Standard dose cisplatin with rhG-CSF allows sufficient harvesting of PBSC for autotransplantation in patients with ovarian cancer

We have investigated the feasibility of a program of autologous peripheral blood stem cell (PBSC) harvesting and transplantation in patients with ovarian cancer. From four patients, PBSC was collected during hematopoietic recovery following aplasia induced by standard dose cisplatin 70 mg m⁻² with etoposide 500 mg m⁻² or adriamycin 40 mg m⁻² and cyclophosphamide 500 mg m⁻² plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) at a dose of 75 µg day⁻¹ given intracutaneously. In apheresed patients, we harvested an average of 2.31 × 10⁵ kg⁻¹ colony-forming unit granulocyte/macrophage (range 0–5.22) per cycle. Low hematologic toxicity was observed during the hematopoietic reconstitution of the four patients subjected to PBSC support with G-CSF (5 µg kg⁻¹ day⁻¹ given by continuous infusion) after high-dose chemotherapy (carboplatin 900 mg m⁻² and etoposide 900 mg m⁻²). The patients were not evaluable for a response because we performed consolidated high-dose chemotherapy. However, no evidence of recurrence has been observed 11.8 months (range 2–19) after high-dose chemotherapy. We can conclude that standard dose cisplatin in combination with etoposide or adriamycin and cyclophosphamide plus rhG-CSF allows sufficient harvesting of PBSC for autotransplantation in patients with ovarian cancer.     

'Moderate-risk' ovarian cancer (stage I, grade 2; stage II, grade 1 or 2) treated with cisplatin chemotherapy (single agent or combination) and pelvi-abdominal irradiation

We placed patients with invasive epithelial ovarian cancer into four distinct prognostic groups: 'low', 'moderate', 'high' and 'extreme' risk. The 'moderate-risk' group contained all residual negative, stage I and II patients with two exceptions: stage Ia or b, grade 1 cancers and grade 3 cancers. They were treated with primary surgery, usually including bilateral salpingo-oophorectomy, hysterectomy and omentectomy. Chemotherapy was then given (cisplatin at 100 mg m⁻² every 2 weeks for three cycles) followed by pelvi-abdominal irradiation (2250 cGy in 10 fractions to the pelvis and 2250 cGy in 22 fractions to the whole abdomen including pelvis). An early cohort with ascites or positive washings instead received six cycles of cisplatin and cyclophosphamide at 75 mg m⁻² and 600 mg m⁻² every 4 weeks with the same pelvi-abdominal irradiation sandwiched between cycles 3 and 4. One-hundred and nine patients were treated between November 1983 and December 1989. Median follow-up was 4.7 years (range 0.7–9 years). The 5-year actuarial overall and failure-free survivals were 81% and 76%, respectively. Chronic toxicity, although usually minor, included 15% with peripheral neuropathy or ototoxicity and 23% with chronic abdominal complaints. Our combined-modality results are similar to those obtained by other centers utilizing either pelvi-abdominal irradiation alone or cisplatin-based chemotherapy alone.     

Neurotoxicity of cisplatin and taxol

Since the discovery of the activity of cisplatin in ovarian cancer approximately 15 years ago, there has been little progress in improving survival for patients with this disease. Thus there has been great enthusiasm in the gynecologic oncology community over the results of GOG111, the Gynecologic Oncology Group (GOG) study randomizing suboptimally debulked ovarian cancer patients to cisplatin with either cyclophosphamide or paclitaxel (Taxol^R). To date, a median survival increase of 13 months has been seen in patients on the taxol-containing arm (ref. 1; W.P. McGuire, personal communication). Although a confirmatory study is about to be implemented by the European Organization for the Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), the GOG results are encouraging enough that the majority of ovarian cancer protocols developed over the next decade will probably incorporate some combination of cisplatin and taxol. Since neurotoxicity is now the dose-limiting toxicity of each of these agents, the potential for synergistic toxicity is of major concern, particularly with the tendency for recent protocols to investigate higher doses of both cisplatin and taxol than those used in the GOG study, which were 75 mg m⁻² and 135 mg m⁻² respectively. This paper will review the clinical manifestations and pathogenesis of the neurotoxicity of cisplatin and taxol as single agents, as well as in combination. The discussion will include several promising compounds which appear to prevent or diminish this sometimes severely disabling neurotoxicity.     

