A randomized comparison of melphalan versus melphalan plus hexamethylmelamine versus adriamycin plus cyclophosphamide in ovarian carcinoma. Cyclophosphamide-cisplatin versus cyclophosphamide-carboplatin in stage III-IV ovarian carcinoma: a comparison of equally myelosuppressive regimens. [Phase III study of carboplatin in ovarian cancer]. Improved therapy with cisplatin regimens for patients with ovarian carcinoma (FIGO Stages III and IV) as measured by surgical end-staging (second-look operation). Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. Controlled prospective trial of combination chemotherapy with cyclophosphamide, adriamycin, and 5-fluorouracil for the treatment of advanced ovarian cancer: a preliminary report. Randomized trial of the addition of cis-platin (DDP) and/or BCG to cyclophosphamide (CTX) chemotherapy for ovarian carcinoma. Long-term survival after chemotherapy for advanced epithelial ovarian carcinoma. Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results--Eastern Cooperative Oncology Group Study E2878. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A Gynecologic Oncology Group Study. A randomized study of single agent vs combination chemotherapy in FIGO stages IIB, III and IV ovarian adenocarcinoma. A prospective randomized trial comparing high-dose cisplatin with low-dose cisplatin and chlorambucil in advanced ovarian carcinoma. Randomized trial in advanced ovarian cancer comparing cisplatin and carboplatin. Comparison of melphalan with cyclophosphamide, methotrexate, and 5-fluorouracil in patients with ovarian cancer. Long-term follow-up of the first randomized study of cisplatin versus carboplatin for advanced epithelial ovarian cancer. Carboplatin alone compared with its combination with epirubicin and cyclophosphamide in untreated advanced epithelial ovarian cancer: a Hellenic co-operative oncology group study. Medical Research Council study on chemotherapy in advanced ovarian cancer. Medical Research Council's Working Party on ovarian cancer. Randomized comparison of cyclophosphamide, doxorubicin and cisplatin (CAP) versus cyclophosphamide and doxorubicin (CA) for the treatment of advanced ovarian cancer (ADOVCA). A EORTC Gynecological Cancer Cooperative Group Study. Intravenous treosulfan versus intravenous treosulfan plus cisplatinum in advanced ovarian carcinoma. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. Treatment of women with disseminated or recurrent advanced ovarian cancer with melphalan alone in combination with 5-fluorouracil and dactinomycin or with the combination of cytoxan, 5-fluorouracil and dactinomycin. Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma. Cisplatin (P) versus cyclophosphamide, adriamycin and cisplatin (CAP) for stage III-IV epithelial ovarian carcinoma: a prospective randomized trial. Low-dose cyclophosphamide versus adriamycin plus cyclophosphamide in advanced ovarian cancer. A randomized clinical study. A randomised study comparing standard dose carboplatin with chlorambucil and carboplatin in advanced ovarian cancer.
A prospective randomized study was conducted in women with suboptimal (greater than or equal to 3 cm residual) Stage III, Stage IV, and recurrent ovarian adenocarcinoma to determine if combination chemotherapy is more effective than melphalan alone in achieving remission and improving survival. Of 233 evaluable patients with measurable disease, there were 64 treated with melphalan alone, of whom 20% achieved a clinical complete response and 17%, a partial response. Of the 97 patients receiving melphalan plus hexamethylmelamine, 28% achieved complete response compared with 32% of 72 patients given Adriamycin plus cyclophosphamide. The partial response rates for the combinations were 24% and 17%, respectively. The effect of these treatments was assessed in an additional 136 evaluable patients without measurable disease by progression-free interval and duration of survival. After statistically adjusting for distribution of cell type and grade, the clinical complete response rate for Adriamycin and cyclophosphamide (32%) in measurable cases was significantly higher (P = 0.04) than for melphalan alone. However, this combination did not improve median survival (12.3, 13.5, and 14.2 months, respectively, for M, M + H, and A + C). None of the other parameters showed a statistically significant advantage for combination chemotherapy, but the combinations caused more hematologic