carcinoma in situ)

Extent of the disease is the most important factor in the treatment decision. The other factors that also influence the treatment decision include age of the patient, fertility preservation and other medical conditions.

Ectocervical lesions

• Loop electrosurgical excision procedure (LEEP).
• Laser therapy.
• Conization.
• Cryotherapy.

Endocervical canal involved

• Laser or cold-knife conization may be used for selected patients to preserve the uterus and avoid radiation therapy and/or more extensive surgery.
• Total abdominal or vaginal hysterectomy is an accepted therapy for the post-reproductive age group and is particularly indicated when the neoplastic process extends to the inner cone margin.
• For medically inoperable patients, a single intracavitary insertion to a dose of 8,000 cGy vaginal surface dose may be used1.

STAGE IA

Stage IA1: Micro-invasive (diagnosed only under microscopy), no greater than 3 mm depth and no wider than 7 mm.

Conization: In patients with IA1 disease if no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients wishing to preserve fertility2.

Total hysterectomy (abdominal or vaginal): In patients with IA1 lesion with no vascular or lymphatic emboli, the frequency of lymph node involvement is very low and hence lymph node dissection is not required. Ovaries can be preserved in young women2.

Intracavitary radiation alone: In IA1 lesions if no capillary lymphatic space invasion is noted, the frequency of lymph node involvement is sufficiently low that external beam radiation is not required. One or 2 intracavitary insertions may be considered up to a dose of 10,000-12,500 cGy vaginal surface dose in women who are not fit for surgery1.

Stage IA2: <5mm below the basement membrane (BM) and <7mm in transverse dimension.

Radical hysterectomy: For patients with tumor invasion 3 - 5mm and no lymphovascular space invasion.

Radical hysterectomy (type II) with pelvic node dissection: Has been recommended3 because of a reported risk of lymph node metastasis of up to 10% However, a study suggests that the rate of lymph node involvement in this group of patients may be much lower and questions whether conservative therapy might be adequate for patients believed to have no residual disease following conization4. Radical hysterectomy with node dissection may also be considered for patients where the depth of tumor invasion was uncertain due to invasive tumor at the cone margins.

Radiation Therapy: Radical intracavitary radiotherapy or intracavitary plus external pelvic irradiation may be considered in women who are not fit for surgery1.

STAGE IB and IIA
Similar cure rates are obtained with surgical and radiotherapeutic treatment approach for stage IB squamous carcinoma of the cervix5. The choice between initial surgical or radiotherapeutic management depends upon the age of the patient, desire to preserve ovarian function, co-morbid conditions, associated gynaecological conditions requiring surgery, facilities and expertise available and patients wish.

Stage IB1:

Radiation therapy: External-beam pelvic irradiation combined with intracavitary applications, which together delivers the dose of equivalent to 80Gy to point A.

Radical hysterectomy and bilateral pelvic lymphadenectomy.

Stage IB2 and IIA:

The treatment options include

• Radical Radiation therapy (External plus intracavitary).
• Radical hysterectomy (Type III) and bilateral pelvic lymphadenectomy
• Radiation therapy plus chemotherapy

Radical hysterectomy (type III) and bilateral pelvic lymphadenectomy involves removal of entire uterus, upper third vagina, bilateral parametria, uterosacral, utero-vesical ligaments and bilateral pelvic lymph nodes. Bilateral salpino-ooperectomy is discretionary.

Adjuvant therapy after radical surgery

High risk: Lymph node metastases, +ve surgical margins:
Adjuvant chemoradiation therapy with external pelvic radiation therapy with concurrent weekly cisplatin chemotherapy is recommended.

Intermediate risk: Deep invasion of cervical stroma, parametrial extension, lymphovascular space invasion:
Adjuvant radiation therapy is recommended.

Low risk: All other patients:
No adjuvant therapy recommended.

Stage IB1 and IIA: Radiation therapy
A combination of external-beam pelvic irradiation covering the uterus, parametria and pelvic nodes and intracavitary irradiation primarily for the central disease is used. The aim is to deliver a dose equivalent of 80Gy to point A.

External radiation: Using conventional fractionation, a dose is 40-50 Gy in 20-25 fractions over a period of 4-5 weeks is recommended. Use of four-field beam arrangement, corner shields and a special midline block (after 20Gy), helps in reducing the dose to rectum, bladder and small bowel during external radiation.

Intracavitary Brachytherapy: Brachytherapy plays a very important role in obtaining high cure rates with minimum complications. A good intracavitary insertion delivers a very high radiation dose to the cervix, upper vagina and medial parametria without exceeding the tolerance doses for rectum and bladder. All the randomized trials comparing low dose rate (LDR) with high dose rate (HDR) brachytherapy in carcinoma cervix have shown that the two modalities are comparable in terms of local control and survival6-8. Thus, either LDR or HDR brachytherapy may be used, taking into account the availability of equipment and other logistics of treatment delivery. HDR brachytherapy can be done as a day procedure in contrast to approximately 20 hours of continuous LDR treatment requiring overnight inpatient stay. However, due to radiobiological considerations, 5 applications of HDR are required in contrast to 2 applications of LDR (for stage I and II) to maintain low complication rates. HDR is being increasingly used now as the control rates are comparable and the toxicity is slightly less.

LDR: Two Intracavitary application (ICA), the first application in the second week of external radiation while the second is delivered just after completion of external radiation. The dose in each application is 30Gy to point A.

HDR: Five weekly intracavitary applications of 7Gy to point A each, starting from second week of external radiation.

Stage IB1 and IIA: Radiotherapy with concurrent chemotherapy
Five randomized phase III trials of radical RT alone versus concurrent cisplatin-based chemotherapy and RT, and their meta-analysis have shown an overall survival advantage with chemoradiotherapy in patients with stage IB2 to IVA disease as well as high risk patients after hysterectomy9-16. While these trials vary somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, they all demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% by concurrent chemoradiation. Based on these results, NCI has recommended that strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.

However the most recent trial17 did not find any additional survival benefit of concurrent weekly cisplatin and the authors stressed that careful attention to RT details is important for achieving optimum outcome.

While chemoradiotherapy is perhaps the new standard of care, it is worth remembering that these results were obtained in a trial setting, in women from affluent countries who had better nutritional or performance status and renal parameters as compared to the majority of our patients from lower socioeconomic status and with more advanced disease. Therefore in women with doubtful compliance or tolerance to combined modality treatment, radical radiotherapy alone can still be considered as an acceptable treatment approach.

STAGE IIB, IIIA and IIIB

These patients are not candidates for curative surgery, hence radiotherapy remains the mainstay of treatment. Platinum based concomitant chemoradiation improves survival and the pros and cons of this approach have been discussed earlier in this chapter.

Radiation therapy:

Stage IIB: The technique and doses of external and intracavitary radiation are same as described for Stage IB.

Stage IIIA: The dose of external beam radiation therapy is 50Gy to the whole pelvis over 5 weeks with 2Gy fractionation. Whenever possible, a midline block should be used after 40Gy. An LDR Intracavitary application with tandem and ovoids to a dose of 30Gy to point A is recommended. Patients, in whom standard ICA is not feasible due to residual disease extending below upper third vagina, intracavitary application using tandem and cylinders to a dose of 15 - 25 Gy to point A (depending on rectal dose) is recommended.

Stage IIIB: The dose of external beam radiation therapy is 50Gy to the whole pelvis over 5 weeks with 2 Gy fractionation. Whenever possible, a midline block should be used after 40Gy. Intracavitary application with Low dose rate (one application of 30Gy to point A) or High dose rate (3 applications of 7Gy to point A each every week, starting from 3rd or 4th week of external radiation) is recommended.

Stage IVA:

The management of patients with stage IVA disease (invasion of bladder and or rectum) has to be individualized, taking into account the extent of bladder / rectal involvement, parametrial infiltration, renal function and patients performance status.

Palliative Radiotherapy: The majority of stage IVA patients have poor general condition and extensive local disease and are best treated with palliative radiation therapy alone. A short palliative regime of 30Gy in 10 fractions over two weeks is generally used and in few patients who respond very well, this is followed by intracavitary application.

Neoadjuvant chemotherapy or concurrent chemoradiotherapy:
Selected patients with good general and renal status and not suitable for surgical extenteration can be treated with this approach.

Surgical extenteration: Selected patients of stage IV, with no or minimal parametrial invasion may be treated with primary exenterative surgery, the extent of which (anterior, posterior or total) would depend on the extent of the lesion.

Stage IVB
No standard chemotherapy regimen is proven in patients with stage IVB cervical cancer. Various single agent chemotherapy drugs have been used with varying response rates in phase I and II studies (cisplat+ifosphomide or cisplatin+paclitaxol). Radiation therapy can be used for palliation of central disease or distant metastasis.