High-dose platinum chemotherapy in advanced ovarian cancer: a phase II study.

From September 1986 to November 1988, 38 patients with previously untreated ovarian cancer, FIGO stages III and IV, were allocated to a study testing the efficacy of high-dose platinum delivered as combined carboplatin and cisplatin. The regimen was as follows: Day 1, 250-350 mg/m2 carboplatin and 500 mg/m2 cyclophosphamide, Day 15, 100 mg/m2 cisplatin. Overall clinical response was 60%, and complete pathologic response, verified at second-look laparotomy, was 24%. Median survival was 17 months and 3-year survival 27%. The results are similar to those obtained by a standard dose of cisplatin, cyclophosphamide, and doxorubicin. Myelotoxicity was dose limiting. After receiving four cycles, 44% of patients had grade 3 or 4 leucopenia and 65% had grade 3 or 4 thrombopenia. Despite this, dose intensity of combined cisplatin and carboplatin was between 30 and 45 mg/m2/week, expressed as cisplatin by assuming that 1 mg cisplatin equals 4 mg of carboplatin. A correlation between dose intensity and response was not found. In conclusion the study showed that the regimen is feasible, but very myelotoxic. The results were not superior to those obtained by combination chemotherapy using standard doses of cisplatin.     

Twelve-year follow-up of a randomized trial comparing cisplatin and cyclophosphamide with cisplatin, doxorubicin and cyclophosphamide in patients with advanced epithelial ovarian cancer

From 1982 to 1984, 131 patients with FIGO stage Ic-IV epithelial ovarian cancer were included in a randomized clinical trial comparing cisplatin 50 mg m⁻² plus cyclophosphamide 600 mg m⁻² (PC regimen) with PC plus doxorubicin 45 mg m⁻² (PAC regimen). Chemotherapy was repeated every 4 weeks for six cycles. The criteria for entry, the characteristics of the elegible patients, the response rates and the toxicities have been previously reported. The study was updated in August 1994 with a median follow-up of 10.5 years (range 10–12 years). In the whole series, the median time to progression is 13 months and the 12-year progression-free survival (PFS) is 18%, whereas the median time to survival is 21 months and the 12-year survival is 21%. By log-rank test survival is significantly related to residual disease after first surgery ( P <0.0001), ECOG performance status (PS) ( P <0.0001), FIGO stage ( P =0.0001) and histologic grade ( P =0.04), but not to type of chemotherapy and age. By Cox proportional hazard model residual disease ( P =0.0004), histologic grade ( P =0.01) and ECOG performance status ( P =0.049), but not FIGO stage, treatment arm and age, are independent prognostic variables for survival. The survival curves are superimposable in the two treatment arms among patients with residual disease <2 cm, whereas there is a trend in favor of the PAC regimen among patients with larger residual disease. By log-rank test PFS is not significantly related to chemotherapy arm. However, it is worth noting that among patients with residual disease >2 cm 12-year PFS is 12.5% for PAC arm, while all patients of PC arm progressed by the sixth year. Conversely, the PFS curves are superimposable in the two treatment arms among patients with residual disease <2 cm.     

