The cyclophosphamide, hexamethylmelamine, 5 fluorouracil (CHF) regimen in the treatment of advanced and recurrent ovarian cancer

Fifty-one patients with advanced ovarian carcinoma were treated with a combination of cyclophosphamide, hexamethylmelamine, and 5-fluorouracil, CHF. Compared to the hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) regimen, the omission of methotrexate in CHF did not detract from its antitumor activity and it was well tolerated with only mild to moderate toxicity. The CHF combination was as effective as Hexa-CAF and was particularly active in patients who had nonmeasurable/residual disease, classified as less than 2 cm in its greatest diameter at the initiation of chemotherapy. In future studies, CHF should be prospectively compared to other combination using Adriamycin and cis-platinum that with extended use can cause renal and cardiac damage in long-term survivors.     

High-dose melphalan and autologous bone marrow support for treatment of ovarian carcinoma with positive second-look operation

Patients with epithelial ovarian carcinoma (OVCA) and positive second-look operation (SLO) have a poor short-term prognosis. Treatment after SLO is still controversial and pilot studies are justified in an attempt to improve survival of these patients. As OVCA is known to be a chemosensitive tumor, it seems logical to treat these patients with high-dose chemotherapy with the support of an autologous bone marrow transplantation. Fourteen patients underwent primary surgery with tumor debulking followed by cis-platinum-based chemotherapy. SLO was performed in each patient and was microscopically positive in five and macroscopically positive with secondary debulking in nine. All patients were treated after SLO with high-dose melphalan (HDM), 140 mg/m2, and autologous bone marrow support. HDM was well tolerated, with a median time to granulocyte recovery of 21 days. There was no death due to treatment toxicity. The mean follow-up after SLO is 43 months. Five patients (35.7%) are disease free at 30 to 60 months after SLO with no further treatment and, thus, a good quality of life. Four patients are alive with recurrent disease. Five patients died of OVCA; actuarial 3-year survival is 64%. This therapeutic procedure is well tolerated and seems to provide long-term survival for patients with no complete response after first-line chemotherapy. Therefore, it might also be applied to patients at high risk of recurrence after a negative SLO.     

High-dose methotrexate with cyclophosphamide and cis-platinum in treatment of advanced ovarian carcinoma.

This study was done to see if the efficacy of high-dose methotrexate with Leucovorin rescue + cyclophosphamide combination as second-line therapy could be enhanced by the addition of cis-platinum. A 10% response rate was obtained when the combination was given as second-line therapy. There were no responders when this combination was used as third-line therapy.     

Treatment of advanced ovarian cancer with cisplatin, adriamycin and cyclophosphamide (PAC)

Forty two ovarian cancer patients with residual disease after the first laparotomy were treated with the combination of cisplatin (80 mg/m2 day 1), adriamycin (50 mg/m2 i.v. day 2) and cyclophosphamide (500 mg/m2 i.v. day 2) (PAC). Forty women were considered evaluable for analysis, with an overall response rate (partial, plus complete responses) of 62.5%. Twelve patients (30%) obtained a complete response (histologically confirmed after second look surgery in 6 cases, surgical complete response, residual tumor completely resected in the second look-in 5 cases and maintained complete clinical remission without second look confirmation in 1 case). Main side effects were nausea and vomiting (90%), leukopenia (70%), mucositis (45%), and anemia (37%). Seventeen percent of the patients were free of disease at 60 months, after a median follow-up of 48 months. The prognostic factors that showed significant influence on survival were the Karnofski index (90-100 vs 80 or less), stage of the disease (II + III vs IV) and the volume of residual tumor after the first surgical procedure (less than or equal to 2 cms vs greater than 2 cms). Patients who achieved a complete remission have not reached the median 5 years survival, which was 10 months for the remaining patients. These results confirm the activity of PAC in ovarian cancer, mainly in those patients with residual tumor of less than 2 cms and good performance status.     

FaFEC: a novel regimen for advanced ovarian cancer

A palliative combination chemotherapy regimen (FaFEC) was developed for patients with relapsed epithelial ovarian cancer in particular patients relapsing after, or ineligble to enter, phase II trials, usually due to lack of evaluable disease. Forty-six patients were enrolled. Patients had received a mean of 2.3 previous drug regimens and nine (19%) had intestinal obstruction at the start of FaFEC. The majority of patients were inevaluable by WHO criteria so objective response data was obtained from serial serum CA125 evaluations. A serological response was demonstrated in 8/44 (18%). The responders included 6/27 women who had a prior relapse-free interval of less than 3 months, four who were resistant to platinum chemotherapy and three patients who had previously received paclitaxel. The major (WHO grade 3/4) toxicities included leucopenia (six patients), anemia (three patients), thrombocytopenia (two patients), nausea and vomiting (four patients) and severe infections (five patients). Following FaFEC the median time to failure was 0.48 years and the median survival was 0.66 years. FaFEC was effective in this group of very poor prognosis patients. The serological response rate of 18% is noteworthy considering the multiple prior treatments that patients had received and the short treatment free intervals. FaFEC may be useful second line therapy in epithelial ovarian cancer patients ineligible for phase II studies and should be considered for a randomized comparison with paclitaxel.     

