High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer

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1 Annals of Oncology 4: 55-6, Kluwer Academic Publishers. Printed in the Netherlands. Original article High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer F. Di Re, S. Bohm, S. Oriana, G. B. Spatti, C. Pirovano, M. Tedeschi, & F. Zunino Istituto Nazionale per lo Studio e la Cum dei Tumori Milan; ' Boehringer Mannheim Italia, Research Center Monza, Milan, Italy Summary Background: On the basis of preliminary results achieved with a high-dose cisplatin regimen including glutathione as chemoprotector, the efficacy and toxicity of the new regimen was further evaluated in a larger series of patients with advanced ovarian cancer (stage HI and IV). Patients and methods: The study included patients with bulky or extensive residual disease after primary laparotomy or with bulky inoperable tumor masses. A total of 9 patients were treated with up to five courses of high-dose cisplatin (4 mg/m daily in normal saline, for four days) plus glutathione (5 mg as a short-term infusion before cisplatin), together with cyclophosphamide (6 mg/m as an i.v. bolus on day 4). A standard i.v. hydration consisting of a total of ml of fluids without diuretics was employed. Results: All eligible patients, who received a total of 45 courses, were assessed for response and toxicity and 5 received the planned five courses of the protocol. Forty-five patients (5%) achieved complete clinical responses and (5%) had partial remissions for an overall response rate of 8%. The response rate was critically dependent on tumor size before chemotherapy. Thirty-eight of 45 patients who had complete clinical responses underwent second-look laparotomy, and 9 had pathological complete responses Introduction A multimodal approach, including aggressive surgical cytoreduction and chemotherapy, has become the standard treatment strategy for patients with advanced ovarian cancer (FIGO stages HI and IV). Chemotherapy has a major role in the management of this tumor, since only a few patients have surgically-curable disease [, ]. Platinum compounds have been recognized as the most active agents, and the superiority of cisplatin-based chemotherapy regimens over other combinations has been well documented [, ]. The difficulty of improving the treatment results produced by regimens containing standard doses of cisplatin (with particular reference to long-term survival) could be ascribed to a lack of new effective agents and to unacceptable toxicity of high-dose cisplatin (or carboplatin) therapy [,4]. Thus, optimum regimens in the treatment of advanced disease remain to be defined. (%). Seventeen of these 9 patients subsequently relapsed (median disease-free interval, months; range, 6-45). With a median follow-up time of 44 months, the median survival for the 9 analyzed cases was 4 months. The toxicity of the regimen was moderate. Nausea/vomiting was the most severe acute toxicity. Myelotoxicity was acceptable, with severe leukopenia and thrombocytopenia (grade 4) occurring in 8% and % of patients, respectively. Nephrotoxicity was minimal with a transient increase (to < mg/dl) in serum creatinine in only 6 patients (8%). Peripheral neurotoxicity and ototoxicity were the most significant long-term toxicities. The severity of these side effects (grade WHO neurotoxicity occurred in only 4% of patients) was apparently less than has been reported with other high-dose cisplatin regimens. Neurotoxicity required discontinuation of therapy in three patients after four courses. Most affected patients had complete or partial recovery of symptoms with time. Discussion: The efficacy and tolerability of the regimen confirm the feasibility of this new approach including glutathione in order to increase cisplatin dose intensity. The superiority of this regimen over standard induction therapy should be confirmed in randomized trials. Key words: advanced ovarian cancer, high-dose cisplatin, glutathione The dose intensity of cisplatin appears to be an important factor in the treatment of ovarian cancer [5], and the optimum one remains to be established []. Unfortunately, attempts to escalate cisplatin doses above mg/mvcourse have resulted in major toxicity problems which limit treatment duration. Peripheral neuropathy and ototoxicity have emerged as dose-limiting complications of high-dose therapy that affect more than 5% of treated patients [4, 6]. The severity of these side effects remains a major obstacle to widespread use of high doses. Thus, clinical experience with cisplatin doses above mg/m is still limited in the treatment of advanced ovarian cancer. However, it is controversial whether high-dose therapy leads to an improved curative potential []. Several approaches to identify safe methods of cisplatin dose escalation have been investigated [,,8]. In particular, the use of nucleophilic sulfur-containing compounds as chemoprotectors has been explored as a Downloaded from at Pennsylvania State University on March 6, 6