Neoadjuvant cisplatin plus ifosfamide in patients with stage IIB cervical cancer: a single center phase II study

The objective of this study was to evaluate cisplatin plus ifosfamide as neoadjuvant chemotherapy with regard to toxicity and clinical response in patients with stage IIB cervical cancer. Sixty-eight patients with previously untreated stage IIB cervical cancer were given two cycles of chemotherapy: cisplatin 20 mg m⁻² on Days 1–5, infused over 1 h; ifosfamide 1.2 g m⁻² on Days 1–5 infused over 30 min. Mesna 120 mg m⁻² was administered as a bolus 15 min before ifosfamide, and a continuous infusion, delivering Mesna 1.2 g m⁻², was given subsequently over the next 16 hours. The treatment cycle was repeated on day 21. Responders were then randomized to surgery or radiation therapy. All 68 patients were evaluable for toxicity. Toxicity was found to be acceptable. One patient died at home one month after completion of the second treatment cycle. There was one grade 4 thrombocytopenia. Grade 3 toxicities included anemia in four patients, leucopenia and nausea and vomiting in one patient each. Sixty-two patients were evaluable for response. A clinical response was documented in 44 of the 55 evaluable patients (80%), with 17 complete responses (31%) and 27 partial responses (49%) (95% confidence limits 69%–91%, 19%–43%, and 36%–62% respectively). The intent-to-treat response rate was 64.7%. Twenty-one patients were randomized to surgery and 23 patients to radiation therapy. Amongst the eight patients with a complete clinical response, one patient had a complete pathological response and one patient had residual intra-epithelial neoplasia. The drug combination of cisplatin plus ifosfamide had acceptable toxicity and gave a clinical response rate of 80% in previously untreated patients with stage IIB cervical cancer.     

Weekly cisplatin ± glutathione in relapsed ovarian carcinoma

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450–650 mg m⁻² were randomized to receive cisplatin 50 mg m⁻² weekly ± 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.     

Paclitaxel in combination with cisplatin is less effective for peripheral blood progenitor cell mobilization

Abstract. Kurata H, Takakuwa K, Tsuneki I, Aoki Y, Tanaka K. Paclitaxel in combination with cisplatin is less effective for peripheral blood progenitor cell mobilization.
The purpose of this study was to determine the efficacy of paclitaxel in combination with cisplatin and granulocyte-colony stimulating factor (G-CSF) for mobilization of peripheral blood progenitor cells (PBPC). Twenty-seven patients with gynecological cancer received paclitaxel and cisplatin (TP, n = 9) or other platinum-based chemotherapy ( n = 18) (etoposide and cisplatin [ n = 5]; cyclophosphamide, adriamycin, and cisplatin [ n = 8]; or pepleomycin, etoposide, and cysplatin [ n = 5]). Each combination was followed by G-CSF. The mean number of colony-forming unit granulocyte macrophage (CFU-GM)/kg and CD34⁺ cells/kg collected per cycle was 1.2 × 10⁵ and 0.8 × 10⁶ after the TP regimen, compared with 2.6 × 10⁵ ( P < 0.05) and 2.0 × 10⁶ for patients who received other platinum-based chemotherapy. The CFU-GM target yield (≥1.0 × 10⁵/kg) was achieved in 56% and 83% patients in the TP and comparison group, respectively. With the TP regimen, a younger age (≤50 years of age) and fewer prior chemotherapy cycles (≤2) were associated with the CFU-GM targeted yield (<0.05). In conclusion, TP mobilized PBPC less effectively than other platinum-based chemotherapy. Therefore, the TP regimen may need to be changed to another appropriate regimen when PBPC mobilization is planned for high-dose chemotherapy in gynecological cancer patients.     

Combined high-dose platinum and etoposide in previously untreated ovarian cancer patients with residual disease

Only a limited number of patients with advanced ovarian cancer obtain a long-term disease-free interval. The purpose of this study is to find new active drugs and/or regimens. Carboplatin 200 mg m⁻² day 1, cisplatin 50 mg m⁻² days 2 and 3, and etoposide 70 mg m⁻² i.v. days 1–5 every 4 weeks for six cycles were given to 43 previously untreated ovarian cancer patients with residual disease after primary laparotomy.
The median observation time was 75 months (range, 63–87 months). Forty-two patients were evaluable for response and the overall pathological response rate was 57% (pathologic complete response (PCR) plus pathological partial response (PPR)), with 26% being PCRs (11/42; 95% confidence interval, 0.14–0.42). The main hematologic toxicity was thrombocytopenia grade 3–4 which occured in 95% of the cycles. Dose-limiting leucocytopenia only occured in 21%. Non-hematologic toxicity caused dose-reduction in 33% of the patients, with nephrotoxicity being the main reason (24%).
The purpose of the study was to give a high total dose of platinum in combination with etoposide. However, this was not feasible due to excessive cumulative hematologic toxicity and nephrotoxicity. As the activity of the combination was no better than that obtained with other, less toxic regimens, the combination cannot be recommended.     