and gastrointestinal toxicity. Between March 1985 and January 1987, 103 women with histologically proven stage III-IV ovarian carcinoma were randomly allocated to groups receiving monthly intravenous regimens of 1 g of cyclophosphamide/m2 plus either 60 mg of cisplatin (CDDP)/m2 or 150 mg of carboplatin (CBDCA)/m2 for 1 year unless disease progressed earlier. The groups were well balanced according to the stratification factors (age, histologic differentiation, extent of residual disease, and performance score), and both treatments were well tolerated and produced similar median first-course leukopenia (2,200 and 2,000 cells/microL) and thrombocytopenia (220,000 and 202,500 cells/microL). The CBDCA regimen was less emetogenic. After an interim analysis in January 1987 revealed superior progression-free survival for the group of 53 patients receiving CDDP (P = .005), the study was closed to further accrual. Those 24 patients still receiving CBDCA were encouraged to cross over to the CDDP-based regimen and 21 of them did. Following treatment crossover, the relative risk of death associated with original allocation to CBDCA receded from 1.79 to 0.97, indicating success of the salvage treatment using the CDDP-based regimen. This aborted study demonstrated the superiority of CDDP over CBDCA when the two platinum compounds were compared at equally myelosuppressive low doses in combination with 1 g of cyclophosphamide/m2. If CDDP is to be supplanted by CBDCA, larger, more myelosuppressive doses of CBDCA will be required. The platinum drug antitumor effect is a critically important therapeutic feature of this combination. A phase III study of carboplatin vs cisplatin in CAP regimen for ovarian cancer was conducted by a cooperative study group consisting of 22 institutions nationwide. The response rate for 23 cases allocated to carboplatin regimen group was 34.8% and 42.1% for 19 cases allocated to cisplatin regimen group. No significant difference was observed between these two regimens in response rates, and no significant differences were noted between the two regimens in each of the clinical toxicities and abnormalities in laboratory findings. Since the carboplatin regimen group did not require hydration, or the use diuretics or antiemetics, these results suggested that carboplatin is more useful in the treatment of ovarian cancer than cisplatin. Between 1974 and 1982, 273 patients with epithelial cancer of the ovary (International Federation of Gynaecology and Obstetrics Stages III and IV) were randomized in four therapeutic trials. In Trial I Adriamycin plus cisplatin versus cisplatin alone versus thiotepa plus methotrexate was tested. The superiority of Adriamycin plus cisplatin in producing the best response rate led to its use as the reference arm in subsequent trials. All investigational arms included cisplatin plus other drugs (cyclophosphamide, Adriamycin, hexamethylmelamine, and thiotepa) in various combinations. Eligibility for second look required complete clinical remission and completion of at least 10 cycles of chemotherapy. To date, 73 second-look operations have been performed on randomized patients. An additional 43 nonrandomized patients underwent second-look procedures and are analyzed separately. Between 40% and 46% of patients treated with cisplatin regimens had no disease at second look. Cell differentiation and volume of postoperative disease did not influence response. To compare cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide as primary chemotherapy for stage III (suboptimal) and stage IV ovarian cancer.
                Three hundred forty-two patients were randomly assigned to treatment with six courses of intravenous (i.v.) cisplatin 100 mg/m2 plus i.v. cyclophosphamide 600 mg/m2, or i.v. carboplatin 300 mg/m2 plus i.v. cyclophosphamide 600 mg/m2.
                The estimated median survivals were 17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the P = .02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. Pathologic complete response rates were similar for both study arms. There was less thrombocytopenia on the cisplatin arm (P less than .001); however, there was less nausea and emesis (P less than or equal to .001 for courses 1 to 5), renal toxicity (P less than .001), anemia (P = .01), hearing loss (P less than .001), tinnitus (P = .01), neuromuscular toxicities (P = .001), and alopecia (P less than .001) on the carboplatin arm.