Para-Aortic nodes: Extended field radiation therapy has been reported to produce long term disease control in women with microscopic or small volume (<2cm) lower para-aortic nodes (below L3) with acceptable complications rates when radiation dose was not exceeded beyond 50Gy and the lymphadenectomy was performed by extraperitoneal rather than transperitoneal route19. In the RTOG randomised trial reported recently20, the 10 year overall survival was improved from 44% with pelvic radiation to 55% with pelvic plus para-aortic radiation in 367 women with stage IB1 and II A disease. Grade 4 and 5 radiation toxicities at 10 years however increased from 4% to 8% with para-aortic irradiation.

Local recurrences after radiation therapy: Patients with predominantly central recurrence with no spread to the pelvic side wall, no extrapelvic disease and good performance status should be offered the option of salvage surgery. The extent of surgery may vary from extrafascial hysterectomy to radical hysterectomy to exenterative surgery, depending on the extent of the disease. Counseling of the patient and stoma clinic advice prior to exenterative surgery is mandatory. This surgery should be undertaken only in centres with facilities and expertise for this surgery available and only by teams who have the experience and commitment to look after the long term rehabilitation of these patients.

Locoregional recurrences not suitable for surgical salvage should be offered palliative chemotherapy or symptomatic & supportive care.

Local recurrences after primary surgery: Should be treated with concurrent chemoradiation therapy.

Extrapelvic or distant metastases: Should be treated with a palliative intent with chemotherapy or symptomatic & supportive care only.

Pain relief: It is an important aspect of the management of advanced stage or recurrent disease and should be undertaken by specialists in pain management in a fully equipped Pain Clinic.

Cervical cancer screening in developing countries.

Cervical Cancer is the leading cause of cancer deaths among women in developing countries. Papinocolaou (Pap) smear, the screening method of choice in developed countries is not suitable in developing countries because of issues related to lack of trained manpower, infrastructure, logistics, quality assurance, frequency of screening and costs involved. Several alternative approaches (listed below) have been evaluated that may be easier to implement in developing countries.

1. Unaided visual inspection: Naked eye visualization of the cervix with out acetic acid application by health workers, widely known as 'down staging'.
2. Cervicography: Photographs of the cervix.
3. Visual inspection after application of acetic acid (VIA) Naked eye visual inspection of the cervix after application of 3-5% acetic acid.
4. VIA with magnification (VIAM): Visual inspection with acetic acid using magnification devices.
5. Visual inspection after application of Lugol's iodine (VILI)
6. Human Papilloma Virus (HPV) DNA testing

VIA is the least expensive and has the greatest potential for screening and treatment in one visit. However, methods that succeed in controlled research settings need to be tested in public health settings before they can be advocated for mass screening programme.

Cross-sectional studies: Two cross-sectional studies21,22 simultaneously evaluated the test characteristics of VIA and cytology. However, these studies suffered from verification bias, as the reference investigations colposcopy with or without biopsy were provided to screen positive women and to a selected proportion of screen negative women only. Thus sensitivity and specificity could not be estimated directly. Pooled analysis of data from these two indicated an approximate sensitivity of 93.4% and specificity of 85.1% for VIA to detect CIN 2 or worse lesions; the corresponding figures for cytology were 72.1% and 91.6%. Thus VIA was found to be more sensitive but less specific than cytology.

Currently, an IARC funded cross-sectional study is being conducted in 4 Indian locations (Mumbai, Calcutta, Jaipur and Trivandrum) to evaluate the test characteristics of various screening methods on a large sample of 30,000 women. The sensitivity and specificity of cytology, HPV DNA testing, and VILI are being simultaneously evaluated using colposcopy and directed biopsy as the reference. Data from the above studies will be pooled for establishing the comparative average test performance of various screening tests in detecting CIN2 and advanced lesions.

Randomized intervention trials: Though there is currently a large body of data on the test accuracy of VIA, the efficacy and cost effectiveness of VIA based screening programme in reducing the cervical cancer incidence and mortality is not known. This is being evaluated in 2 cluster-randomized controlled intervention trials in India, which have been initiated in 2000. Information on the comparative trends in incidence/mortality, incidence and mortality rate ratios following the introduction of the screening interventions in the above two randomized trials is expected to emerge around 2007.

OVARIAN CANCER

Epithelial ovarian cancer

The definitive diagnosis of epithelial ovarian cancer requires a surgical specimen. Pathological diagnosis should be made according to the WHO classification. Established subtypes are serous, mucinous, endometroid, clear cell, Brenner, mixed and undifferentiated carcinomas.

Investigations and Work-up

• Clinical examinaion
• Haematological and biochemical investigations
• Ultrasonography of abdomen & pelvis (transabdominal + transvaginal) with colour doppler in selected cases
• Imaging modalities for abdomen & pelvis to document extent of spread e.g. CT scan, MRI
• Tumour markers e.g. CA-125, beta HCG, AFP and CEA.
• Others Cytological examination of ascitic / pleural fluid if present
• Fine needle aspiration cytology of the mass, only if the disease is stage III & above and primary surgery not contemplated in view of clinically unresectable disease (to achieve cytological diagnosis prior to neo- adjuvant chemotherapy)

Staging: (AJCC & FIGO 1998)
Ovarian carcinoma is a surgico-pathologically staged cancer. It requires a laparotomy with a thorough examination of the abdominal cavity. If disease appears confined to the ovary, biopsy of the diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum, para-aortic and pelvic nodes, infracolic omentum are required in addition to peritoneal washings. In the event the patient receives chemotherapy prior to surgery, clinical staging is followed. However, every effort must be made to stage the disease as accurately as possible by imaging studies or laparoscopic evaluation.

Stage I: Growth limited to the ovaries
1A: Growth limited to one ovary; no tumour on the external surface; capsule intact; no ascites.
1B: Growth limited to both ovaries; no tumour on the external surface; capsule intact; no ascites
IC: IA or IB but with tumour on the surface of one or both ovaries; rupture of capsule; malignant ascites or positive peritoneal washings

Stage II: Growth involving ovaries with pelvic extension
IIA: Extension/metastases to uterus and or tubes
IIB: Extension to the pelvis.
IIC: IIa or lIb but with tumour on the surface of one or both ovaries; rupture of capsule; malignant ascites or positive peritoneal washings

Stage III: Tumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes. Superficial liver metastases equals stage III. Tumour is limited to true pelvis but with histologically verified malignant extension to small bowel or omentum
IlIA: Tumour grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces"
IIIB: Tumour of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes negative.
IIIC: Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes

Stage IV: Growth involving one or both ovaries with distant metastases. If pleural effusion is present, cytological test results must be positive to allot a case to stage IV. Parenchymal liver metastases equals stage IV.

TREATMENT OF EARLY STAGE DISEASE

Patients with stage I or II should undergo primary surgical exploration for diagnosis, staging and definitive treatment. The surgery should entail total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, pelvic lymphadenectomy and para-aortic lymph node sampling and comprehensive surgical staging.

Conservative surgery in the form of unilateral salpingo-oophorectomy with preservation of normal contralateral ovary and uterus is only recommended in young patients desirous of child bearing provided they have stage IA well differentiated or borderline cancers with favourable histology, after thorough intraoperative staging. These women should be explained the potential risk of ovarian preservation prior to the procedure and should be encouraged to undergo completion surgery after first childbirth. The extension of indications of conservative surgery to patients with stage IC and/or grade II/Ill patients is investigational at present and may be offered on an individual basis with prior counselling of patients and should be followed by adjuvant chemotherapy.

Risk grouping in early stage disease and adjuvant therapy:

Low risk (Borderline or Grade I/II, stage 1A/B tumours with non-clear cell histology): No adjuvant therapy recommended

High risk (Grade III and/or stage IC tumours or clear cell histology)
Adjuvant therapy recommended. Presently, there is no consensus regarding the optimum adjuvant therapy, route of administration, timing of adjuvant therapy etc. However, the consensus is to give 3-6 cycles of platinum based chemotherapy.

Stage II disease: All patients with should receive 6 cycles of adjuvant platinum based chemotherapy.

TREATMENT OF ADVANCED STAGE DISEASE
Radical surgical cytoreduction followed by adjuvant chemotherapy is the standard of care for advanced epithelial ovarian cancer.

Primary cytoreductive surgery: Surgery performed to remove as much of the tumour and their metastasis as possible before subsequent therapy is instituted. Surgery should include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, pelvic lymphadenectomy with para-aortic lymph node sampling / lymphadenectomy and excision of all metastatic masses.

