Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial.

Patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receive adjuvant therapy after surgery but it is not clear whether radiotherapy (RT) or chemotherapy (CT) is better. We randomly assigned 345 patients with high-risk endometrial carcinoma to adjuvant CT (cisplatin (50 mg m(-2)), doxorubicin (45 mg m(-2)), cyclophosphamide (600 mg m(-2)) every 28 days for five cycles, or external RT (45-50 Gy on a 5 days week(-1) schedule). The primary end points were overall and progression-free survival. After a median follow-up of 95.5 months women in the CT group as compared with the RT group, had a no significant hazard ratio (HR) for death of 0.95 (95% confidence interval (CI), 0.66-1.36; P = 0.77) and a nonsignificant HR for event of 0.88 (95% CI, 0.63-1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 78, 69 and 62% in the RT group and 76, 66 and 62% in the CT group. The 3, 5 and 7-year progression-free survivals were, respectively, 69, 63 and 56 and 68, 63 and 60%. Radiotherapy delayed local relapses and CT delayed metastases but these trends did not achieve statistical significance. Overall, both treatments were well tolerated. This trial failed to show any improvement in survival of patients treated with CT or the standard adjuvant radiation therapy. Randomised trials of pelvic RT combined with adjuvant cytotoxic therapy compared with RT alone are eagerly awaited.

Consolidation therapies revisited: weekly paclitaxel.

Most patients with advanced ovarian cancer exhibit clinically relevant objective and subjective responses to platinum/paclitaxel-based combination, which is now considered the standard chemotherapeutic regimen. Unfortunately, responses are generally of limited duration, and long-term disease-free survival is experienced by few patients. Efforts should be taken to maintain such a response as long as possible, where it realistically might be hoped that continuation of chemotherapy could consolidate the absence of clinically detectable disease. In this regard, the administration of paclitaxel on a weekly schedule seems to be particularly attractive, especially after the demonstration that a weekly regimen in heavily pretreated women bearing metastatic breast, head, and neck or lung cancers was proven to be well tolerated without the requirement of granulocyte colony-stimulating factors, with limited neurotoxicity and with substantial anticancer activity, thanks to its pro-apoptotic and antiangiogenesis properties. In Italy, a multi-institutional phase II prospective study (After-6 Protocol 2) has been initiated to verify the effectiveness of paclitaxel, administered on a weekly schedule (60 mg/m2 for 21 courses), in patients bearing microscopic residual disease detected at second-look operation to define its effectiveness after completing their primary platinum/paclitaxel chemotherapy treatment. When possible, patients were surgically re-evaluated thorough a third-look operation to evaluate the percentage of conversion of microPR into a pathological complete remission status. An interim evaluation based on 534 cycles administered to 41 patients showed than only one patient experienced grade 4 anemia, 7.4% grade 2 transient peripheral neurotoxicity, and 2.7% delay in treatment delivery. Therefore, weekly paclitaxel has been proven to be easily administered even in heavily pretreated patients, with acceptable hematological and neurological toxicity.

Cancer in women.

Incidence, mortality and survival trends for the most frequent cancers affecting women are presented on a worldwide basis. Data sources are represented by several different cancer databases, as no single world cancer database covers these epidemiological measures. Monitoring cancer incidence, mortality and survival are fundamental indicators which allow estimates and predictions of geographical and temporal changes of these diseases, enabling the design and set-up of adequate cancer control activities and national health programs. The observed differences in cancer incidence, mortality and survival in more developed countries compared with less developed countries (as defined by WHO) are mainly due to different individual and social risk factors between the two geo-political areas. For some cancers, advancements in screening, diagnosis and treatment in the more developed areas were the most effective factors in reducing incidence and mortality as well as prolonging survival. These effects were not detected in the less developed areas because of the limited access to primary and specialist care.

Cisplatin, doxorubicin and ifosfamide in carcinosarcoma of the female genital tract. A phase II study of the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group (EORTC 55923).

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Systemic therapy for gynecological neoplasms: ovary, cervix and endometrium.

Early-stage endometrial carcinomas should be treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. In a small subset of patients, who wish to have children, conservative treatment (hormonal therapy) could be considered. The most effective agents for palliation of advanced disease are doxorubicin plus cisplatin.

Staging of gynecologic malignancies.

The staging of gynecologic cancer is one of the fundamental aspects of the activity of the Committee on Gynecologic Oncology of the International Federation of Gynecology and Obstetrics. The rules for proper staging according to scientific evidence are presented in this article. Some of the most debatable issues are also discussed.

Early stage ovarian cancer: the Italian contribution to clinical research. An update.