                Carboplatin-cyclophosphamide proved to have a significantly better therapeutic index than cisplatin-cyclophosphamide in patients with stage III (suboptimal) and stage IV ovarian cancer. nan A prospective randomized trial has compared cyclophosphamide (CTX) with CTX plus cis-diamminodichloroplatinum (DDP) as the initial chemotherapy for advanced ovarian carcinoma. A secondary randomization compared the addition of BCG treatment to either chemotherapy. The addition of DDP had no measurable impact on survival, but a small survival trend favoring BCG-treated patients was noted (P less than 0.08). Toxicity from BCG treatment was insignificant, but the addition of DDP increased both early nausea and vomiting and later hematologic toxicity. There were three long-term complete remission patients, and these all came from the group of six patients with pretreatment residual disease less than 2 cm. A univariate analysis of pretreatment prognostic factors indicated significantly better prognosis (P less than 0.02) for patients with no palpable tumor, platelet count less than 400,000/mm3, residual tumor less than 2 cm, resting pulse less than 91/min. and LDH less than 250 U/L. The authors conclude that for patients with large (greater than 2 cm) residual disease, there is no compelling evidence that initial combination therapy is superior to aggressive single alkylating agent treatment. Four hundred twenty-nine patients were entered into four prospective randomized clinical studies between January 1, 1973, and July 1, 1979. The records of 395 of these were analyzed to determine the proportion of patients surviving 48 months after therapy initiation. Ninety-six patients (24%) were living at 48 months, 89 of whom had second-look laparotomies. Of the 96 living patients, 53 (55%) were clinically free of disease and 43 (45%) had disease. Combination-agent chemotherapy produced a larger proportion of 48-month survivors than single-agent therapy (P = 0.001); 70% of these survivors were clinically free of disease. Patient characteristics, such as age, International Federation of Gynaecology and Obstetrics (FIGO) stage, histologic grade of tumor, and amount of residual tumor present prior to chemotherapy exerted a strong influence on length of survival. Long-term survival was not totally dependent on a complete response to chemotherapy; in fact, persistent treatment with drug regimens induced bone marrow disorders and death due to toxicity in five patients. The continued fall in survival curves after 48 months suggests that current therapy regimens are not dramatically changing long-term survival rates. Following surgical debulking, most patients with international Federation of Gynecology and Obstetrics (FIGO) Stage III or IV carcinoma of the ovary receive treatment with combination chemotherapy. However, the optimal postsurgical therapy for ovarian carcinoma remains to be defined.
                To define better the role of initial therapy with a cisplatin-based chemotherapy regimen, the Eastern (Cooperative Oncology Group (ECOG) initiated a randomized, Phase III trial, EST 2878, comparing initial therapy with a single, orally administered alkylating agent, melphalan, versus a complex regimen employing cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD). Women who failed treatment with melphalan were crossed-over to treatment with CHAD minus the cyclophosphamide (HAD). Study endpoints included response to therapy, time to treatment failure, and overall survival.
                Between October, 1978, and November, 1980, EST 2878 accrued 253 patients with advanced epithelial carcinoma of the ovary. There were 118 eligible patients initially treated with melphalan and 126 with CHAD. Two patients experienced lethal toxicities, including gastrointestinal hemorrhage (1 patient) and neutropenic sepsis (1 patient), and 22 patients experienced life-threatening toxicities, including hematologic toxicity (21 patients) and anaphylaxis (1 patient). Response to treatment and clinical complete response rates were higher in women receiving CHAD (60% and 38%, respectively) versus melphalan (42% and 21%, respectively) (P = 0.037 and P = 0.024, respectively), but these differences were confined to women older than 50 years of age. Likewise, time to treatment failure was significantly longer in women receiving CHAD (P = 0.014), but the difference was again confined to women older than 50 years of age and to women suboptimally debulked at the time of surgery. Survival did not differ between the two arms (median survivals of 17.5 months with initial melphalan therapy and 19.5 months with CHAD), probably because women treated initially with melphalan received salvage therapy with HAD). Twenty-three patients survived longer than 10 years. Among 18 long term survivors who had retrospective pathologic review, 8 had borderline tumors of the ovary.