Definitive conclusions regarding the role of surgical cytoreduction in advanced epithelial ovarian cancer cannot be drawn due to lack of randomized studies or level I evidence regarding the same. Nevertheless, radical surgical cytoreduction is considered the standard primary treatment. The optimum goal of cytoreductive surgery to leave behind no visible or palpable residual disease but the minimum goal should be to leave behind less than 1 cm (preferably less than 0.5 cm) residual disease at any given site.

The role of primary cytoreductive surgery in patients with stage IV disease is controversial. Patients with pleural effusion only or supraclavicular node metastasis can be treated on the lines of stage ill disease. Primary debulking is not recommended in patients with liver or lung metastases.

Interval cytoreductive surgery: An operative procedure performed in patients after a short course (3 cycles) of induction (neo-adjuvant) chemotherapy, to remove as much primary and metastatic disease as possible in order to facilitate response to subsequent chemotherapy and to improve survival.

In patients with clinically unresectable pelvic disease or bulky upper abdominal metastatic disease, when one does not anticipate optimal cytoreduction, neoadjuvant chemotherapy (3 cycles) followed by interval cytoreductive surgery in responders seems an acceptable alternative. Patients with stage IV disease with parenchymal liver or lung metastases may also be treated with this approach. Patients with suboptimal cytoreduction at the time of primary cytoreductive surgery should also be offered interval cytoreductive surgery, with survival benefit. Although the survival benefit with interval cytoreduction in patients with suboptimal cytoreduction has been proved in a randomized controlled trial, its value in all patients of stage III/IV is yet unresolved.

CHEMOTHERAPY FOR EPITHELIAL OVARIAN CANCERS

Till recently, combination chemotherapy with paclitaxel (135 mg/m2 24 hour infusion or 175 mg/m2 as 3 hour infusion) and cisplatin (75mg/m2) or carboplatin (AUC 6 and above) was considered the standard of care of adjuvant therapy based on results of randomized clinical trials, for patients with both optimal and suboptimal cytoreduction. However, recently published trials (GOG 132 & ICON 3) have found single agent cisplatin or carboplatin as good as combination of paclitaxel and platinum compound. These trials indicate that single agent carboplatin (AUC 7 or above) is the new standard or care of adjuvant therapy in patients with advanced epithelial ovarian cancer. These results have further been confirmed in a recent meta-analysis of all trials comparing combination of paclitaxel & platinum compound with platinum compound alone.

There is general consensus that 6 cycles of adjuvant chemotherapy are adequate and additional cycles have failed to increase response rates or survival without compromising safety in randomized trials.

Prospective randomized trials have failed to demonstrate that there is a clinically significant advantage for dose escalation of cisplatin, carboplatin or paclitaxel.

There is no established role for high dose chemotherapy with peripheral stem cell transplantation in any subset of patients with advanced ovarian cancer.

Intra-peritoneal chemotherapy should not be considered standard therapy at present, till the results of earlier phase III trials are reproduced in additional prospective randomized trials.

Second look surgery: An exploratory laparotomy to assess the cancer status of a patient performed in women who are clinically, radiologically and serologically free of disease after the completion of a defined course of 6 cycles of chemotherapy. Second look surgery may be used a part of the treatment protocols where informed consent obtained but should not be used as a routine standard clinical practice.

TREATMENT OF RECURRENT DISEASE:

Recurrences predominantly peritoneal and intra abdominal

Work Up
Abdominal + Pelvic examination
CA-125 levels
Imaging studies
X-ray chest

Treatment
Secondary cytoreductive surgery whenever feasible: Performed on patients who have either persistent disease at the completion of a planned course of chemotherapy or who subsequently experienced clinical relapse after a treatment-free interval. Most secondary cytoreductive surgeries are done for localized relapses.

Optimum candidates for secondary cytoreductive surgery are:

• Tumours relapsing 12 or more months after completion of chemotherapy
• Tumours responding to primary chemotherapy
• High performance status
• Potential for complete resection based on pre-operative evaluation.
• Resectable tumours at the time of second look surgery
• Tumour size:< 5 cm

Although there is no level I evidence of survival benefit with secondary cytoreductive surgery in all patients, its role can be supported by the reported improved survival in patients undergoing secondary cytoreductive surgeries. It has the capacity for improving survival in certain well-selected patients.

Serological relapse (no clinical or radiological evidence of relapse) Presently, there is no evidence that early management of isolated CA-125 elevation is beneficial in terms of survival as compared to when treatment is commenced at the time of clinical or radiological relapse. There is no consensus about the type of therapy, the chemotherapy regimen and number of cycles to be given, if early treatment is instituted. Treatment must be instituted on an individual basis after counselling the patient about the anticipated benefits and risks of early treatment.

RECURRENT DISEASE

Chemotherapy
When the patient is not found to be an optimum candidate for secondary cytoreductive surgery, second line chemotherapy remains the only options of management. The likelihood of benefit from second-line therapy must be balanced against the potential toxicity of the treatment. Patients who are likely to benefit from this therapy are those with good performance status, relatively small residual size (<5 cm), long treatment-free interval, serous histology and a low number of sites. The choice of treatment depends on the recurrence-free-interval after completion of primary treatment (platinum sensitive versus platinum resistant) based chemotherapy.

Treatment free interval >12 months (sensitive recurrent disease) May be treated with re-challenge with the initial platinum-containing chemotherapy or single agent carboplatin.

Treatment free interval 4-12 months (intermediate group):
May be treated with established second-line drugs e.g. paclitaxel (if not used in initial therapy), doxorubicin, oral etoposide, ifosfamide, topotecan, gemcitabine, liposomal doxorubicin etc.

Tumour progression during initial treatment or recurrence free interval of <4 months (refractory disease)
May be treated with experimental or newer drugs or novel therapies, preferably in the setting of a clinical trial.

Palliative surgery
Recommended for patients who manifest symptoms and signs of progressive disease, in an effort to relieve symptoms for a minimally acceptable period. The decision regarding palliative surgery should be made as part of a multidisciplinary evaluation of the patient. In general, surgery should be kept to a minimum and correction of intestinal obstruction should be performed in patients who appear most likely to benefit from such a surgery and with a reasonably long life expectancy.

Follow up
History, physical examination including pelvic examination, CA 125 and imaging if indicated every 3 months for 2 years, every 4 months during the third year and every 6 months during the next two years, or until progression is documented.

BORDERLINE EPITHELIAL OVARIAN CANCER

• Borderline epithelial tumours have low malignant potential.
• Investigations and staging for the borderline epithelial tumours is similar to invasive epithelial cancers.
• Conservative surgery is recommended for stage I unilateral borderline epithelial tumours, after thorough intra-operative staging manoeuvres.
• In advanced stage borderline epithelial tumours, radical surgical cytoreduction with excision of all primary and metastatic disease should be done.
• There is no role of adjuvant chemotherapy in borderline tumours.

GERM CELL TUMOURS OF OVARY:
Germ cell tumours occur predominantly in young girls and hence preservation of fertility is as important a goal as cure. Apart from investigations described for epithelial cancers, markers (AFP & beta-HCG) should be done.

Early stage disease

• Staging manoeuvres are same as in epithelial cancers, with more stress on lymph node dissection.
• Biopsy of normal-looking contralateral ovary is not essential.
• Conservative surgery with preservation of normal contralateral ovary & uterus is recommended whenever possible.
• If both ovaries are involved, preservation of normal ovarian tissue on one side, if possible, should be attempted and the ovarian masses removed. Uterus should be preserved unless involved by disease.

Chemotherapy for ovarian germ cell tumours

• Stage IC disease:
  Adjuvant chemotherapy with bleomycin, etoposide and cisplatin (BEP) regimen for 3 cycles.
• Advanced stage disease:
  1. If ovarian masses are resectable, primary surgery should be done followed by chemotherapy.
  2. If on clinical or radiological grounds, the masses are considered to be unresectable or there is bulky metastatic disease in lymph nodes or upper abdomen, anterior chemotherapy with 3 cycles of BEP chemotherapy followed by surgery is recommended.
  3. Surgery should be conservative if possible, with the aim of preservation of normal ovarian tissue without compromising complete resection.
  4. Resection of all post- chemotherapy residual masses should be done.
• Visceral metastases (lung, liver or bone)
  Should be treated with induction chemotherapy BEP 3 cycles followed by surgery (excision of primary and residual metastases) in responders. For non responding or progressive and unresectable disease, salvage chemotherapy ( 3 cycles of VIP / ifosfamide, etoposide and cisplatin) followed by response evaluation is recommended.
  
  For patients with advanced or metastatic disease who undergo surgery, the following information is necessary for further management decision.