Polychemotherapy with carmustine, cyclophosphamide plus adriamycin in the treatment of advanced ovarian cancer

The Authors describe their experience with a combination therapy with carmustine (BCNU), cyclophosphamide (CTX) plus adriamycin (ADM) in the treatment of advanced ovarian cancer. The complete remission was obtained in 33.3% of subjects, the partial remission in 37.5%. Almost all patients suffered nausea, vomiting and alopecia. Myelosuppression was acceptable. No heart damage was observed. This pharmacological association can be considered an effective medical treatment in the management of ovarian carcinomas in advanced stages.     

Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer

OBJECTIVE: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer. METHODS: Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted. RESULTS: A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity. CONCLUSION: The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity.     

A prospective randomized clinical trial of melphalan and cis-platinum versus hexamethylmelamine, adriamycin, and cyclophosphamide in advanced ovarian cancer

From May 1978 until November 1980, 169 previously untreated patients with advanced epithelial ovarian cancer were entered into a prospective randomized clinical trial comparing the combination of hexamethylmelamine, Adriamycin, and cyclophosphamide (HAC) to a combination of melphalan and cis-platinum. Eleven patients were excluded from analysis and another 5 patients were excluded from response analysis. Of 153 patients evaluable for response, there were 47, or 30.7%, complete responders (all determined surgically), 6 partial responders, and 100 nonresponders. The response rate for the HAC group was 31% and for the melphalan-platinum group was 37.8%. The overall response rate was 34.6%. Residual tumor diameter (less than or greater than 2 cm) exerted a statistically significant effect on response--47.8 vs 24.4%. Of the 47 complete responders, 7, or 14.9%, have relapsed, with the median duration of remission of 44+ months. Of the 158 patients evaluable for survival, 90 patients have died, with a median survival time of 27.9 months (HAC = 26.4 months, melphalan-platinum = 29.6 months). Age, FIGO stage, histologic grade, and residual disease all exerted a significant effect on survival time. Second-line therapy in the treatment failures was of no benefit. Hematologic toxicity was greater in the melphalan-platinum group. Gastrointestinal toxicity was severe in both groups. Other toxicities were minor and infrequent.     

Treatment of advanced epithelial ovarian cancer with cisplatin and cyclophosphamide

Between June 1981 and June 1984, 50 patients with stage III or IV epithelial ovarian cancer underwent initial surgery followed by combination chemotherapy with cisplatin 50 mg/m2 iv and cyclophosphamide 500-1000 mg/m2 iv at 28-day intervals. No patients with borderline or well-differentiated tumors were included. If patients were clinically disease-free after 12 cycles of therapy, a second-look laparotomy was performed. A complete response was noted in 12 patients (24%), 11 of whom were surgically evaluated. A partial response was noted in 4 patients (8%), 3 of whom were surgically evaluated. Thirty-four patients (68%) had no response to therapy. The median progression-free survival (PFS) for the entire group was 19.8 months, with a median survival of 27 months. Patients with less than or equal to 2 cm residual disease had a superior median PFS (25.4 months vs 18 months) and median survival (29.4 months vs 19.5 months) to those patients with greater than 2 cm residual disease. Patients who underwent primary debulking had a longer median survival than patients who underwent "interval" debulking after two to four cycles of chemotherapy (29.2 months vs 17.3 months). Thirteen patients (26%) are alive without evidence of disease, 4 patients are alive with disease, and 33 patients are dead of disease. Toxicity was very moderate. In summary, the activity and toxicity of the combination of cisplatin and cyclophosphamide compare favorably to other cisplatin combination regimens.     