                In women with advanced ovarian cancer, initial therapy with a cisplatin-based combination chemotherapy regimen resulted in higher clinical complete response rates and longer time to failure compared with initial therapy with a single, oral alkylating agent; however, the benefits of this approach were confined to women older than 50 years of age at diagnosis, and there was no significant difference in survival. A randomized clinical trial was conducted in women with bulky (suboptimal) Stage III and Stage IV ovarian carcinoma, using doxorubicin (Adriamycin) and cyclophosphamide with or without cisplatin. There were 440 evaluable cases, of which 227 had measurable disease. One hundred twenty of these latter patients were treated with cyclophosphamide and doxorubicin (CA), while 107 received cyclophosphamide, doxorubicin and cisplatin (CAP). The clinical complete response (CR) rate for CA was 26% (31/120) compared with 51% (55/107) for CAP (P = less than 0.0001). Of 23 CRs receiving CA who had a second-look laparotomy, only four were negative; of 39 CRs receiving CAP and a second-look, 13 were negative (not statistically significant). The response duration for patients with measurable disease (median 14.6 versus 8.8 months), progression-free interval for all patients (13.1 versus 7.7 months), and survival for patients with measurable disease (19.7 versus 15.7 months) showed a statistically significant advantage for CAP; however, there was no difference in survival of patients with nonmeasurable disease. Toxicity was more severe with CAP but was tolerable. Thus, the addition of cisplatin improves the chemotherapy of advanced ovarian carcinoma. From 1977 until 1980, 179 patients with newly diagnosed FIGO stages IIB, III or IV ovarian adenocarcinoma were randomized in a two-armed clinical trial: dihydroxybusulfan (B) 600 mg/m2 p.o. for 4-6 weeks q 12 weeks or cyclophosphamide (C) 150 mg/m2 p.o. for 7 days q 4 weeks vs a combination of cyclophosphamide 400 mg/m2 i.v., doxorubicin 30 mg/m2 and 5-fluorouracil 400 mg/m2 i.v., days 1 and 8 q 4 weeks (CAF). In addition, stage IIB patients were randomised to +/- pelvic irradiation. The patients were stratified according to anatomic stage. The treatment groups were comparable with respect to performance status, age and histology. Twenty-three patients were excluded because of protocol violation, leaving 156 patients evaluable for survival with an observation period of 3-6 yr. Twenty patients were in stage IIB, while the remaining 136 patients were classified as stages III and IV. No statistically significant difference was found in survival or response between the two single agents. The overall median response rate (single drug: 27%; CAF: 47%) and the median response duration (single drug: 5 months; CAF: 10 months) were significantly superior for the CAF group compared to the single agent group. No statistical difference in median survival was observed between single-drug treatment (12 months) and CAF (14 months), despite the fact that responders lived significantly longer than nonresponders (17 vs 10 months). In stage IIB patients receiving chemotherapy no benefit of pelvic irradiation was found. Thirty patients (19%) underwent second-look laparotomy, with 15 (50%) being completely free of disease. So far only one patient (7%) has relapsed. Two additional patients, who had microscopic disease removed at second-look laparotomy, seem to have been rescued by this procedure. Sixty-one patients with FIGO stage III ovarian carcinoma and 30 patients with stage IV ovarian carcinoma were randomized to receive either high-dose cisplatin (100 mg/m2) or low-dose cisplatin (20 mg/m2) and chlorambucil. Overall response rates were similar in both arms, with 68% and 49% of stage III patients and 61% and 72% of stage IV patients responding to high-dose cisplatin and the combination, respectively. There was a strong trend for better survival in stage III (P less than .05) but not in stage IV patients treated with cisplatin alone. The toxicity suffered by patients treated with high-dose cisplatin was severe, and in 15 patients cisplatin therapy was stopped because of unacceptable toxicity. The aim of this multicenter randomized trial was to compare carboplatin (400 mg/m2) and cisplatin (100 mg/m2) in patients with untreated advanced epithelial ovarian cancer. Toxicity and treatment efficacy assessed by pathological response rate, progression-free survival, and survival were the endpoints of the study. One hundred seventy-three patients with advanced epithelial ovarian cancer, F.I.G.O. (International Federation of Gynecology