1. Intra-operative assessment of residual disease.
2. Histological assessment for post chemotherapy viable disease.
3. Serial AFP / beta HCG levels (if initially elevated).

• Post chemotherapy Viable residual disease after surgery or post-op persistent elevation of beta HCG or AFP: Three courses of salvage chemotherapy (ifosfamide, etoposide and cisplatin) is recommended.
• No viable disease and normal tumour markers after surgery: Only close observation is warranted.

Follow up
History, physical examination including pelvic examination, and tumour markers every 3 months for 2 years, every 4 months during the third year and every 6 months during the next two years, or until progression is documented.

Gynaecological Cancers Abstracts

1.Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ.
Grigsby PW, Perez CA. Int J Radiat Oncol Biol Phys 1991;21:375-8
The objective of this study was to define the role of radiotherapy alone for medically inoperable patients with Carcinoma in Situ (CIS) and Stage IA carcinoma of the uterine cervix. At the Mallinckrodt Institute of Radiology, Radiation Oncology Center from January 1959 through December 1986 21 patients with CIS and 34 with Stage IA were treated. All patients had histologically proven disease. The average age was 56 years for CIS and 51 years for Stage IA patients. Therapy for patients with CIS consisted of a single intracavitary insertion with a uterine tandem and colpostats. The average radiation doses were 4612 cGy to point A, 9541 cGy to the surface of the cervix, and 5123 milligram-hours (mgh). Radiotherapy for Stage IA tumors was delivered with intracavitary irradiation alone in 13 (average doses were 5571 cGy to point A, 10,430 cGy vaginal surface dose, and 6488 mgh). The other 21 patients were treated with external beam and intracavitary irradiation. The average whole pelvis dose was 1443 cGy with an additional 2354 cGy boost to the parametria with a midline stepwedge shield. The average intracavitary doses were 5200 cGy to point A, 10234 cGy to the vaginal surface, and 6293 mgh. None of the patients with CIS developed recurrent disease and none had severe sequelae of therapy. Only one patient with Stage IA developed recurrent disease in the pelvis. None developed metastatic disease. The severe complication rate was 5.9% (2/34) for Stage IA and only occurred in those receiving intracavitary irradiation and external beam irradiation. We conclude that irradiation consisting of intracavitary implants alone is excellent treatment for patients with medically inoperable Stage IA and CIS of the cervix.

2.Microinvasive carcinoma of the cervix.
Sevin BU. Cancer 1992;70:2121-8.
BACKGROUND. Microinvasive carcinoma of the cervix (MIC) has been poorly defined in the past and is still a focus of persistent controversy. In 1985, the International Federation of Gynecology and Obstetrics (FIGO) defined Stage IA as "preclinical invasive carcinoma, diagnosed by microscopy only," subdividing it into Stage IA1 or "minimal microscopic stromal invasion," and Stage IA2 or "tumor with invasive component 5 mm or less in depth taken from the base of the epithelium and 7 mm or less in horizontal spread." In 1974, the Society of Gynecologic Oncologists (SGO) defined MIC as any lesion with a depth of invasion of 3 mm or less from the base of the epithelium, without lymphatic or vascular space invasion. METHODS. To assess the risk of lymph node metastasis and treatment failures, pathologic material and clinical data on 370 patients with Stage I carcinoma of the cervix, who were treated by radical hysterectomy and pelvic-aortic node dissection, were reviewed. Histopathologic analysis of tumors was based on a uniform format, including measurement of the maximum depth of invasion, the width and length of the horizontal tumor spread, invasive growth pattern, cell type, tumor grade, and lymphatic or vascular space involvement. RESULTS. Of the 370 patients, 110 had a depth of invasion of 5 mm or less. Of these, 54 patients fulfilled the SGO definition of MIC; 42, the new FIGO Stage IA2 definition; and 27, both definitions. None of the patients with MIC, as defined by either the SGO or the new FIGO Stage IA2, had lymph node metastases or tumor recurrence. These data support the conclusion that MIC, defined by either the SGO or FIGO definitions, have a low risk for lymph node metastasis or recurrent carcinoma. A review of the literature indicated a recurrence rate for Stage IA2 of 4.2%. In addition to depth of invasion, lymph vascular space invasion is a better predictor of lymph node metastasis and recurrence than the surface dimension. CONCLUSIONS. The authors recommend adoption of the SGO definition of MIC. Patients with a depth of invasion of 3 mm or less without lymph vascular space invasion safely can be treated conservatively.

3. Early invasive carcinoma of the cervix.
Jones WB et al. Gynecol Oncol 1993;51:26-32.
Ninety-two patients with early invasive carcinoma of the cervix (5 mm or less) treated between July 1977 and June 1990 are reviewed. Eighty patients had squamous cell carcinomas and 12 had adenocarcinomas. The diagnosis was established by conization in 77 of 92 (83.6%) patients. Thirty-six patients (39%) had a depth of stromal invasion of 1 mm or less, 32 patients (35%) between 1 and 3 mm, and 24 patients (26%) between 3 and 5 mm. Forty-four patients were treated with radical hysterectomy and bilateral pelvic lymphadenectomy (RHND). None of these patients had positive lymph nodes. Thirty-three patients were treated with conservative hysterectomy (CH), 4 with modified radical hysterectomy, and 2 with trachelectomy. Six patients received radiotherapy. Three patients were treated by conization only. Two patients developed in situ carcinoma (CIS) of the vagina 12 months after CH for lesions on conization that invaded less than 1 mm. In both cases the cone margins were positive, and in one a microscopic focus of CIS of the cervix was present at the resection margin of the hysterectomy specimen. A third patient developed an invasive lesion of the vagina 25 months after CH for a lesion that invaded 2.5 mm in a cone whose margins were not specified, but the hysterectomy margins were clear. All 3 patients were successfully retreated. The remaining patients are free of disease for a median follow-up of 51 months. The results of the study indicate that CH is adequate therapy for patients in whom the diagnosis of early invasive cervical cancer is established by conization with free margins and the depth of invasion is 3 mm or less. Although only 1 of 24 patients with invasion > 3 mm but < or = 5 mm had a CH, pathologic findings in 18 patients who had RHND suggest that CH would have been sufficient for these since there were no instances of spread to nodes or parametrium.

4.Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study.
Creasman WT. Am J Obstet Gynecol 1998;178:62-5.

OBJECTIVE: Our purpose was to evaluate the risk factors and prognosis in patients with stage IA squamous cell carcinoma of the cervix and 3 to 5 mm of invasion. STUDY DESIGN: From 1981 to 1984 the Gynecologic Oncology Group conducted a prospective clinicopathologic study of patients with stage I carcinoma of the cervix. A selective study group that was previously defined and reported included patients with squamous cell carcinoma of the cervix who were treated with radical hysterectomy and pelvic lymphadenectomy and who had disease confined to the uterus, with or without microscopically positive lymph nodes. RESULTS: One hundred eighty-eight patients had invasion of 3, 4, or 5 mm as determined by central pathology review. Patients who satisfied the 3 to 5 mm invasion definition of the current stage IA2 classification of the International Federation of Gynecology and Obstetrics (1995) are the subject of this report. CONCLUSIONS: Patients with stage IA2 carcinoma of the cervix who have 3 to 5 mm of invasion present on conization with no invasion in the hysterectomy specimen are at very low risk for lymph node metastases, recurrences, or death caused by cancer.

5. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer.
Landoni F, et al. Lancet 1997;350:535-40.
BACKGROUND: Stage Ib and IIa cervical carcinoma can be cured by radical surgery or radiotherapy. These two procedures are equally effective, but differ in associated morbidity and type of complications. In this prospective randomised trial of radiotherapy versus surgery, our aim was to assess the 5-year survival and the rate and pattern of complications and recurrences associated with each treatment. METHODS: Between September, 1986, and December, 1991, 469 women with newly diagnosed stage Ib and IIa cervical carcinoma were referred to our institute. 343 eligible patients were randomised: 172 to surgery and 171 to radical radiotherapy. Adjuvant radiotherapy was delivered after surgery for women with surgical stage pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive nodes. The primary outcome measures were 5-year survival and the rate of complications. The analysis of survival and recurrence was by intention to treat and analysis of complications was by treatment delivered. FINDINGS: 170 patients in the surgery group and 167 in the radiotherapy group were included in the intention-to-treat analysis; scheduled treatment was delivered to 169 and 158 women, respectively, 62 of 114 women with cervical diameters of 4 cm or smaller and 46 of 55 with diameters larger than 4 cm received adjuvant therapy. After a median follow-up of 87 (range 57-120) months, 5-year overall and disease-free survival were identical in the surgery and radiotherapy groups (83% and 74%, respectively, for both groups), 86 women developed recurrent disease: 42 (25%) in the surgery group and 44 (26%) in the radiotherapy group. Significant factors for survival in univariate and multivariate analyses were: cervical diameter, positive lymphangiography, and adeno-carcinomatous histotype. 48 (28%) surgery-group patients had severe morbidity compared with 19 (12%) radiotherapy-group patients (p = 0.0004). INTERPRETATION: There is no treatment of choice for early-stage cervical carcinoma in terms of overall or disease-free survival. The combination of surgery and radiotherapy has the worst morbidity, especially urological complications. The optimum therapy for each patient should take account of clinical factors such as menopausal status, age, medical illness, histological type, and cervical diameter to yield the best cure with minimum complications.

6. Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial.
Patel FD et al. Int J Radiat Oncol Biol Phys 1994;28:335-9.

PURPOSE: This study is a prospective randomized clinical trial undertaken at our center to compare low dose rate versus high dose rate intracavitary brachytherapy for the treatment of carcinoma uterine cervix. METHODS AND MATERIALS: From June 1986 to June 1989, 482 patients with previously untreated invasive squamous cell carcinoma of the uterine cervix were entered into the study. After an initial clinical examination and investigative work-up the patients were staged according to FIGO staging system. Depending upon the stage of the disease, the size of the local growth and the local cervical anatomy, the patients were divided into two main groups. In group I patients, the predominant treatment was by intracavitary therapy and in group II patients, the predominant therapy was by external beam radiation. In both the groups at the time of intracavity brachytherapy the patients were alternately randomized to receive either low dose rate or high dose rate brachytherapy. There were thus two hundred forty-six patients in the low dose rate group and two hundred thirty-six patients in the high dose rate group. The patients were analyzed for local control, 5 years survival and late radiation morbidity. RESULTS: Stage for stage the local control rates in the low dose rate group and high dose rate group were similar. The overall local control achieved in the low dose rate group was 79.7% as compared to 75.8% in the high dose rate group. The 5 years survival figures in the low dose rate and high dose rate group were also comparable. In Stage I, it was 73% for low dose rate patients and 78% for high dose rate patients, for Stage II it was 62% and 64% respectively and for Stage III patients it was 50% and 43%. The only statistically significant difference was found in the incidence of overall rectal complications which was 19.9% for the low dose rate group as compared to only 6.4% for the high dose rate group. However, the more severe grade 3-4 complications were not significantly different between the two groups (2.4% vs. 0.4%, respectively). The bladder morbidity in both the groups was similar. CONCLUSION: Thus high dose rate intracavitary brachytherapy is an equally good alternative to conventional low dose rate brachytherapy in the treatment of carcinoma of the uterine cervix.

7. HDR and MDR intracavitary treatment for carcinoma of the uterine cervix. A prospective randomized study.
el-Baradie M, Inoue T, et al. Strahlenther Onkol 1997; 173:155-62

AIM: Treatment of carcinoma of the uterine cervix by remote afterloading brachytherapy has been accompanied with new isotopes having dose rates different from the classical low-dose rate (LDR) radium source. The dose rate conversion factor from LDR to high-dose rate (HDR) found to be around 0.54 in most studies. As regards medium-dose rate (MDR) brachytherapy, the published data are very few and the experience is still short. In this study the experience of Osaka University Hospital with micro-HDR-Selectron and Selectron-MDR, as a preliminary report of the clinical trial, is presented. PATIENTS AND METHOD: From August 1991 through April 1993, a total of 45 patients with carcinoma of the uterine cervix were randomly allocated to either microSelectron-HDR or Selectron-MDR at the Osaka University Hospital. As regards HDR, dose to point A was adjusted to 32 Gy (for stages I and II). 30 Gy/4 fractions, and 22.5 Gy/3 fractions, for stages III, and IV, respectively. The corresponding values in case of MDR were 35.6, 34 Gy/4 fractions, and 25.5 Gy/3 fractions. External irradiation, according to the stage, was the same in the 2 groups. Nucletron Planning System (NPS) was used for pre-treatment dose calculation at point A, rectal and bladder wall. The dose rate at point A ranged from 24 to 75.6 cGy/min for the HDR group, while for the MDR group ranged among 174.8 to 229.6 cGy/h. RESULTS: The 3-year survival and loco-regional control rates for both modalities were nearly equivalent (62% and 67% for HDR and 68% and 74% for MDR). The cumulative rectal and bladder complication rates were the same in both groups (29% at 3 years), with only 1 patient (MDR-group) developed grade 3 rectal and bladder complication. In this study, point A dose rate correction factor from LDR to HDR was 0.53 and 0.6 from LDR to MDR. CONCLUSIONS: From the previous reports from Osaka University Medical School, as well as others, HDR was proposed as an alternative to LDR brachytherapy for treatment of carcinoma of the uterine cervix. In this report, Selectron-MDR was nearly equivalent to the microSelectron-HDR as regards survival and loco-regional control rates as well as radiation-induced complication. This is a preliminary report, and the study still needs larger number of patients, and longer follow-up period.

8. High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial.
Hareyama M et al. Cancer 2002;94:117-24.

BACKGROUND: This was a prospective randomized clinical trial undertaken at our institution to compare low-dose-rate (LDR) intracavitary radiation therapy versus high-dose-rate (HDR) intracavitary radiation therapy for the treatment of cervical carcinoma. METHODS: From January 1984 to December 1997, a total of 132 patients with Stage II or IIIB of invasive carcinoma of the uterine cervix were entered into this randomized study. Treatment arm by HDR or LDR was allocated according to the month of each patient's birth. External irradiation consisted of whole pelvis irradiation and pelvic irradiation. Doses of external irradiation for both groups were identical. The authors used 0.588 as the conversion factor of total intracavitary dose from LDR to HDR. RESULTS: The 5-year disease specific survival rates of Stage II and III patients treated with HDR were 69% and 51% whereas those with LDR were 87% and 60%, respectively. The 5-year pelvic recurrence free survival rates of Stage II and III patients treated with HDR were 89% and 73% whereas those with LDR were 100% and 70%, respectively. There was no significant difference in disease specific survival or pelvic recurrence free survival rates between HDR and LDR. The actuarial complication rate (Radiation Therapy Oncology Group Grade 3, 4, or 5) at 5 years was 10% in the HDR group and 13% in the LDR group, and the difference between the HDR and LDR groups was not statistically significant. CONCLUSIONS: The pelvic control or actuarial complication rates were comparable between HDR and LDR treatment. The difference between the disease specific survival rates for HDR and LDR was not statistically significant for Stage II or III, although in Stage II, patients treated with LDR appeared to have a better survival rate than those treated with HDR.

9. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Green J, Kirwan J, Tierney J, et al. Cochrane Database Syst Rev 2001;(4):CD002225.

Background: The National Cancer Institute (USA) alert in February 1999 stated that concomitant chemoradiotherapy should be considered for all patients with cervical cancer, based on evidence from five randomized controlled trials.
Objectives: To review all known randomized clinical controlled trials (RCTs) comparing concomitant chemotherapy and radiation therapy with radiotherapy for locally advanced cervical cancer.
Search strategy: We searched electronic databases, trials registers and reference lists of published trial reports and review articles were also searched.
Selection criteria: This review includes RCTs in cervical cancer comparing concomitant chemoradiation with radiotherapy. In the experimental arm, further adjuvant chemotherapy was allowable. Hydroxyurea was considered inactive and allowable. Trials using radiosensitisers or radioprotectors in the experimental arm were excluded.
Data collection and analysis: Two authors reviewed trials for inclusion and extracted data. For meta-analyses of time-to-event outcomes (survival, progression-free survival), a hazard ratio (HR) was extracted or estimated from trial reports, where possible. Only overall rates of local and distant recurrence were presented in many reports so only an odds ratios (OR) of recurrence rates could be calculated, which takes no account of time to recurrence or censoring. The HRs and ORs for individual trials were combined across all trials, using the fixed effect model.
Few trials reported acute toxicity adequately. Data were therefore grouped and the number of toxic events was used to calculate a single OR for each site and grade. Late toxicity was rarely described so could only be reviewed qualitatively.
Main results: Nineteen trials (17 published, two unpublished) were identified including 4580 patients, although due to patient exclusion and differential reporting 62 -to 78% were available for the analyses. The review strongly suggests chemoradiation improves overall survival and progression free survival, whether or not platinum was used with absolute benefits of 12% and 16% respectively. There was, however, statistical heterogeneity for these outcomes There was some evidence that the effect was greater in trials including a high proportion of stage I and II patients. Chemoradiation also showed significant benefit for both local and distant recurrence. Haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group. Details of late morbidity were sparse.
Reviewers' conclusions: Concomitant chemoradiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also reduces local and distant recurrence suggesting concomitant chemotherapy may afford cytotoxic and sensitisation effects. Some acute toxicity is increased, but data on long term side effects were sparse.

10. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Green JA. Lancet 2001;358:781-6.

BACKGROUND: The US National Cancer Institute alert in February, 1999, stated that concomitant chemotherapy and radiotherapy should be considered for all patients with cervical cancer. Our aim was to review the effects of chemoradiotherapy on overall and progression-free survival, local and distant control, and acute and late toxicity in patients with cervical cancer. METHODS: With the methodology of the Cochrane Collaboration, we did a systematic review of all known randomised controlled trials done between 1981 and 2000 (17 published, two unpublished) of chemoradiation for cervical cancer. FINDINGS: The trials included 4580 randomised patients, and 2865-3611 patients (62-78%) were available for analysis. Cisplatin was the most common agent used. The findings suggest that chemoradiation improves overall survival (hazard ratio 0.71, p<0.0001), whether platinum was used (0.70, p<0.0001) or not (0.81, p=0.20). A greater beneficial effect was seen in trials that included a high proportion of stage I and II patients (p=0.009). An improvement in progression-free survival was also seen with chemoradiation (0.61, p<0.0001). Thus, the absolute benefit in progression-free and overall survival was 16% (95% CI 13-19) and 12% (8-16), respectively. A significant benefit of chemoradiation on both local (odds ratio 0.61, p<0.0001) and distant recurrence (0.57, p<0.0001) was also recorded. Grade 3 or 4 haematological (odds ratio 1.49-8.60) and gastrointestinal (2.22) toxicities were significantly greater in the concomitant chemoradiation group than the control group. There was insufficient data to establish whether late toxicity was increased in the concomitant chemoradiation group. INTERPRETATION: Concomitant chemotherapy and radiotherapy improves overall and progression-free survival and reduces local and distant recurrence in selected patients with cervical cancer, which may give a cytotoxic and sensitisation effect.

11. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.
Whitney CW. J Clin Oncol 1999;17:1339-48.

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

12. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. Morris M. N Engl J Med 1999;340:1137-43

BACKGROUND AND METHODS: We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. RESULTS: Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. CONCLUSIONS: The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.

13. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer.
Rose PG. N Engl J Med 1999;340:1144-53.
BACKGROUND AND METHODS: On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens -- cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone -- in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 micromol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3). RESULTS: The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively. CONCLUSIONS: Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.

14. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma.
Keys HM. N Engl J Med 1999;340:1154-61.

BACKGROUND: Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS: Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS: The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS: Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.

15. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix.
Peters WA. Clin Oncol 2000;18:1606-13.

PURPOSE: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma. PATIENTS AND METHODS: Patients with clinical stage IA(2), IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m(2) and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT. RESULTS: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P =.003) and 1.96 (P =. 007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group. CONCLUSION: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

16. Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy.
Thomas GM. N Engl J Med 340: 1198-200, 1999. [Editorial]
Despite screening programs, approximately 14,000 cases of invasive cervical cancer are diagnosed annually in the United States. In approximately half these cases, locally advanced disease is present at the time of diagnosis. In developing countries, the disease is usually advanced by the time of diagnosis, the prevalence is much higher, and cervical cancer is the principal cause of death due to cancer in women. Pelvic radiation has been the standard, definitive therapy for advanced disease. With this treatment, the overall five-year survival rate is approximately 65 percent, but it ranges from 15 to 80 percent, depending on the extent of the disease. The main cause of death among women with cervical cancer is uncontrolled disease within the pelvis. Although increasing the dose of radiation improves the control of pelvic disease, the dose that can be delivered is limited by the severe late complications of the treatment.
There have been no substantial improvements in the treatment of cervical cancer since the advent of megavoltage irradiation in the 1950s. Many attempts have been made to improve the outcome of radiotherapy, but none of these have been successful. As a result, strategies involving combination therapy, especially the concurrent use of chemotherapy with radiotherapy, have been considered. The administration of chemotherapy concurrently with radiotherapy has theoretical advantages over the use of radiotherapy alone. The two treatments may interact to increase the killing of tumor cells without delaying the course of radiotherapy or protracting the overall treatment time, which may accelerate the proliferation of tumor cells. Theoretically, chemotherapy may act synergistically with radiotherapy by inhibiting the repair of radiation-induced damage, promoting the synchronization of cells into a radiation-sensitive phase of the cell cycle, initiating proliferation in nonproliferating cells, and reducing the fraction of hypoxic cells that are resistant to radiation. Chemotherapy may also independently increase the rate of death of tumor cells. Nevertheless, since the doses of chemotherapeutic drugs that are administered concurrently with radiation are less than the usual amounts used for solid tumors, it is not likely that such treatment will affect any distant metastases that may be present.
Since the 1980s, many phase 1-2 studies have established that treatment with cisplatin, fluorouracil, and mitomycin can safely be combined with pelvic irradiation. Since the rate of complete response expected with the use of radiotherapy alone is high, whether there is any incremental benefit from the added chemotherapy could not be assessed in phase 2 studies. Answers to this question have now come from phase 3 trials of this strategy. Three large randomized studies by Keys et al, Rose et al, and Morris et al appear in this issue of the Journal, and a fourth was published elsewhere. The promising results of the three studies in the Journal and the preliminary results of other trials prompted the National Cancer Institute to issue a rare clinical announcement that "strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer".
Why did the National Cancer Institute make this recommendation? One reason is the well-conducted study by Keys et al for the Gynecologic Oncology Group, which compared radiotherapy alone with a regimen of six weeks of cisplatin and pelvic irradiation given concurrently in 369 patients with node-negative bulky stage IB cervical cancer. The combined regimen was well tolerated and did not increase the median treatment time, which was 50 days in both groups. The concurrent use of cisplatin and radiation in this particular stage of cervical cancer significantly improved control of pelvic disease and prolonged survival. The second reason is the study by Rose et al of women with more advanced stages of cervical cancer. Rose et al. assessed data on 526 women with stage IIB, III, or IVA cervical cancer who were randomly assigned to receive radiotherapy concomitantly with one of three chemotherapy regimens: weekly cisplatin; two courses of a three-drug combination consisting of hydroxyurea, cisplatin, and fluorouracil; or twice-weekly hydroxyurea. Almost half the patients in this study had disease involving the pelvic wall (stage IIIB) or the bladder (stage IVA).
The progression-free survival rates at 24 months were significantly higher in the two groups that received cisplatin (67 percent and 64 percent) than in the group that received hydroxyurea (47 percent). Because there was less toxicity with cisplatin alone than with the three-drug regimen, the former is probably the preferable regimen to use in combination with radiotherapy. The results of this study send a clear message that it is time to abandon the use of hydroxyurea, which has never been widely accepted as a treatment for cervical cancer.
Keys et al. used a somewhat low dose of radiation, and Rose et al. not only used a relatively low total dose of radiation but also had a protracted treatment time (median, 63 days). Even though neither of the studies included a group that was given radiation alone at a dose and within an interval that are considered optimal, there is no doubt that adding cisplatin-containing chemotherapy to the various regimens of radiotherapy that were used was beneficial. Nevertheless, doubt remains about the magnitude of the benefit that might have accrued by adding chemotherapy to an optimal regimen of radiotherapy.
The third reason for the optimistic bulletin from the National Cancer Institute is the study by Morris et al, which involved 388 women with a spectrum of advanced disease ranging from bulky stage IB through stage IVA. The women were assigned to receive either three cycles of cisplatin and fluorouracil in combination with pelvic radiation or irradiation of the pelvis and para-aortic lymph nodes alone. Morris et al. used a higher dose of radiation and a somewhat shorter overall treatment time than Rose et al. (median, 58 days vs. 63 days). The addition of chemotherapy improved the control of pelvic disease and significantly increased overall survival rates (73 percent, as compared with 58 percent with the use of irradiation alone).
It is unclear whether the results of this study are applicable to all stages of cervical cancer, since only 30 percent of the patients had stage III or IVA disease. The study by Rose et al. offers the only available evidence of the benefit of combined therapy in women with stage III or IVA cervical cancer, and that applies only to a special group of women without involvement of lymph nodes outside the pelvis. Confirmatory data are required, particularly those of the now completed study by the National Cancer Institute of Canada, which compared concurrent treatment with cisplatin and radiation with an optimal dose of radiation, and those of the Gynecologic Oncology Group study of women with advanced disease, which compared cisplatin and fluorouracil with hydroxyurea alone.
The results of the five trials listed in table 1 how similar reductions in the risk of death from cervical cancer and similar absolute improvements in survival. These results are supported by the findings in comparable studies of other solid tumors and squamous-cell cancers of the head and neck.
Currently available data do not allow conclusions to be drawn as to which drugs or regimens are optimal in the treatment of cervical cancer. Until further data become available, it is reasonable to suggest that cisplatin-based chemotherapy - most likely consisting of weekly cisplatin - should be given concurrently with radiotherapy. One must also keep in mind that the reported improvements in survival are associated only with concurrent chemotherapy and not with neoadjuvant chemotherapy (chemotherapy given before or after radiotherapy). Eight of nine large published studies of cervical cancer and a meta-analysis of 31 randomized trials of head and neck cancer revealed no significant benefit for the latter strategy.