The adjuvant treatment of ovarian cancer: result of the pilot study of a new combination chemotherapeutic regimen (DAC)

Twenty-three previously untreated ovarian cancer patients were treated, from January 1986 to March 1987, with combination chemotherapy consisting of cisplatin, cyclophosphamide and cytarabine (DAC regimen). All patients had advanced disease, which included 18 stage III and 5 stage IV patients. Sixteen patients had serous, 6 undifferentiated and 1 mixed histotype. Surgery consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy and appendicectomy was performed in only 11/23 patients. Seventeen patients had bulky disease when the treatment was started. Four courses of chemotherapy were initially administered to all patients; second look laparotomy was performed in patients with no clinically measurable disease or with presumable entirely resectable tumor. Vomiting was the major side effect of chemotherapy: myelotoxicity was mild and in only one patient permanent renal damage occurred. A total of 14 objective clinical responses (73.7%) were observed, of which 9 were complete (47.4%). Six clinical complete remissions (37.5%) occurred in the group of patients with bulky disease. At second-look laparotomy six patients were found disease free (26%), 4 of whom originally had bulky disease (25%). Short-term DAC regimen seems to be a very effective treatment, with acceptable toxicity, in patients with ovarian cancer.     

The treatment of advanced ovarian carcinoma with high dose,intravenous cyclophosphamide

Twenty-six patients with Stage III or IV ovarian carcinoma have been treated with high dose, intravenous, pulsatile cyclophosphamide. An initial objective response of 88% has been achieved. Several patients who have had second look operations have been free of disease at that time and have remained so.     

Phase II study of carboplatin and cyclophosphamide combination chemotherapy for the treatment of advanced ovarian cancer

The efficacy and toxicity of intravenous carboplatin (300 mg/m2) and cycloprosphamide (600 mgs/m2) was evaluated in 44 newly diagnosed patients with advanced stage epithelial ovarian cancer. Cycles were administered at four weekly intervals for a total of 6 cycles, and therapy was provided on an out-patient basis without prehydration or forced diuresis. During treatment patients were assessed by physical, gynaecological and radiological examinations. Forty-four patients with a median age of 54 years (range 28-76) were entered into the study. The majority of patients had serous cystadenocarcinoma, 82% had stage III or IV disease and 87% had grade II or III histologic subtype. Optimal debulking surgery was carried out in only 46% of patients. The overall response rate to carboplatin/cyclophosphamide was 73%, with 55% achieving a clinical complete response. The median survival for all patients was 18+ months (range 2-41+). For those patients who received optimum surgery, median survival was 26+ months, compared with 11+ months for those whose lesion could not be completely resected. Treatment was well tolerated by most patients, with significant nausea and vomiting (WHO grade III-IV) observed in only 11% of 226 cycles of therapy. Myelosuppression was acceptale, with a mean nadir white cell count 4.3 x 10(9)/L (range 1.4-9.0) and a mean nadir platelet count of 273 X 10(9)/L (range 39-536) observed on day 21. There were no therapy-related infective episodes. Significant alopecia developed in 4 patients, but significant nephrotoxicity, ototoxicity or neurotoxicity has not been observed in any patients. This study demonstrates that combination carboplatin/cyclophosphamide is well tolerated in women with advanced stage epithelial ovarian cancer and produces overall response rates and median survival similar to those obtained with cisplatin-containing chemotherapy.     

Epirubicin and paclitaxel (EPI-TAX regimen) for advanced ovarian cancer after failure of platinum-containing regimens

BACKGROUND: The place of anthracyclines in the treatment of advanced ovarian cancer remains a matter of debate. We have assessed the feasibility and evaluated the tolerance of epirubicin (EPI) combined with paclitaxel (TAX) in heavily pretreated ovarian cancer patients. METHODS: Between March 1996 and March 1998, 34 patients with ovarian cancer in relapse after platinum-based chemotherapy received EPI (75 mg/m(2)/day, iv) and TAX (175 mg/m(2)/day, 3-h infusion). Cycles were repeated every 3 weeks. This treatment was second-line for 10 patients and third/fourth-line for 24. RESULTS: Of the 34 assessable patients, 15 (44%) (95% confidence interval 27-60%) achieved objective response (3 complete and 12 partial responses). The number of previous lines of chemotherapy or previous anthracycline treatments did not influence response rates. Responders to previous paclitaxel-based regimens had a significantly higher response rate to EPI-TAX combination (57%) than nonresponders (11%) (P = 0.05). Median response duration was 40 weeks (range 12-94). Median survival from inclusion was 10.7 months (range 1-40). Myelosuppression was the most frequent side effect. Grade 3/4 neutropenia occurred in 31 patients (91%), febrile neutropenia episodes in 17%, and grade 3/4 anemia and thrombopenia in 27 and 24%, respectively. The main nonhematological toxicities included alopecia and grade 2 peripheral neuropathy (12%). Cardiac dysfunction was observed in one patient after the fourth treatment cycle. CONCLUSIONS: Toxicity of the EPI-TAX regimen was acceptable in this population of heavily pretreated ovarian cancer patients. The regimen was effective and it is considered an option for patients previously responding to paclitaxel-based therapy.     

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

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%).     