Combined radio-chemotherapy in advanced cervical cancer: a phase-II trial with weekly applied carboplatin, 5-fluorouracil and folinic acid

The 5-year survival of patients with advanced cervical cancer is poor. Major problems are the high frequency of pelvic recurrences and distant metastases. To prevent both, various efforts have been made to combine local radiotherapy with systemic chemotherapy. In this prospective study, 28 previously untreated patients with advanced cervical cancer (FIGO IIB-IVB) were treated with a newly designed therapy consisting of fractionated external beam irradiation (54 Gy) followed by two intracavitary cesium (Cs) applications (2 × 15 Gy), combined with carboplatin (70 mg m⁻²), 5-fluorouracil (5-FU) (400 mg m⁻²) and folinic acid (400 mg m⁻²). Cytotoxic agents were given intravenously on days 1, 8, 15, 22 and 29 as 1-day courses during external irradiation followed by three 3-day courses with carboplatin (100 mg m⁻² i.v. daily), 5-FU (400 mg m⁻² i.v. daily) and folinic acid (400 mg m⁻² i.v. daily) after 8, 12 and 16 weeks of treatment.
Acute toxicities ( WHO grade 2) were leucopenia (27 of 28 patients), diarrhea (23/28), abdominal pain (19/28), nausea (14/28) and skin desquamation (12/28). Clinically diagnosed pelvic response was achieved in 88.5% (23/26) with a complete response of 34.5% (9/26). As yet, 19 of 26 patients (73.1%) are alive and well (persistent complete/partial remission), two patients (7.7%) are alive with local progression, four (15.4%) have died from pelvic and/or distal recurrence and one (3.8%) died some weeks after the start of therapy. The combined modality treatment concept has to be considered for the therapy of advanced cervical cancer and a prospective and randomized trial with a greater number of patients is warranted.     

A short and intensive single-agent cisplatin regimen for recurrent carcinoma of the uterine cervix

Between May 1991 and September 1993, 36 patients with recurrent carcinoma of the uterine cervix were treated with single-agent cisplatin using an intensive regimen of four weekly cycles of 50 mg m⁻² followed in responders by a further four cycles given every fortnight. The response rate was 47% (95% CI: 27–66%), 56% in those with pelvic recurrence, and 38% in those with metastatic disease. All responses but one were seen within 4 weeks of commencing treatment. Three patients (9%) had a complete response, although in two cases this was of short duration. The treatment was moderately well tolerated and the principle toxicities were myelotoxicity and emesis. The median survival was 32 weeks, and the 18-month survival was 13%.
This regimen gives a response rate similar to that seen with more toxic combination chemotherapy regimens such as BIP (bleomycin, ifosfamide and cisplatin). It has the particular advantages of a short duration of treatment and early response, allowing treatment to be stopped after 4 weeks in non-responders. The response rate in pelvic recurrence was better than that seen in most previous chemotherapy trials, particularly as 78% of the evaluable patients with pelvic recurrence had previously received radical radiotherapy to the pelvis.
Weekly, followed by fortnightly cisplatin, is an appropriate palliative treatment for patients with recurrent carcinoma of the uterine cervix for whom chemotherapy is indicated.     

