J.P. Neijt

Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Prevention of Cisplatin Neurotoxicity with an ACTH(4–9) Analogue in Patients with Ovarian Cancer

Abstract In a randomized, double-blind, placebo-controlled study, we assessed the efficacy of an ACTH(4–9) analogue, Org 2766, in the prevention of cisplatin neuropathy in 55 women with ovarian cancer. The analogue was given subcutaneously in a dose of 0.25 mg (low dose) or 1 mg (high dose) per square meter of body-surface area before and after treatment with cisplatin and cyclophosphamide (75 and 750 mg per square meter every three weeks). The threshold of vibration perception was used as the principal measure of neurotoxicity. After four cycles of chemotherapy, the mean (±SEM) threshold value for vibration perception in the placebo group increased from 0.67±0.12 to 1.61±0.43 μm of skin displacement (P<0.0001). In the high-dose treatment group, there was no increase in the threshold value after four cycles (from 0.54±0.12 to 0.50±0.06 μm). After six cycles of chemotherapy, the threshold value was 5.87±1.97 μm in the placebo group (more than an eightfold increase from base line), as compared with 0.88±0.1...

LONG-TERM SURVIVAL IN OVARIAN-CANCER - MATURE DATA FROM THE NETHERLANDS JOINT STUDY-GROUP FOR OVARIAN-CANCER

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

Randomised Trial Comparing Two Combination Chemotherapy Regimens (HEXA-CAF VS CHAP-5) In Advanced Ovarian Carcinoma

186 patients with advanced epithelial ovarian carcinoma were treated with either a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) or cyclophosphamide and hexamethylmelamine alternating with doxorubicin and a 5-day course of cisplatin (CHAP-5). Treatment with CHAP-5 resulted in more complete remissions as determined by laparatomy or peritoneoscopy (p = 0.004), better overall response (p = 0.0001), and longer overall survival and progression-free survival (p less than 0.002). Therapy, histological grade, and Karnofsky index were reliable predictors of overall response, whereas therapy, FIGO-stage, and size of residual tumour before chemotherapy were independent predictors for complete remission and for prolonged survival. Peripheral neurotoxicity was a major problem in patients assigned to the CHAP-5-group and was likely to be due to the simultaneous administration of hexamethylmelamine and cisplatin. The CHAP-5 regimen is one of the most effective regimens for the initial treatment of ovarian cancer.

Incidence of neuropathy in 395 patients with ovarian cancer treated with or without cisplatin

In two consecutive trials, a total of 395 patients with ovarian cancer were treated with a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5‐fluorouracil chemotherapeutic regimens including cisplatin or without this drug. With respect to neurotoxicity, 387 patients were fully eligible. The median follow‐up for survival was 45 months. Neurotoxicity in any grade of severity developed in 47% of the patients treated with a cisplatin‐containing regimen and in 25% of those treated with the non‐cisplatin‐containing regimen. The severity of neurotoxicity was much higher, however, in the cisplatin‐treated patients. Neurotoxicity‐free survival decreased below 50% at cumulative doses of cisplatin between 500 and 600 mg/m2. No additional effect of hexamethylmelamine on the incidence or severity of neurotoxicity could be demonstrated. In patients who survived for more than 5 years, the incidence of cisplatin neuropathy was 61%. Prognostic variables (age, International Federation of Gynecology and Obstetrics [FIGO] stage, performance status, and others) possibly associated with high‐risk subgroups could not be identified. The only consistent factor correlated with neurotoxicity was the total dose of cisplatin received.

Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non seminoma : a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group

We investigated the efficacy and toxicity of induction chemotherapy with cisplatin and etoposide with either bleomycin or ifosfamide in patients with intermediate-prognosis testicular non-seminoma. A total of 84 eligible patients were randomized to receive four cycles of etoposide, ifosfamide, cisplatin (VIP), or four cycles of bleomycin, etoposide, cisplatin (BEP). Intermediate prognosis was defined as any of the following: lymph node metastases 5-10 cm in diameter, lung metastases more than four in number or > 3 cm, HCG 5000-50,000 IU l(-1), AFP > 1000 IU l(-1). The complete response (CR) rates to VIP and BEP were similar, 74% and 79% respectively (P = 0.62). Including the cases in whom viable cancer was completely resected with post-chemotherapy debulking surgery, the percentages of patients who achieved a no-evidence-of-disease status were 80% on VIP and 82% on BEP (P = 0.99). In addition, there were no differences in relapse rate, disease-free and overall survival after a median follow-up of 7.7 years. The 5-year progression-free survival was 85% (95% CI 74-96%) in the VIP arm and 83% (95% CI 71-96%) in the BEP arm, hazard ratio (VIP/BEP) 0.83 (95% CI 0.30-2.28). The VIP regimen was more toxic with regard to bone marrow function; the frequency of leucocytes below 2000 microl(-1) throughout four cycles was 89% on VIP and 37% on BEP (P < 0.001). Our study does not indicate that ifosfamide is superior to bleomycin in combination with cisplatin and etoposide. The sample size in this study is small as the study was prematurely discontinued when data became available from a competing study that showed no improved effectiveness of VIP compared with BEP. Taken together with these data, bleomycin should not be replaced by conventional-dose ifosfamide.