17.Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix.
Pearcey R et al. J Clin Oncol 2002;20:966-72.

PURPOSE: To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS: A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy - 40 mg/m2 (arm 1) or the same RT without chemotherapy (arm 2). RESULTS: A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION: This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m2 to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.

18. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 2002;20: 891-3.
[No abstract available].

19. Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes.
Vigliotti AP et al. Int J Radiat Oncol Biol Phys 1992;23:501-9.

Forty-three patients were treated with extended field irradiation for periaortic metastasis from carcinoma of the uterine cervix (FIGO stages IB-IV). Twelve patients (28%) remained continuously free of disease to the time of analysis or death from intercurrent disease, 20 (46%) had persistent cancer within the pelvis, 11 (26%) had persistent periaortic disease, and 23 (53%) developed distant metastasis. The actuarial 5-year survival rate was 32%. The results correlated well with the periaortic tumor burden at the time of irradiation. None of 19 patients (0%) with microscopic or small (less than 2 cm) periaortic disease had periaortic failures, compared to 29% (4/14) of those with moderate-sized (2-5 cm) disease and 70% (7/10) of those with massive (greater than 5 cm) periaortic metastasis. Similarly, the 5-year survival rates were 50% (6/12) with microscopic disease, 33% (2/6) with small gross disease, 23% (3/13) with moderate-sized disease, and 0% (0/10) with massive periaortic metastases. Only 10% (1/10) of patients whose tumor extended to the L1-2 level survived 5 years, compared with 31% (9/29) of those whose disease extended no higher than the L3-4 level. The periaortic failure rates correlated to some extent with the dose delivered through extended fields, although the difference was not statistically significant. Only 8% (1/13) of those who had undergone extraperitoneal lymphadenectomies developed small bowel complications, compared with 25% (7/29) of those who had had transperitoneal lymphadenectomies. The incidence of small bowel obstruction was 8% (1/13) following periaortic doses of 4000-4500 cGy, 10% (1/10) after 5000 cGy, and 32% (6/19) after approximately 5500 cGy. From this, we concluded that the subset of patients who would benefit most from extended field irradiation are those in whom the residual disease in the periaortic area measures less than 2 cm in size at the time of treatment, whose disease extends no higher than L3, and whose cancer within the pelvis has a reasonable chance of control with standard radiation therapy techniques.

20. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20.
Rotman M et al J Clin Oncol 2002;20:891-3.

OBJECTIVES--To investigate whether irradiation to the standard pelvic field only improves the response rate and survival in comparison with pelvic plus para-aortic irradiation in patients with high-risk cervical carcinoma, and to investigate patterns of failure and treatment-related toxicity. DESIGN--Randomized controlled trial from November 1979 to October 1986, with stratification by histology, para-aortic nodal status, and International Federation of Gynecology and Obstetrics (FIGO) stage. SETTING--Radiation Therapy Oncology Group (RTOG) multicenter clinical trial. PATIENTS--A total of 367 patients with FIGO stage IB or IIA primary cervical cancers measuring 4 cm or greater in lateral diameter or with FIGO stage IIB cervical cancers were randomized to RTOG protocol 79-20 to receive either standard pelvic only irradiation or pelvic plus para-aortic irradiation. INTERVENTION--Pelvic only irradiation consisted of a midplane pelvic dose of 40 to 50 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. Pelvic plus para-aortic irradiation delivered 44 to 45 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. A total dose of 4000 to 5000 mg/h of radium equivalent or 30 to 40 Gy was provided by intracavitary brachytherapy to point A. MAIN OUTCOME MEASURES--Response rate, overall and disease-free survival, patterns of failure, and treatment-related toxicities. RESULTS--Ten-year overall survival was 44% for the pelvic only irradiation arm and 55% for the pelvic plus para-aortic irradiation am (P = .02). Cumulative incidence of death due to cervical cancer was estimated as significantly higher in the pelvic only arm at 10 years (P = .01). Disease-free survival was similar in both arms; 40% for the pelvic only arm and 42% for the pelvic plus para-aortic arm. Locoregional failures were similar at 10 years for both arms (pelvic only, 35%; pelvic plus para-aortic, 31%; P = .44). In complete responders, the patterns of locoregional failures were the same for both arms, but there was a lower cumulative incidence for first distant failure in the pelvic plus para-aortic irradiation arm (P = .053). Survival following first failure was significantly higher in the pelvic plus para-aortic arm (P = .007). A higher percentage of local failures were salvaged long-term on the pelvic plus para-aortic arm compared with the pelvic only arm (25% vs 8%). The cumulative incidence of grade 4 and 5 toxicities at 10 years in the pelvic plus para-aortic arm was 8%, compared with 4% in the pelvic only arm (P = .06). The death rate due to radiotherapy complications was higher in the pelvic plus para-aortic arm (four [2%] of 170) compared with the pelvic only arm (one [1%] of 167) (P = .38). The proportion of deaths due to radiotherapy complications in the pelvic plus para-aortic arm was higher than in the pelvic only arm (four [6%] of 67 vs one [1%] of 85; P = .24). If the patient had abdominal surgery prior to para-aortic irradiation, the estimated cumulative incidence of grade 4 and 5 complications was 11%, compared with 2% in the pelvic only arm. CONCLUSIONS--The statistically significant difference in overall survival at 10 years for the pelvic plus para-aortic irradiation arm, without a difference in disease-free survival, can be explained by the following two factors: (1) a lower incidence of distant failure in complete responders and (2) a better salvage in the complete responders who later failed locally.

21. Performance of visual inspection after acetic acid application (VIA) in the detection of cervical cancer precursors.
Sankaranarayanan R, Wesley R, Somanathan T, et al. Cancer 1998; 83: 2150-56.

BACKGROUND. Organized cervical cytology screening programs are not feasible in many developing countries where cervical carcinoma is an important cause of mortality among adult women. This study compared visual inspection of the cervix after application of 3-4% acetic acid (VIA, or cervicoscopy) with cytology as methods for the detection of cervical carcinoma and its precursors. METHODS. Three thousand women were examined by both VIA and cytology. Those positive on one or both of the screening tests (n = 423) or those who had clinically suspicious lesions even if the tests were negative (n = 215) were invited for colposcopy. Directed biopsies were obtained from 277 of 573 women at colposcopy. Those with moderate dysplasia or worse lesions diagnosed by histology were considered true-positives. Those with no lesions or with reactive or reparative changes at colposcopy and those for whom histology revealed no pathology, reactive or reparative changes, atypia, or mild dysplasia were considered false-positives. The detection rate of true-positive cases and the approximate specificity of the two tests were compared. RESULTS. VIA was positive in 298 women (9.8%), and cytology was positive (for atypia or worse lesions) in 307 women (10.2%). Of the 51 true-positive cases (20 cases of moderate dysplasia, 7 of severe dysplasia, 12 of carcinoma in situ, and 12 of invasive carcinoma), VIA detected 46 (90.1%) and cytology 44 (86.2%), yielding a sensitivity ratio of 1.05. VIA detected five lesions missed by cytology, and cytology detected three missed by VIA; both missed two lesions. The approximate specificities were 92.2% for VIA and 91.3% for cytology. The positive predictive value of VIA was 17.0%, and that of cytology was 17.2%. CONCLUSIONS. These results indicate that VIA and cytology had very similar performance in detecting moderate dysplasia or more severe lesions in this study. VIA merits further evaluation as a primary screening test in low-resource settings.

22. Cervical cancer screening in Porto Alegre, Brazil: Alternative methods for detecting cancer precursors in a developing country. Naud P, et al. Jr. of Lower Genital Tract Disease 2001; 5:24-28.