2 56 potentially useful method to minimize dsplatin toxicity. Among sulfur-containing compounds, the natural thiol tripeptide glutathione (GSH) is one of the most promising chemoprotectors proposed for clinical development due to its safety and selective protective effect against renal toxicity [9, ]. A preliminary report showed that GSH allows the safe administration of five courses of high-dose cisplatin (6 mg/m /course) []. On the basis of the encouraging therapeutic outcome of this new approach, the efficacy and toxicity of high-dose cisplatin and GSH was further evaluated in a large series of patients with advanced ovarian cancer. Only patients with bulky (or extensive) disease were included in the study, since they were considered unlikely to attain complete remission with regimens containing standard cisplatin doses [6,]. The efficacy of the new protocol appears to be substantiated by the expected survival of this poor-prognosis group of patients. Patients and methods Patients were eligible for the study if they had stage ID bulky (> cm) and IV epithelial ovarian cancer, as histologically confirmed by the Department of Pathology of our Institute. Further inclusion criteria were: no prior chemotherapy or radiotherapy; age >8 but < years; Karnofsky Performance Status >; life expectancy > months; normal bone marrow, liver and kidney function as indicated by leukocyte and platelet counts of at least 4, and 5,/ mm, respectively; normal serum bilirubin, SGOT, SGPT and serum creatinine levels. Informed consent was obtained from each patient. This study was approved by the Institutional Human Investigations Committee. The patient characteristics are presented in Table. Treatment program Patients judged to be operable underwent initial surgery for debulking and staging. Patients with minimal residual disease were excluded from the study, and those with bulky (at least one residual lesion > cm in diameter) or extensive residual disease received five courses of chemotherapy. When adequate debulking surgery was initially judged to be infeasible on the basis of clinical and radiologi- Table. Characteristics of the eligible patients. No. of entered patients No. of eligible patients Median age (range), years FIGO stage, n (%) III rv Histology Serous Undifferentiated Endometrioid Mixed Clear cell Unclassified Grade Ungraded (-69) 48 (6) (4) cal examinations, patients underwent laparoscopy for staging and biopsy and, as soon as possible, were treated with chemotherapy. All responding patients of this subgroup underwent debulking surgery during chemotherapy. Second-look surgery was performed in patients who had achieved clinical complete remissions by the end of the therapeutic program. Chemotherapeutic regimen The regimen consisted of cisplatin (4 mg/m given daily for 4 consecutive days as a min infusion in 5 ml normal saline) and cyclophosphamide (6 mg/m given as an i.v. bolus on day 4 only). GSH (,5 mg) was given in ml of normal saline over 5 min before each cisplatin administration; it was provided by Boehringer Mannheim Italia (Milan, Italy) as a sterile, freeze-dried powder in -ml vials containing,5 mg of drug. Standard i.v. hydration (, ml of fluid) without routine diuretics was used: h prior to initiation of the cisplatin infusion, patients were hydrated with, ml normal saline to which meq of KC and 5 meq of MgSO 4 had been added. Post-hydration was continued for h after cisplatin infusion with, ml of normal saline containing meq of KC. Patients were hospitalized during therapy. Cycles were repeated every -4 weeks for a total of five courses except in instances of disease progression or severe toxicity. Evaluation of response Second-look laparotomy was recommended for all patients in clinical complete response. To assess pathological response, secondlook laparotomy included multiple biopsies from areas of macroscopic disease, from sites of previous disease, and from any suspicious or high-risk area (diaphragm, paracolic gutters and pelvic peritoneum). A complete response was considered to be pathologically documented if all the biopsies and washings were negative. A clinically complete response was defined as the complete disappearance of disease detectable by physical and/or radiological examinations. A partial response was defined as a reduction of >5% in all measurable lesions at second surgery. Objective tumor response to treatment was defined clinically in patients with clinical progression. Statistical methods The Kaplan-Meier method [] was used for calculating survival time curves. Survival was measured from the initiation of therapy to death. Analysis was as of April 99. Evaluation of toxicity Myelotoxicity, nephrotoxicity and hepatotoxicity were assessed on the basis of routine hematological and biochemical parameters. A complete blood count and platelet count as well as values for serum blood urea nitrogen (BUN), creatinine and electrolytes were obtained before and after treatment, daily during treatment, and weekly between courses. Liver function tests were done every weeks. Ototoxicity was assessed clinically and by audiography before treatment and at the end of the chemotherapeutic program. Neurotoxicity was evaluated by clinical examination before the treatment and after five courses of chemotherapy. An electrophysiological investigation was not routinely performed in this study. When significant neurotoxicity symptoms occurred, peripheral neuropathy was assessed by neurophysiological parameters including assessment of sensory action potentials and motor conduction velocities. Results Between November 986 and June 99,89 previously untreated consecutive patients entered the study, Downloaded from at Pennsylvania State University on March 6, 6