and Obstetrics) stage III and IV were accrued in the trial. The median follow-up time was 15 months (maximum, 34); three patients in each treatment arm were not eligible (four, nonepithelial ovarian cancer type; one, no data, and one, stage II). Patient characteristics were similar in the two groups. In the carboplatin-treatment arm, the overall pathological response rate was 57.3% and the complete pathological response rate was 26.8%. In the cisplatin-treatment arm, the overall pathological response rate was 71.6% and the complete pathological response rate was 24.7%. There was no statistical difference in the two arms in survival or progression-free survival. Cisplatin was more nephrotoxic while carboplatin induced a higher degree of myelosuppression, especially thrombocytopenia; however, severe hematological toxicity was seldom observed. Carboplatin is a cisplatin analog with definite activity in ovarian cancer, but it is more active than the parent compound. Because of less nonhematological toxicity, carboplatin is undoubtedly a useful substitute in patients who cannot be given cisplatin. Further experience is needed to indicate whether or not carboplatin should completely displace cisplatin in the clinical treatment of ovarian cancer. Melphalan (L-PAM) was compared to (C) cyclophosphamide, (M) methotrexate, and (F) 5-fluorouracil (CMF) in 413 patients with advanced ovarian carcinoma. L-PAM was given 3.5 mg/m2 twice daily for 5 days every 5 weeks. CMF doses were: C, 400 mg/m2; M, 15 mg/m2; and F, 400 mg/m2 IV on days 1 and 8 every 28 days. Three hundred seventy-five patients have been analyzed (L-PAM, 190; CMF, 185). One hundred fifty-three patients (41%) had measurable disease, 109 (29%) had evaluable disease, and 113 (30%) had nonmeasurable, nonevaluable disease. Response rates for patients with measurable and evaluable disease combined were similar: L-PAM, 32/130 (24%) (15% complete response); CMF, 47/132 (35%) (18% complete response). Patients with Stage IV measurable disease had a greater response rate to CMF, 22/52 (42%) versus L-PAM, 6/39 (15%). Survival and time to treatment failure were similar for both treatment regimens. Survival was improved in responders. Medians are: complete response, 28.1 months; partial response, 12.3 months; and no response, 6.7 months. Disease stage, performance status and age were identified as important prognostic variables for both survival and time to treatment failure. A phase III trial was performed between October 1981 and June 1984 to compare the efficacy of single-agent cisplatin and single-agent carboplatin in previously untreated patients with International Federation of Gynecology and Obstetrics stage III or IV carcinoma of the ovary following surgery. This report describes the survival rates of patients in this study after a minimum follow-up duration of 8 years.
                Sixty-four patients were randomized to receive cisplatin and 67 patients to receive carboplatin. Cisplatin was administered every 4 weeks for a total of 10 courses, courses 1 to 5 at a dosage of 100 mg/m2 and courses 6 to 10 at 30 mg/m2. Carboplatin was administered at a dosage of 400 mg/m2 every 4 weeks for 10 courses. Patients who had clinical or radiologic evidence of response after five courses of chemotherapy underwent second-look surgery. The study was designed to allow crossover between the two arms. Thirteen patients were excluded from response analyses because they were incorrectly randomized. Patients were crossed over to the other arm of the study because of progressive disease (PD), nonresponse, or toxicity.
                The overall response rate for patients randomized to the cisplatin arm was 53.8% (28 of 52; 95% confidence interval [CI], 39% to 68%) and for those randomized to the carboplatin arm, 38.4% (20 of 52; 95% CI, 25% to 53%). There were 16 (30.8%) and 14 (26.9%) complete remissions (CRs) in the cisplatin and carboplatin arms, respectively. None of these differences were statistically significant. The median duration of response for the cisplatin and carboplatin arms was 21 months and 17 months, and the 5-year relapse-free survival rates were 22% and 25%, respectively. The median survival durations for the cisplatin and carboplatin arms were 19.5 and 13 months, and the 5-year survival rates were 15% (95% CI, 8% to 26%) and 19% (95% CI, 11% to 30%), respectively. None of these differences was statistically significant. The median follow-up duration of patients is 9 years. Crossover due to toxicity was more frequent in the cisplatin than the carboplatin arm, occurring in 50% and 3.3% of patients, respectively.