Objective. This study was conducted to test the performance characteristics of cervical cancer screening by visual inspection of the cervix with acetic acid and iodine solution. Methods. A total of 100 women were screened for cervical cancer by Pap smear and naked eye inspection of the cervix after application of acetic acid and iodine solution. Results. Comparing visual inspection to the Pap test, a sensitivity of 85.7%, specificity of 78.5%, and concordance of 79% (p = .0011) was established. Comparing the Pap test with colposcopy, the corresponding figures were 42.9%, 92.3%, and 66.6% (p = .077), respectively. Visual inspection compared to colposcopy showed corresponding figures of 100%, 7.7%, and 55.5% (p = .48), respectively. Colposcopy and biopsy had an agreement of 100%. Conclusions. Visual inspection with acetic acid and iodine solution proved to be a reasonable method of screening for cervical cancer precursors.

First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence.
Sandercock J, Parmar MK, Torri V, Qian W. Br J Cancer 2002;87:815-24
Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of 'crossover' to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen 'within' and 'between' groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity 'within' and 'between' groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer.

Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial.
Lancet 2002;360:505-15

BACKGROUND: Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. METHODS: Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. FINDINGS: With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% CI 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% CI -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% CI 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% CI -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. INTERPRETATION: Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemo therapy for ovarian cancer.

Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.
McGuire WP, Hoskins WJ, Brady MF et al. N Engl J Med 1996 4; 334:1-6.

BACKGROUND. Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. METHODS. We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin (75 mg per square meter of body-surface area) with either cyclophosphamide (750 mg per square meter) or paclitaxel (135 mg per square meter over 24 hours). RESULTS. Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). CONCLUSIONS. Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.

Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A gynecologic oncology group study.
Muggia FM, Braly PS, Brady MF et al. J Clin Oncol 2000;18:106-15

PURPOSE: To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS: After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS: Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION: Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.
Piccart MJ; Bertelsen K; James K, et al. J Natl Cancer Inst 2000; 92: 699-708.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Chemotherapy for advanced ovarian cancer. Advanced Ovarian Cancer Trialists Group.
Cochrane Database Syst Rev 2000; (2) :CD001418

BACKGROUND: Ovarian carcinoma is the seventh most common cancer of women in the world and is responsible for the greatest number of deaths from gynaecological malignancy in Europe and North America. Although many studies have explored the use of chemotherapy in this disease, most individual trials have been too small to show clear benefit of one type of chemotherapy over another. OBJECTIVES: The type and intensity of chemotherapy used routinely for women with advanced ovarian cancer has varied because of uncertainty about the effectiveness of the different regimens. The objective of this review was to compare single drugs versus combinations of drugs, platinum versus non-platinum, and carboplatin versus cisplatin-based chemotherapy in women with advanced ovarian cancer. SEARCH STRATEGY: Search strategy: We searched MEDLINE, and CancerLit bibliographic databases and the National Cancer Institute and the UK Co-ordinating Committee on Cancer Research registers of trials. We also hand searched the proceedings of meetings and contacted experts in the field and drug companies. SELECTION CRITERIA: Randomised trials of: (1) single non-platinum versus non-platinum combination chemotherapy (2) single non-platinum versus platinum combination chemotherapy (3) non-platinum regimen versus the same regimen plus cisplatin (4) single platinum versus platinum combination chemotherapy (5) cisplatin versus carboplatin-based chemotherapy in women with advanced ovarian cancer. DATA COLLECTION AND ANALYSIS: Individual patient data were obtained from the trial investigators, checked by the reviewers and finally verified by the trial investigator. MAIN RESULTS: Main results: 49 trials involving 8763 women were included. The data were combined to calculate hazard ratios (HR) for survival on an intention-to-treat basis. For single non-platinum versus platinum combination chemotherapy the overall HR for survival was 0.93, 95% confidence interval (CI) 0.83-1.05 in favour of platinum-based combination chemotherapy. For non-platinum regimens compared with the same regimen plus cisplatin the survival HR was 0.88, 95% CI 0.79- 0.98 in favour of the addition of platinum to drug regimens. Single platinum compared with platinum combination therapy gave a HR of 0.91, 95% CI 0.79-1.05 in favour of combination chemotherapy. Cisplatin versus carboplatin gave a HR of 1.02, 95% CI 0.93-1.12. Sub-group analyses for age, stage, grade, histology, resection, bulk of residual tumour and performance status were undertaken for cisplatin versus carboplatin only. No difference in effect was found. REVIEWER'S CONCLUSIONS: The available evidence, although not conclusive, suggests that platinum-based chemotherapy is better than non-platinum therapy. There is some evidence that combination therapy improves survival compared with platinum alone. No difference in effect has been shown between cisplatin and carboplatin.

ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer.
Lancet 1998;352:1571-6

BACKGROUND: A series of meta-analyses of randomised controlled trials raised the question of whether the three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less effective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer. METHODS: We carried out an international, multicentre, randomised trial to compare CAP with single-agent carboplatin in women with ovarian cancer requiring chemotherapy. 1526 patients were entered from 132 centres in nine countries. Analyses were by intention to treat. FINDINGS: 728 patients have died (368/766 allocated CAP vs 360/760 allocated carboplatin) and the survival curves show no evidence of a difference between CAP and carboplatin (hazard ratio 1.00 [95% CI 0.86-1.16]; p=0.98). The results indicate a median survival of 33 months and a 2-year survival of 60% for both groups. We found no evidence that CAP or carboplatin were more or less effective in different subgroups defined by age, stage, residual disease, differentiation, histology, and coordinating centre. CAP was substantially more toxic than carboplatin, causing more alopecia, leucopenia, and nausea. More thrombocytopenia occurred with carboplatin. INTERPRETATION: Single-agent carboplatin, with the dose calculated by the area-under-the-curve method, is a safe, effective, and appropriate standard of treatment for women with advanced ovarian cancer.

Meta-analysis of cisplatin, doxorubicin, and cyclophosphamide versus cisplatin and cyclophosphamide chemotherapy of ovarian carcinoma.
Fanning J, Bennett TZ, et al. Obstet Gynecol 1992;80:954-60.

OBJECTIVE: To compare the survival with cisplatin, doxorubicin (Adriamycin), and cyclophosphamide versus that of cisplatin and cyclophosphamide in women with advanced epithelial ovarian cancer, to evaluate the effect of dose intensity, and to evaluate meta-analysis methodology. METHODS: Meta-analysis was done on 30 studies of 2060 women with stages III and IV epithelial ovarian cancer. All had 3-year survival data, adequate follow-up, no other chemotherapy, no radiation therapy, and had information for various prognostic variables (age, stage, grade, and residual disease). We used four different methods of meta-analysis: pooled published data and modified effect-size analyses of the entire group (30 studies), and pooled published data and effect-size analyses of the subset of five prospective randomized studies. RESULTS: Three-year survival for the entire group was 43% for cisplatin, doxorubicin, and cyclophosphamide versus 36% for cisplatin and cyclophosphamide; for the five prospective randomized studies, the rates were 46 and 35%, respectively. The survival advantage of cisplatin, doxorubicin, and cyclophosphamide was statistically significant when analyzed by the pooled published data and modified effect-size meta-analysis of the entire group and the pooled published data meta-analysis of the five prospective randomized studies. The effect-size meta-analysis of the five prospective studies did not reach statistical significance. Total dose intensity and doxorubicin dose intensity were not significantly associated with survival advantage in cisplatin, doxorubicin, and cyclophosphamide use. CONCLUSIONS: There seems to be a survival advantage to treatment with cisplatin, doxorubicin, and cyclophosphamide versus treatment with cisplatin and cyclophosphamide. We believe this to be due to the properties of multiagent chemotherapy (the addition of doxorubicin) rather than to increased dose intensity. In addition, we believe that physicians need to familiarize themselves with meta-analysis methodology.

Long-term results of a randomized trial comparing cisplatin with cisplatin and cyclophosphamide with cisplatin, cyclophosphamide, and adriamycin in advanced ovarian cancer. GICOG. Gynecol Oncol 1992;45:115-7.

We report the long-term results of a randomized trial comparing cisplatin (P) with cisplatin and cyclophosphamide (CP) with cisplatin, cyclophosphamide, and adriamycin (CAP) in advanced ovarian cancer. Overall, this update confirms previously published data on 529 cases. Median survival times for the three treatments--CAP, CP, and P--are, respectively, 23, 20, and 19 months. The differences among the three arms are still nonsignificant and the estimated percentage survival at 7 years and confidence limits are, respectively, 21.7 (14.9-28.4), 17.0 (11.0-22.9), and 12.2 (6.9-17.4). According to the results of the Cox regression model on prognostic factors, higher grading, a larger residual tumor size, and performance status less than 80 (Karnofsky) all were independently associated with a poorer outcome, while a serous histotype was related to a better prognosis. The other variables (age, stage, center, type of surgery) initially included in the model did not appear to be significantly related to prognosis. The implications of these long-terms results relative to the application of combination chemotherapy with CAP or CP are discussed.