Early ovarian cancer (stages IA-IIA) accounts for 30% of all epithelial ovarian cancer. Even if relatively uncommon, when "high risk" patients are considered, it is lethal in 25-30% of the cases. Mainstay of treatment is surgery followed by either adjuvant chemotherapy or radiotherapy when indicated on the basis of still debatable prognostic factors. Literature data show a great variability in survival rate due to the great heterogeneity of patients considered in different reports and few randomized trials affected by a consequent low power. Italian groups have contributed both in investigating the role of surgery and of chemo or radiotherapy in the treatment of this disease. An important contribution in surgery has been made by Italian institutions in reducing the extent of surgery in young patients wishing to retain their reproductive capability showing that a "conservative surgery" (unilateral oophorectomy) can be safely performed in initial stages without affecting the probability of cure. Another important surgical topic investigated by Italian institutions concerns the role of lymphadenectomy. In early ovarian cancer the node involvement ranges between 14-24% in stage I and 37-50% in stage II. Although the node positivity rate detectable by sampling (SA) is lower than the one shown by a systematic procedure (LY), no data at the moment show that patients undergoing a sampling evaluation have a poorer prognosis. From 1992 through 1994, 202 patients (SA: 99; LY: 103) were enrolled by six Italian institutions in a randomized trial aimed to assess the diagnostic and therapeutic role of SA vs. LY in early stage ovarian cancer. Positive nodes were detected in 9.9% vs. 19.3% respectively as well as a different proportion of intra/perioperative complications occurred. No difference in time to relapse nor in overall survival were detected in the two groups showing no evidence of efficacy in favor of extensive staging of the retroperitoneum. From 1983 to 1990, 271 stage I ovarian cancer patients entered two prospective multicentric randomized trials conducted by Italian institutions. Trial I compared cisplatin (50 mg/m2, six cycles repeated every 28 days) vs. no further treatment in stage IA-B grade 2-3 patients; Trial II compared the same dose and schedule of cisplatin vs. intraperitoneal P32 in stage IC patients. Cisplatin significantly reduced the relapse rate by 65% in Trial I and by 61% in Trial II, but survival was not affected (Trial I: HR = 1.15, 95% CI = 0.44-2.98; Trial II: HR = 0.72, 95% CI = 0.37-1.43). The final conclusion drawn by these two important Italian studies was that adjuvant cisplatin treatment in early ovarian cancer prevents relapse although the impact of chemotherapy remains unclear. For this reason two international trials have been performed (ICON1 and ACTION) aimed at assessing the role of platinum-based chemotherapy on survival. Italian collaboration in both trials has been important, including about half of the total number of the 900 randomized patients. Results will probably be available during this year and are expected with a great interest by the whole scientific international community.

D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group Study.

Between March and September 1988, 74 patients with progressive ovarian cancer after prior platinum-based therapy were treated with the luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin (Decapeptyl degrees). Treatment consisted of i.m. injection of 3.75 mg of microencapsulated Triptorelin on days 1, 8 and 28 followed by 4-weekly injections until tumor progression. No objective responses were observed. Eleven out of 68 evaluable patients (16%) had stable disease. The median progression-free survival was 5 months in patients with disease stabilization and 2 months for all evaluable patients. The median survival for patients with disease stabilization was 17 months, whereas for all patients it was 4 months. The treatment was well tolerated; the only reported adverse events were incidental hot flushes. This study showed that the LHRH agonist Triptorelin has only modest efficacy in patients pretreated with platinum-containing chemotherapy.

Quality of life: gynaecological cancers.

The clinical management of gynaecological cancer patients has been mainly focused on prolonging the survival of the patients. Thus, research on MEDLINE using as keywords 'Quality of Life' (QoL) allowed us to identify few papers which reported data on QoL in gynecological oncology. However, the assessment of QoL is becoming one of the most important issues in gynecological oncology, and there is a growing interest in including quality of life measurements in clinical trials. In fact, in several randomised trials on ovarian cancer now ongoing in Europe, the evaluation of QoL has been planned. The one underlying this article focuses on the symptoms and problems particular to gynecologic cancer and the treatments of them that could affect quality of life evaluations. These include limitations of sexual activity and fertility, early menopause, chemotherapy induced toxicity, and loss of body image. In this report, we will discuss the aspects affecting the QoL in gynaecological cancer in relation to surgical treatment, medical therapy, and follow-up.

Quality control in multicentric clinical trials. An experience of the EORTC Gynecological Cancer Cooperative Group.