A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma

Abstract.   Valerio MR, Tagliaferri P, Raspagliesi F, Fulfaro F, Badalamenti G, Arcara C, Cicero G, Russo A, Venuta S, Guarneri G, Gebbia N. A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma. Int J Gynecol Cancer 2006; 16(Suppl. 1): 79–85
We carried out a phase II nonrandomized study to examine the level of activity of oxaliplatin, pegylated liposomal doxorubicin, and cyclophosphamide in a patient population with relapsed ovarian cancer pretreated with platinum derivatives and paclitaxel. Patients received oxaliplatin (85 mg/m²), pegylated liposomal doxorubicin (30 mg/m²), and cyclophosphamide (750 mg/m²). A total of 49 patients (39 assessable for toxicity and response) were enrolled in this trial. Neutropenia grade 3 was observed in six patients (15%) and anemia grade 3 in one patient (0.2%). Fatigue grade 1–2 occurred in 26 patients (66%), nausea/vomiting grade 1 in 23 patients (58%), and alopecia grade 1–2 in 19 patients (48%). Twenty-one (53%) patients experienced grade 1–2 peripheral neuropathy. The overall response rate was 46% (95% CI 23.6–68.7). Median progression-free survival was 28 weeks (range 12–52 weeks) and median survival was 45 weeks (range 26–136+ weeks). The mean duration of response was 34 weeks (range 16–52 weeks). In platinum-resistant and -refractory ovarian cancer patients, the overall response rate was 37% (CI 95% 14.4–60.8) with a progression-free survival of 28 weeks (range 12–52 weeks) and a median survival of 42 weeks (range 28–84 weeks). This combination chemotherapy is generally well tolerated and is an active second-line regimen against ovarian cancer.     

Neither toxicity nor dose intensity of carboplatin is affected by glomerular filtration rate versus body surface area dose calculation in gynecologic malignancy

Twelve patients were given 31 courses of carboplatin using a glomerular filtration rate (GFR)-based area under the curve (AUC) dose schedule, and nine patients were given 35 cycles at a body surface area (BSA) dose of 350 mg m⁻² every 3 weeks. The GFR was determined using technetium-99m-DTPA. The dose given was calculated according to AUC, 5 for previously treated and 7 for previously untreated patients × GFR + 25. Patients treated using the GFR had a 22% lower projected dose intensity (DI) and a 15% lower received DI compared with controls. The percentage difference between the received and projected DI was not different between the two groups of patients. In 11 of 12 patients treated according to the GFR, if the BSA calculation dose had been used it would have resulted in a higher dose of carboplatin. Twenty per cent (six of 30 courses) of GFR-based doses were delayed compared to 29% (10 of 35) of the BSA-calculated control groups. We conclude that giving a dose according to a BSA of 350 mg m⁻² leads to a higher DI and total dose and does not substantially effect toxicity. It is also cost effective as it eliminates the need for unnecessary radiometric GFR determination.     

Neurotoxicity of cisplatin +/− reduced glutathione in the first-line treatment of advanced ovarian cancer

Several drugs have been proposed for chemoprevention from cisplatin (CDDP)-induced neurotoxicity. For the purpose of this study the effectiveness of reduced glutathione (GSH) during CDDP-based first-line treatment was evaluated in a series of 54 patients affected by epithelial ovarian cancer. Neurotoxicity was assessed by clinical examination, vibrametry and neurophysiology before, during and after chemotherapy. First of all, it is noteworthy that GSH cotreatment did not impair CDDP antineoplastic effectiveness. Non-neurological side effects were similar in the two groups, with the exclusion of oliguria which occured more frequently in CDDP alone-treated patients. From a neurological point of view, the comparison between CDDP alone and CDDP+GSH treated groups at the end of treatment (CDDP total dose 500–675 mg m⁻²) constantly evidenced a trend toward less severe neurotoxicity after cotreatment with all methods. Although neuroprotection was not complete, these findings are in agreement with previous preclinical and clinical data and further support the view that chemoprevention with GSH should be considered in CDDP-treated patients.     