A meta-analysis of prognostic factors in advanced ovarian cancer with median survival and overall survival (measured with the log (relative risk)) as main objectives

We performed a meta-analysis of 38 articles containing 66 treatment groups and 3443 patients in order to evaluate prognostic factors in advanced epithelial ovarian cancer. To evaluate overall survival we designed a method to summarize the overall survival curve into one single figure: the log (relative risk) (LRR). This is the first meta-analysis using overall survival (measured with the LRR) as an objective. We found that the main prognostic factors predicting an improved survival (measured with the LRR) are: chemotherapy including cisplatin as initial treatment, a residual tumour mass of less than 2 cm prior to therapy, FIGO stage II/III and a good performance status. In a multivariate model, the use of cisplatin and the residual tumour were found to be the only factors of prognostic relevance. No relation between median survival and the overall clinical response rate of all patients entered in the denominator, could be demonstrated. Undifferentiated tumours and patients treated with cisplatin regimens had higher response rates to treatment but younger patients and those with endometrioid histology were less likely to respond. A surgical complete remission was encountered more frequently among studies that included a high number of patients with small tumour masses prior to treatment. Trials using cisplatin included more patients with small tumour nodules in their patient material compared to studies not using this drug. The data illustrate the danger of comparing studies with each other. In the trials with a high percentage of patients with small tumour residuals in the study population more toxic deaths were seen. This probably reflects the fact that they had received more intensive treatment. The LRR correlated strongly with the median survival, response and the percentage of surgical complete remissions. We concluded that the introduction of the LRR can be a meaningful addition to the evaluation of the influence of prognostic factors on overall survival.

Efficacy of the neuropeptide Org.2766 in the prevention and treatment of cisplatin-induced neurotoxicity in rats

In rats chronic systemic treatment with cisplatin results in a sensory neuropathy as evidenced by a reduction in the sensory conduction velocity in the sciatic nerve. Concomitant administration of the neurotrophic ACTH4-9 analog, ORG.2766, prevents the occurrence of the neuropathy. In addition, treatment with ORG.2766 stops further deterioration and improves recovery of an already established cisplatin-induced neuropathy. Furthermore, concomitant administration of ORG.2766 during a first cisplatin treatment period results in a better resistance against neurotoxicity in a second exposure period. Finally, ORG.2766 was shown not to hamper the anti-tumor effect of cisplatin in mice, carrying implanted tumor cells from a FMa human tumor line. These data are discussed in view of the potential clinical use of ORG.2766 in prevention and treatment of cisplatin-induced neuropathy.

Org. 2766 protects from cisplatin-induced neurotoxicity in rats

One of the side-effects of the cytotoxic drug, cisplatin, is its neurotoxicity. In rats this neurotoxicity can be measured as a slowing of the H-reflex-related sensory nerve conduction velocity. Concurrent treatment with Org.2766 (an ACTH4-9 analog) prevents this neurotoxic side effect while leaving the antitumor activity of cisplatin unaffected.

Evaluation of cis-diamminedichloroplatinum (II) (Cisplatin) neurotoxicity in rats

Cisplatin neurotoxicity was studied in rats by using electrophysiological and functional tests. The drug was injected intraperitoneally two times a week (1 mg/kg) up to a cumulative dose of 19.0 mg/kg body wt. At this dose the H-reflex-related sensory nerve conduction velocity was reduced. After cessation of drug administration, the H-reflex-related sensory nerve conduction velocity slowly improved. The motor nerve conduction velocity remained unaffected throughout the intoxication period and concentric needle investigation showed no signs of denervation. In addition, the sensorimotor response to a noxious stimulus presented locally to the foot sole was not affected by the cisplatin treatment. It is concluded that measurement of H-reflex-related sensory nerve conduction velocity is a useful and accurate tool in the evaluation of cisplatin neurotoxicity in rats.