Data Quality is a central requirement of scientific research and external monitoring is essential in multicentric clinical trials (MCT). A quality control (QC) study was conducted in the main Institutions participating in EORTC-GCCG Protocol number 55863 - randomised phase III trial of vindesine, cisplatin, bleomycin and mitomycin-C (BEMP) versus cisplatin (P) in disseminated squamous cell carcinoma of the uterine cervix - in order to assess the impact of variations in data quality on the conclusions of the trial. The reliability of the different centres in following the protocol was investigated by a questionnaire covering drug prescription, local facilities and the procedure for preparation and administration of chemotherapy. The 'treatment protocol adherence' was evaluated by recalculation of the ideal protocol dose and its comparison with the actual delivered dosage at each cycle of chemotherapy. 'Data quality control' was assessed by comparison of data on case report forms (CRFs) with the corresponding items in the medical records. Eleven centres participating in the trial were visited by the same team of reviewers. Striking differences were noted in the chemotherapy administration procedures and between the type and quality of hospital files. Overall, there was an acceptable level of data quality and protocol compliance. Data accuracy was 81.8% (range: 65. 6-97%) of the 4424 items checked. Incorrect data were found in 7.0% (2.3-14.5%), data were missing on the form in 3.6% of cases (0-12%) and data was on the form but not in the file in 7.6% of cases (0. 7-17.5%). Causes of inaccuracy were analysed. Both problems in data management but also in a lack of clarity of the protocol and/or CRFs were to blame. Training and supervision of data managers, precision in writing protocols, standardisation of some aspects of CRFs and the use of a checklist for chemotherapy data and treatment toxicities would have avoided many of these errors. The need for QC in all collaborative groups performing MCT is emphasised. A literature review on QC in MCT dealing with chemotherapy is included.

Surgery of advanced malignant epithelial tumours of the ovary.

Surgery is still the cornerstone in the management of advanced epithelial ovarian cancer (AEOC) patients. It involves: i. establishment of diagnosis and staging; ii. primary cytoreduction; iii. interval cytoreduction, interval debulking surgery (IDS) or surgery after neoadjuvant chemotherapy; iv. secondary cytoreduction during the assessment of the status of the disease at the end of primary chemotherapy - second look; v. surgery for recurrence; vi. palliation. Substantial evidence exists to demonstrate that if surgery is performed by gynaecologists with a special training in gynaecological oncology, a survival advantage can be achieved when compared with that obtained when general surgeons are primarily treating AEOC. Primary surgery with diagnostic and cytoreductive intent should be performed in accordance with the European Guidelines of Staging in Ovarian Cancer. Whether or not cytoreduction should systematically include lymphadenectomy is still a controversial issue. The strong correlation between chemosensitivity, successful debulking surgery and survival strongly support the concept that it is the biological characteristic of the disease rather than the aggressiveness of the surgeon to allow a successful cytoreduction to the real optimal disease status. It should be now recognised as the complete absence of disease at the end of the surgical procedure. Both IDS and neoadjuvant chemotherapy represent a strong effort to achieve such a status through less morbidity and a better quality of life for the patient. Surgery for recurrence and palliation need to be optimised both in terms of patient selection and a better integration with chemotherapy and ancillary management.

The use of carbon-dioxide laser surgery in the treatment of intraepithelial neoplasia of the uterine cervix.