A phase I study of paclitaxel, topotecan, cisplatin and Filgrastim in patients with newly diagnosed advanced ovarian epithelial malignancies: a Gynecologic Oncology Group study

OBJECTIVES: To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. METHODS: Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m2/3 h, followed 2 h later by cisplatin 50 mg/m2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m2 (cohort 1), or 3 days beginning at 0.5 mg/m2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. RESULTS: Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.5 mg/m2 daily x 5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.75 mg/m2 daily x 3 with Filgrastim. CONCLUSION: In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.     

Chemotherapy in Advanced Ovarian Carcinoma: Current Standards of Care Based on Randomized Trials

The mainstay of the treatment of advanced (stage III or IV) ovarian carcinoma is systemic therapy. The following review bases conclusions regarding standards of care on large, randomized trials of chemotherapy in advanced ovarian carcinoma. As of 1976, "standard" chemotherapy was single alkylating agent usually with melphalan. Studies of combination chemotherapy failed to show superiority over single alkylating agent until the introduction of cisplatin. The Gynecologic Oncology Group conducted a series of two trials in patients with large-volume disease, the first randomizing patients to either single-agent melphalan or a combination of doxorubicin and cyclophosphamide and the second to doxorubicin plus cyclophosphamide with or without cisplatin. These studies demonstrated superiority for the cisplatin-based combination in terms of overall response rate, clinical complete response rate, progression-free survival, and overall survival. Subsequent randomized trials demonstrated several important facts. First, platinum-based combinations yielded results superior to single-agent cisplatin. Second, a two-drug combination of cisplatin plus cyclophosphamide provides benefit equivalent to the three-drug combination of the same two drugs plus doxorubicin. Third, substitution of carboplatin for cisplatin yields similar results. Finally, dose escalation of chemotherapy by a factor of 2 does not offer a therapeutic advantage. The next major advance after the introduction of the platinum compounds was the demonstration of the activity of taxol, a new agent with a unique mechanism of action and apparent clinical non-cross-resistance with the platinum compounds. A recently completed GOG trial of cisplatin plus cyclophosphamide versus cisplatin plus taxol in patients with large-volume disease shows that the taxol-based combination has a superior overall response rate, clinical complete response rate, rate of achieving a state of no gross residual disease at second-look laparotomy, and progression-free survival. Survival analysis awaits maturation of the data, but the control arm has already been shown to have a median survival of 23.2 months with the median not yet reached for the taxol-based arm. These data suggest that a combination of taxol plus cisplatin should be considered the standard of care for patients with advanced ovarian carcinoma. Ongoing trials seek to define further the role of taxol in frontline chemotherapy for ovarian carcinoma. In conclusion, the standard chemotherapy for advanced ovarian carcinoma should be considered a combination of taxol plus a platinum compound.     

A phase II study of ifosfamide and bleomycin in advanced or recurrent cervical carcinoma

Thirty-seven patients with advanced or recurrent cervical squamous cell carcinoma were treated with ifosfamide 1.5 g m⁻² on days 1–5 (with mesna as a uroprotector), and bleomycin 30 mg on day 1, every 3 weeks. A partial response rate of 21% (95%CI: 6–36%) was obtained in patients who had not received prior chemotherapy, with a median duration of response of 5 months. No complete responses were seen. The median survival of all patients was 6 months. Nausea and vomiting, white cell suppression and encephalopathy were the main toxic effects. The results suggest that the addition of bleomycin to ifosfamide is not advantageous and increases toxicity, and that the interaction between these two agents is not contributory to the activity of the bleomycin, ifosfamide and cisplatin combination regimen (BIP). The potentially more severe toxicity of combination regimens must be considered when treating this group of patients.     