                The mature data from this study of patients with advanced ovarian cancer show that cisplatin and carboplatin have similar long-term survival results. We compared, in a multicentric randomised prospective study, the efficacy and toxicity of carboplatin 400 mg/m2 as a single agent (CB) to a combination of carboplatin 300 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (CB-EC) in advanced ovarian cancer patients. The treatment was scheduled to be administered every 3 weeks for six courses. Following initial laparotomy and cytoreductive surgery, 130 previously untreated patients entered the study. 73 patients were treated with carboplatin alone while 57 received the combination chemotherapy. In the majority of the patients, the regimens had to be given every 4 weeks due to myelosuppression. Nausea, vomiting and alopecia were more severe in the CB-EC arm. Overall, clinical complete response was observed in 73 (56%) and partial response in 20 (15%) patients. The median time to progression was 16.89 months and median survival was 29.54 months. No significant differences in response rate, time to progression, disease-free survival and overall survival were observed between the two treatment arms. The prognostic role of residual disease after initial surgery, complete remission at second-look laparotomy, tumour stage and performance status was confirmed. A total of 264 eligible patients with advanced ovarian cancer were randomised to single or triple agent cytotoxic therapy; 261 were available for analysis. The treatments were continuous oral cyclophosphamide (arm S), and a combination of oral cyclophosphamide, hexamethylmelamine and methotrexate on a pulsed basis (arm T). Mortality attributed to cancer was slightly lower on arm T (p = 0.06), but this was offset by the greater toxicity of this regimen, and overall survival and activity index were similar on the two arms. There was thus little evidence of greater clinical benefit on the triple agent regimen. Tumour mass removed at operation, extent of remaining tumour and age all showed significant correlation with prognosis. Survival was longer in patients whose disease responded to either therapeutic regimen. The possible advantage of adding cisplatin (P) to cyclophosphamide (C) + adriamycin (A) in the management of stages III and IV ovarian cancer of epithelial origin was tested in a trial in which 149 patients were randomized to receive, after initial surgery, either CAP (C = 600 mg/sqm, A = 45 mg/sqm, P = 50 mg/sqm) or CA (C = 600 mg/sqm, A = 45 mg/sqm) every 4 weeks for 6 to 12 cycles, at which time follow-up laparotomoy was to be performed in responding or clinically disease-free patients. Fifteen patients were not included in the final analysis and the remaining 134 patients were considered fully or partially evaluable and are used in analysis of response and survival. The complete and partial response rates were 45.6% in the CAP arm and 45.4% in the CA arm, but the CAP regimen is of special importance in patients with bulky disease. Median survival CAP = 24 m and CA = 24.2 m), time to progression and survival was found not significantly different when CAP and CA were compared. However, more patients in the CA regimen had no macroscopic disease left after surgery than in CAP regimen (11 versus 6) and more patients in the CAP arm dose reductions and schedule delays than in the CA arm (61.1% versus 38.2%). In a prospective, multicentre, randomized trial, the efficacy and tolerance of treosulfan alone was compared with that of treosulfan plus cisplatinum in 135 women with advanced ovarian carcinoma. No statistically significant difference was found between the two treatments in terms of median survival. Combined treatment was associated with significantly greater side-effects and haematological toxicity. Optimal survival with minimal toxicity can be achieved by using treosulfan alone in patients (mainly stages Ic or II) with minimal postoperative residual disease. Patients (likely to be stage III or IV) with greater residual disease should receive treosulfan plus cisplatinum. Given the potential for improved tolerance, a trial was initiated to compare the toxicity and efficacy of a standard regimen of cisplatin-cyclophosphamide (75 mg/m2 and 600 mg/m2, respectively) with an experimental regimen of carboplatin-cyclophosphamide (300 mg/m2 and 600 mg/m2, respectively) in women with postoperative macroscopic residual ovarian cancer.
                Between 1985 and 1989, 447 (417 eligible) patients were randomized. Treatment arms were well balanced; most patients had stage III (82%), grade 3 (54%) tumors with bulky residual (greater than 2 cm in 59%), and good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1, 77%). Response was assessed after six 4-week cycles.
                The treatments were equally deliverable, with 76% of patients completing their allocated regimen. The reported reasons for failure to complete treatment differed; toxicity/refusal predominated on the cisplatin arm, and progressive disease predominated on the carboplatin arm (P = .0092). Cisplatin-treated patients were more likely to develop neuropathy and nephropathy, and carboplatin patients experienced myelosuppression, particularly thrombocytopenia. Efficacy was similar, with no significant differences for the cisplatin and carboplatin arms in clinical response rate (57% v 59% in those with measurable disease), pathologic response rate (52% v 54% in those suitable for relaparotomy), time to progression (median, 56 v 58 weeks), or overall survival (median, 100 weeks v 110 weeks). Time to progression and survival were predicted by residual disease size, performance status, and treatment center (with those treated at centers that accrued more patients doing better).