From October 1989 to June 1997, 1841 patients (pts) suffering from different diseases of the lower genital tract have been treated with CO2 laser surgery in our Institution: among them, 782 were affected by cervical intraepithelial neoplasia (CIN). All pts underwent CO2 laser procedure for CIN after adequate colposcopic evaluation of the entire lower genital tract, colposcopic guided biopsy of the lesion, adequate pre-surgical work-up for possible infectious and coagulation associated disease. In 736 (94.1%) pts, the procedure was performed on an ambulatory basis while 46 pts (5.9%) were admitted for 1 or 2 days. A CO2 laser Sharplan 55 associated to a Zeiss operative colposcope was employed. The preoperative diagnosis of the 782 pts treated for CIN was 297 CIN1, 255 CIN2, 171 CIN3 and 59 CIS. Mean age was 33.6 years without statistical difference among the grade of disease: 605 pts underwent laser vaporization according to specific selection criteria. The depth of cervical destruction was less than 6 mm in 26 cases, between 6 and 10 mm in 549, between 11 and 15 mm in 157, more than 15 mm in 50 pts. 742 procedures were performed under local anesthesia and pain was absent in 667 pts. (89.9%), mild in 51 (6.8%), moderate in 19 (2.5%) and severe in 5 (0.7%). Intraoperative bleeding was severe in 30 pts. (3.8%), moderate in 77 (9.8%), mild in 204 (26.1%) and absent in 471 (60.2%). The conization procedure was shown to have a higher risk of bleeding but no direct relation was observed with the depth of cervical destruction. Late complications were scarce: 1.3% of late hemorrhages, 1.4% of stenosis of cervical external orifice and cervical endometriosis in 0.3%. In 76 pts (42%) of the 177 conizations the final pathology report was in accordance with the previous biopsy, in 56 (30.9%) a lower grade of CIN was observed, in 53 (29.3%) a worse grade of the lesion was retrieved. Among these latter pts. 10 showed a microinvasive and 2 an invasive cancer: both the invasive but only 3 of the 10 microinvasive cancer pts underwent a surgical procedure (2 radical and 3 extrafascial hysterectomies, respectively). After a mean follow up of 37 months our incidence of recurrence is 2.3% (18 pts): 5 CIN1, 7 CIN2, 3 CIN3, 2 CIS and 1 microinvasive disease. In 78% of the instances the recurrence has occurred within the first year of follow up. All 18 recurrences were successfully treated with further vaporization in 8 cases, conization in 9 and hysterectomy in 1. 93 term pregnancies occurred in 83 pts after CO2 laser treatment of CIN. No cervical incompetence occurred (no cervical cerclage employed) while the incidence of spontaneous abortion was not statistically significant. 82 pregnancies were delivered vaginally without significant variation of labor phase duration. The incidence of caesarian section (11.8%) was lower than the mean incidence in our Institution. These data confirm the successful complete restitutio ad integrum of the cervix after an adequate CO2 laser surgical procedure without any further risk of cervical incompetence, premature delivery or premature rupture of membranes. The use of CO2 laser surgery is recommended as modality treatment of choice in the management of cervical intraepithelial neoplasia.

PVB chemotherapy in patients with recurrent or advanced dysgerminoma: a Phase II study of the EORTC Gynaecological Cancer Cooperative Group.

Dysgerminoma accounts for 1% of all ovarian cancers and for 50% of all ovarian germ cell malignancies. Low stage patients (50%) can be cured with local treatment. The aim of this trial was to study the objective tumour response rate and toxicity of PVB (cisplatin, vinblastine, bleomycin) chemotherapy in patients with pure advanced or recurrent dysgerminoma. Eighteen eligible patients with advanced dysgerminoma were entered into this study. Three patients had local bulky recurrence only; all the others also had metastatic disease. The median age at entry was 27 years (range 1348). Seventeen patients had had prior surgery and one had undergone prior radiotherapy. The WHO performance status was 0 in 12 patients, 1 in three patients, and 2 in three patients. The treatment consisted of: intravenous or intramuscular bleomycin 30 mg on days 2, 9 and 16, intravenous vinblastine 0.15 mg/kg on days 1 and 2, and intravenous cisplatin 20 mg/m2 on days 1-5. This regimen was given at 3-week intervals for a total of four cycles. Twelve patients obtained a complete response (66%), five a partial response (28%), and one could not be evaluated because radiotherapy was administered immediately after chemotherapy. After a median follow-up of 76 months (range 4-132), 14 (78%) patients were alive and well. Two died of disease progression, one of neutropenic septicaemia and one of lung fibrosis. No unusual toxicity was reported. Alopecia, as well as nausea and vomiting, were common. Leucopenia (78%), thrombocytopenia (17%) and infection (11%) were the other severe (grade 3-4) side effects. The PVB chemotherapy regimen is highly effective in patients with advanced ovarian dysgerminoma. However, the BEP (bleomycin, etoposide, cisplatin) regimen, which is equally as potent and less toxic, is preferred.

Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer.

PURPOSE: To compare the efficacy of a treatment with cisplatin plus cyclophosphamide given for 5 months and a short treatment with cisplatin alone in advanced ovarian cancer, we conducted a multicenter randomized clinical trial. PATIENTS AND METHODS: Eligibility criteria were as follows: first diagnosis of histologically confirmed invasive epithelial ovarian cancer of International Federation of Gynecology and Obstetric (FIGO) stage III-IV, age younger than 75 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Within 28 days of cytoreductive surgery, eligible women were randomly assigned treatment with weekly cisplatin 50 mg/m2 for nine courses or cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 every 21 days for six courses. RESULTS: A total of 607 women were entered onto the study. There was no difference in the response to treatment. Pathologic complete response (CR) was documented in 63 of the weekly cisplatin cases and 70 of the cisplatin plus cyclophosphamide group (chi 1(2) = 1.43; P = .23). The median follow-up time was 3 years. There were 151 and 148 deaths in the weekly cisplatin and cyclophosphamide plus cisplatin arms, respectively. Survival curves were similar in the two groups, with a 3-year percent survival estimate of 44.1 (SE = 3.4) in the weekly cisplatin and 44.6 (SE = 3.4) in the cisplatin plus cyclophosphamide group (log-rank test chi 1(2) = 0.004; P = .96). CONCLUSION: This study found that 2-month monochemotherapy treatment with cisplatin was as effective as 5-month polychemotherapy including cisplatin at a similar doses but different dose-intensity plus cyclophosphamide.

Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study.

PURPOSE: Topotecan is a topoisomerase I inhibitor with preclinical activity against various tumor types. We conducted a large multicenter phase II study with topotecan in ovarian cancer in patients who had failed to respond to one prior cisplatin-based chemotherapeutic regimen. PATIENTS AND METHODS: Topotecan 1.5 mg/m2/d was administered intravenously by 30-minute infusion for 5 days repeated every 3 weeks. As the cisplatin-free interval relates to response in subsequent treatment, patients were stratified in subgroups, ie, cisplatin-refractory, cisplatin-resistant, and cisplatin-sensitive. RESULTS: One-hundred eleven patients entered the study. Nineteen patients were considered to be ineligible; 92 patients were assessable for response. A total of 552 courses were given (median, four per patient; range, one to 17). The major toxicities were leukocytopenia and neutropenia, which were grade 3 to 4 in 54.2% and 69.1% of courses, respectively, but with only 4.3% of these being grade 4 neutropenia plus fever or infectious complications. Prophylactic granulocyte colony-stimulating factor (G-CSF) was given in 20.5% of courses to maintain dose-intensity. Other relatively frequent side effects were alopecia (82%), nausea (36.4%), and vomiting (17.5%). The overall response rate was 16.3%, with one complete response (CR) and 14 partial responses (PRs). In the cisplatin-refractory, cisplatin-resistant, and cisplatin-sensitive strata, the response rates were 5.9%, 17.8%, and 26.7%, respectively. The median duration of time of documented response was 21.7 weeks (range, 4.6 to 41.9). CONCLUSION: Topotecan in a daily-times-five schedule is an effective regimen as second-line treatment in ovarian cancer. Further investigations of topotecan in ovarian cancer, including first-line use and combination with other active agents, are indicated.

Adjuvant treatment for early epithelial ovarian cancer: results of two randomised clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P). G.I.C.O.G.: Gruppo Interregionale Collaborativo in Ginecologia Oncologica.

BACKGROUND: From 1983 to 1990, 271 consecutive patients with stage I ovarian cancer entered two randomised trials, aimed at assessing the role of adjuvant chemotherapy after radical surgery in early stages of ovarian cancer. Trial I compared cisplatin (50 mg/m2 with repeated courses every 28 days for 6 cycles) to no further therapy in F.I.G.O. stage Ia & b Grade II-III patients; trial II compared cisplatin (same dose and schedule) to 32P in Iaii & bii and Ic patients. METHODS: Both studies were multicentric and centrally randomized. Treatment was allocated by phone and stratified by center. All patients satisfying major eligibility criteria (histological and grade, no previous neoplasms) were analysed according to treatment allocated by randomisation. RESULTS: With a median observation time of 76 months, cisplatin significantly reduced the relapse rate by 65% (HR = 0.35; 95% CI = 0.14-0.89, p = 0.028; Cox Model) in trial I and 61% (HR = 0.39; 95% CI = 0.19-0.77, p = 0.007; Cox Model) in trial II. Survival was not significantly different (trial I - Kaplan-Meier overall 5-year survival: cisplatin = 88%, control = 82%, HR = 1.15; 95% CI = 0.44-2.98; p = 0.773; Cox Model); trial II - overall 5-year survival: cisplatin = 81%, 32P = 79%, HR = 0.72; 95% CI = 0.37-1.43; p = 0.354; Cox model). In both studies the risk of dying after relapse increased for patients originally randomized to the cisplatin arms: in trial I, 6 of 7 patients in the cisplatin relapsed arm and died of tumor compared with 8 of 14 patients in the control arm. In trial II 11 of 12 patients on cisplatin, and 18 of 26 on 32P succumbed to tumor recurrence. CONCLUSION: Adjuvant cisplatin treatment in early ovarian cancer significantly prevents relapse in comparison to 32P in stage IC patients or to no immediate treatment in earlier stage women. The impact of cisplatin adjuvant treatment on survival remains, however, unclear.