Platinum plus cyclophosphamide plus radiotherapy is superior to platinum alone in 'high-risk' epithelial ovarian cancer (residual negative and either stage I or II, grade 3, or stage III, any grade)

Patients with epithelial ovarian cancer (EOC) referred to our institution are stratified into risk groups based on their stage, grade and presence of residual cancer, with a specific treatment policy for each group. One-hundred and thirty-one patients with no visible residual tumor following primary surgery and either stage I, grade 3; stage II, grade 3; or stage III, any grade EOC were treated between November 1983 and the end of December 1991. Regimen A (cisplatin 75 mgm⁻² and cyclophosphamide 600 mgm⁻² intravenously every 4 weeks for 6 cycles with abdominopelvic irradiation between cycles 3 and 4) was used until April 1989 and was then replaced with Regimen B (cisplatin 75 mgm⁻² intravenously every 3 weeks for 6 cycles). The 5-year actuarial overall and failure-free survivals were 78% and 64% respectively. Multivariate analysis identified increasing stage and treatment with Regimen B as independent adverse prognostic factors for failure-free survival. The importance of treatment regimen reached statistical significance for the stage I patients ( P = 0.04) but not stage II ( P = 0.11) or stage III ( P = 0.79). It is possible to undertreat EOC as shown by the inferior results achieved with Regimen B (single agent cisplatin) compared to Regimen A (cisplatin-cyclophosphamide, irradiation). This effect of treatment regimen was particularly important for the lower-stage patients. Our postulate is that treatment resistant clones are less regularly present in lower-stage patients, and that a certain minimum amount of treatment is required to eliminate all the sensitive cancer.     

The effect of prolonged cisplatin-based chemotherapy on progression-free survival in patients with optimal epithelial ovarian cancer: "maintenance" therapy reconsidered.

From 1978 until 1988, 116 patients with epithelial ovarian cancer were entered onto one of three consecutive prospective clinical trials involving cisplatin-based combination chemotherapy. They had the following characteristics: (1) stage III or IV disease, (2) grade 2 or 3 tumors, and (3) optimally debulked tumors (residual disease < or = 2 cm). The purpose of the study was to investigate the influence of duration of chemotherapy on survival. The treatment plans were as follows: Trial 1, 12 cycles of cisplatin/melphalan (43 patients); Trial 2, 12 cycles of cisplatin/cyclophosphamide (24 patients); and Trial 3, 6 cycles of cisplatin/cyclophosphamide (49 patients). The total dose of cisplatin was 60 mg/m2 in the first trial and 50 mg/m2 in the second and third trials. Median survival times for the three groups were 58, 29, and 35 months, respectively (NS). Median progression-free survival (PFS) times were 37, 23, and 15 months, respectively (P = 0.0008). Combining patients from the first two trials, the median PFS for patients receiving 12 planned cycles of chemotherapy was 30 months versus 15 months for patients receiving 6 planned cycles (P = 0.0004). Using a forward stepwise Cox proportional hazard model, the use of 12 cycles of therapy and melphalan predicted increased PFS (P = 0.0001 and P = 0.0002, respectively). In view of these results, the lack of published data supporting the superiority of 6 over 12 cycles of chemotherapy, and the rather recent availability of less toxic maintenance therapy (i.e., carboplatin), we believe that a multiinstitutional trial comparing the 6-cycle regimen with more prolonged chemotherapy is justifiable.     

Lack of effect from mitomycin c plus 5-fluorouracil in platin-resistant ovarian cancer: a phase II study

Sixteen patients with advanced ovarian cancer were included in a phase II study with mitomycin c (MMC) plus 5-fluorouracil (5-FU). All patients had previously received platin-based combination therapy, but were resistant to this treatment. A MMC 10 mg m⁻² intravenous (iv) bolus was given on day 1 every 6 weeks, and 5-FU 1000 mg m⁻² was given iv on days 1–3 every 3 weeks, as a continuous infusion over 72 h. Fifteen patients were evaluable for response. There were no responders, neither partial nor complete. The median survival was 6 months. The toxicity was primarily bone marrow suppression. The treatment was generally well tolerated. No patients had grade 4 toxicity and only five had grade 3 hematologic toxicity. In conclusion, we find the present regimen to be ineffective in the treatment of platin-resistant ovarian cancer.