                Neither regimen is optimal in that relapse remains the norm. It may be inappropriate to expect that any single regimen can be an effective therapy for all patients with advanced ovarian cancer. Both cisplatin and carboplatin are likely to have a role in future treatment strategies. The purpose of this study was to determine the efficacy of single and multiple drug chemotherapeutic regimens in the treatment of patients with advanced or recurrent, Stage III and IV, ovarian epithelial carcinoma. Patients were randomly assigned to one of four treatment regimens postoperatively, or at the time of recurrence: Regimen I--Melphalan (MEL) 0.2 mg/kg/day for five days every four weeks; regimen II--MEL as in Regimen I plus 5-fluorouracil (FU) 15 mg/kg/day for five days every four weeks; regimen III--MEL and FU as in regimen II plus dactinomycin (AC) 0.5 mg daily for five days every four weeks; and regimen IV--Cytoxan (CY) 7 mg/kg/day, FU 8 mg/kg/day and AC 0.5 mg/day for five days every four weeks. Four hundred and twenty-seven patients were in the study, 314 of whom are evaluable for progression-free interval (PFI), survival, and toxicity: 102 in regimen I, 80 in regimen II, 83 in regimen III, and 49 in regimen IV. Of these, 293 were considered evaluable for response. Because of excessive toxicity, entry of patients to regimen IV was discontinued midway through the study. The overall toxicity was quite high but was most severe in regimen II and IV where 16 toxicity deaths were recorded. The complete and partial response rate with Melphalan alone was 29.2%. This response rate was not enhanced by the addition of FU or FU and AC and not substantially different than the response rate of AC, FU, and CY. A total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18-36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity. In 1982 a randomized trial was started to compare a cisplatin-containing polychemotherapy (CAP: cyclophosphamide - CPA 750 mg/m2, adriamycin - ADM 50 mg/m2, cisplatin - P 50 mg/m2 on day 1 every 21 days) with full-dose cisplatin as single agent (P 60 mg/m2/day on days 1 and 2 every 28 days) in 44 patients undergoing exploratory laparotomy or debulking surgery for stage III-IV epithelial ovarian carcinoma with residual disease greater than 5 cm. The response was evaluated at second-look surgery with random biopsies and peritoneal washing. On the basis of the final results the authors underline some data which, although merely indicative (because of the small number of patients) appear to be worth considering since they are in accordance with the latest reports: a) similar response rate (CR + PR = 47%) to first-line treatment in the two groups; b) the CAP treatment may achieve a longer median duration of CRs than the P treatment (20 versus 11 months); c) overall survival seems similar in the two groups of patients (19 versus 18 months), whereas the survival of CRs seems longer in the CAP treated patients (greater than 32 versus 25 months). The authors also discuss some observations on a possible salvage therapy. After intensive staging 74 ovarian cancer patients were randomized to two arms balanced for stage and post-surgery residual tumor. The two regimens were CTX 100 mg/day continuously and ADM 50 mg/m2 IV every 4 weeks plus CTX 100 mg/day. The response rates were respectively 42% and 52%. Median survival times were 13 and 14 months. The incidence of side effects was significantly higher in the combination-treatment arm. No other statistical differences were found. A total of 161 previously untreated patients with FIGO stage III or IV epithelial ovarian cancer were randomised after surgery to receive six courses of either carboplatin 400 mg m-2 alone (Arm A) or carboplatin 300 mg m-2 with chlorambucil 10 mg day-1 for 7 days (Arm B). The median progression free survival (PFS) was similar: arm A: 45 weeks; arm B: 61 weeks (P = 0.830). Multivariate Cox regression analysis showed that the extent of residual disease and performance status were the most important prognostic factors for PFS. Fifty-two per cent of patients received dose escalations based on nadir blood counts, and 89% of all dose adjustments were made according to protocol. Failure to achieve a significant degree of leucopenia was associated with worse progression free survival (P less than 0.001). A total of 29.4% of patients fall into this category. The median survival was similar in both arms, i.e. 75 weeks. It is unlikely that there is any major clinical advantage to adding chlorambucil to single agent carboplatin for the management of advanced ovarian cancer, but whether used in combination or a single agent, the dose of carboplatin should be sufficient to cause at least grade I leucopenia. This may best be achieved by determining the initial dose based on renal function, and then adjusting subsequent doses according to nadir blood counts.