Treatment of advanced ovarian cancer with combination chemotherapy using cyclophosphamide, adriamycin and cis-platinum

Summary. Fifty-four patients with advanced ovarian cancer have been treated with combination chemotherapy using cyclophosphamide, adriamycin and cis-platinum. The toxicity of the regimen was manageable but few patients were prepared to tolerate more than 6 months of treatment. Those in complete clinical remission at that time were offered second-look laparotomy and if apparently free of disease, therapy was discontinued. Forty-seven patients could be assessed of whom 33 had had no previous therapy. Twenty-two of these were clinically free of disease after completion of chemotherapy of whom 12 had no detectable disease at second-look laparotomy. Of 14 patients who had failed previous therapy only one remains clinically free of disease. The results in the untreated patients demonstrate the primary importance of bulk reduction at initial laparotomy. The use of the regimen in patients who have failed on previous treatment or in patients with bulk disease seems to be palliative and the toxicity should be assessed in this context.     

Treatment of advanced ovarian cancer with combination chemotherapy using cyclophosphamide, adriamycin and cis-platinum

Fifty-four patients with advanced ovarian cancer have been treated with combination chemotherapy using cyclophosphamide, adriamycin and cis-platinum. The toxicity of the regimen was manageable but few patients were prepared to tolerate more than 6 months of treatment. Those in complete clinical remission at that time were offered second-look laparotomy and if apparently free of disease, therapy was discontinued. Forty-seven patients could be assessed of whom 33 had had no previous therapy. Twenty-two of these were clinically free of disease after completion of chemotherapy of whom 12 had no detectable disease at second-look laparotomy. Of 14 patients who had failed previous therapy only one remains clinically free of disease. The results in the untreated patients demonstrate the primary importance of bulk reduction at initial laparotomy. The use of the regimen in patients who have failed on previous treatment or in patients with bulk disease seems to be palliative and the toxicity should be assessed in this context.     

Repetitive high-dose topotecan, carboplatin, and paclitaxel with peripheral blood progenitor cell support in previously untreated ovarian cancer: results of a Phase I study

OBJECTIVE: In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support. METHODS: Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC = 5 and 175 mg/m(2) of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily x5 schedule, paclitaxel (250 mg/m(2) over 24 h), and carboplatin (AUC = 12-16). RESULTS: Nineteen patients with a median age of 49 years (range 21-63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m(2)/day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m(2)/day), paclitaxel (250 mg/m(2)) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m(2)/day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pathological CR. With a median follow-up of 28 months (range 11-40 months), the median PFS is 36 months and OS has not been reached. CONCLUSION: When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m(2)), the recommended topotecan dose is 3.5 mg/m(2)/day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.     

Accurate laboratory predictions of the clinical response of patients with advanced ovarian cancer to treatment with cyclophosphamide, doxorubicin, and cisplatin

Seventy-six patients with advanced ovarian cancer treated with cyclophosphamide, doxorubicin, and cisplatin (CAP) at 3-week intervals were tested for the response of their tumors to treatment with CAP in the subrenal capsule tumor implant assay. Thirty-four of the patients' tumors were assayed prospectively before clinical treatment and 33 were assayed retrospectively, after clinical treatment with CAP. Nine of the patients' tumors were assayed both prospectively and retrospectively. All of the patients underwent a tumor debulking laparotomy. Of the patients with clinically measurable residual disease, 17 had a partial response of at least 50% regression of disease, and 11 had a progression of disease. Of the patients with known residual but nonmeasureable disease, 7 had surgically verified complete responses, 8 at least 50% regression, and 23 had progression of disease: 10 had no evidence of disease clinically but had not had surgical confirmation. Twenty-six of the tumors were adenocarcinomas not otherwise specified (2 grade I, 2 grade II, and 22 grade III), 39 were serous adenocarcinomas (7 grade I, 9 grade II, and 23 grade III), 7 were endometrioid adenocarcinoma (all grade III), 3 were mucinous adenocarcinomas (1 each of grade I, II, and III) and 1 was an adenosquamous carcinoma (grade III). Thirty-four of the patients failed the therapy. The subrenal capsule (SRC) assay predicted 21 of these failures (4 prospective and 17 retrospective). Thirty-two of the patients responded to CAP chemotherapy. The SRC assay accurately predicted the clinical regression of the tumors of 22 of the patients (15 prospective and 7 retrospective). Second-look laparotomy confirmed 7 patients with no evidence of disease, 5 patients with minimal disease, and 5 patients with a greater than 50% reduction of their disease. The SRC assay predicted the response of all these patients except 2 with partial responses to chemotherapy. Thus, while the overall positive predictive value of the SRC assay in this study is 65%, it is 100% for those patients whose tumors respond completely and for those who have minimal residual disease after CAP chemotherapy.