3 which included only patients with extensive residual disease following initial laparotomy or with bulky inoperable tumor masses. Six patients, who underwent optimal debulking surgery before chemotherapy (i.e., residual lesions < cm in diameter), received the chemotherapy regimen according to the same protocol, since they had multiple peritoneal nodules, infiltrating lesions and/or positive retroperitoneal nodes (i.e. stage Hie) []. These patients were ineligible for the study and were excluded from the assessment of response and survival. In four patients, ineligibility was due to another primary cancer, viral hepatitis, Brenner tumor, and fallopian tube carcinoma. All eligible patients had clinically detectable disease by physical and/or radiological examination. Fifty-seven percent of the eligible patients (45/9) had residual disease after surgery or inoperable tumor masses > cm. As of October 99, 9 of the 89 accrued patients were assessed for response and toxicity. Twenty-nine patients in whom adequate tumor removal was thought to be impossible initially on the basis of clinical and radiological examinations (including laparoscopy), were treated with primary chemotherapy. In of these patients debulking surgery was performed during chemotherapy (after at least two courses). Surgery was not attempted in seven cases (for progressive disease in 4 cases). Two patients died after just one course of treatment each, one because of bowel obstruction and the other of perforation, and were considered nonresponders. Treatment feasibility The 9 evaluable patients received a total of 45 cycles, and 5 patients received the planned five courses of the protocol. The fifth course was cancelled due to grade neurotoxic manifestations in three patients and because of ototoxicity in one patient. In two other patients, the cisplatin dose in the fifth course was decreased to 9 mg/m because of delayed recovery from myelotoxicity. Treatment was discontinued in 9 additional patients after -4 courses due to progressive disease, lack of significant response (eleven patients), refusal of further therapy (five patients) or complications unrelated to chemotherapy (three patients), consisting of post-surgical complications and viral hepatitis in two cases, and myocardial ischemic disorders in a 6-year-old patient. Two patients died after one course of therapy. Patients with complete responses following second-look laparotomy received no further therapy. Second-line treatment was not homogeneous in patients who did not achieve complete responses or in relapsed patients. Analysis of toxicity data for the 9 analyzed patients (Table ) confirmed the treatment tolerability previously described for the first 4 patients of the study population []. Indeed, most patients were able to complete the planned treatment program with acceptable toxicity. The last course of the program was omitted in four Table. Toxicity. Toxic effects Gastrointestinal Nausea only Nausea and vomiting, controllable Intractable vomiting Life-threatening Leukopenia (cells/mm ) ^ - - < Thrombocytopenia (cells/mm ),-5, 5,-,,-5, <, Anemia (hemoglobin, g/ ml) <.9 Nephrotoxicity Creatinine (mg/dl):.5-. Peripheral neuropathy - Grade - Grade - Grade - Grade 4 5 No. of patients* 9" Ototoxicity - audiogram abnormalities only 5 - audiogram abnormalities + tinnitus + mild hearing loss 5 - disabling hearing loss Visual disturbances Liver enzyme elevations 5 Number of patients who developed the indicated grade of toxicity on at least one occasion. b Generally on day 4. c According to WHO toxicity criteria. patients due to toxicity. Dose reductions were necessary in two patients. There were no toxic deaths. Prolonged nausea/vomiting was a frequent problem. Using an antiemetic regimen based on metoclopramide, emesis was partially controlled except on day four of the course. Although this side effect was more severe (>8 emetic episodes/4 h) than that observed with standard doses of cisplatin and was usually protracted for two days after chemotherapy, it never resulted in alteration of therapy and never required additional replacement therapy for dehydration. In spite of moderate hydration, nephrotoxicity was minimal. Only six patients developed a mild, transient elevation of serum creatinine up to < mg/dl (including one patient with altered renal function because of ureteral compression). In no patient was cisplatin discontinued for nephrotoxicity. Hypomagnesemia (<.5 meq/l) occurred in 5 patients. None of the patients developed Downloaded from at Pennsylvania State University on March 6, 6

4 58 persistent hypomagnesemia. No clinical manifestation of hypomagnesemia was observed. The moderate changes in serum magnesium level (abnormal magnesium levels ranged from. to.5 meq/l in of the 5 patients) returned to normal by day. Peripheral neuropathy was the most frequent cumulative side effect, occurring in 56% of patients. Neurotoxicity generally developed after 4-5 courses of highdose cisplatin in the form of moderate paresthesias, decreased (or absent) deep tendon reflexes. Grade WHO peripheral neuropathy occurred in only three patients (4%). In one patient neurologic toxicity progressed in the form of severe sensory loss after cisplatin therapy was stopped. It required discontinuation of therapy in three patients after four courses. In patients available for long-term follow-up, cessation of cisplatin therapy was followed by partial or complete reversal of symptoms of peripheral neuropathy. Ototoxicity was detected as audiogram abnormalities only in 5 patients; five patients experienced significant subjective hearing loss. Hematologic toxicity was common but manageable. Severe leukopenia (< WBC/mm ) and severe thrombocytopenia (<, cells/mm ) occurred in six (8%) and two patients (%), respectively. There were no episodes of treatment-related infection or hemorrhage. In general, myelosuppression was of short duration, and reduction of the cisplatin dosage was performed in only two patients as a consequence of prolonged leukopenia after four courses. Severe anemia requiring transfusion occurred in 5 patients, generally after 4 courses. Response to treatment and survival The results regarding clinical response are summarized in Table. The overall (complete + partial) response rate was 8%. Of the 9 evaluable patients, a total of 45 (5%) achieved complete clinical response. The complete response rate appeared to be critically influenced by the volume of pretreatment disease, since in patients with massive disease (> cm in diameter) the therapy produced a lower response rate (44%) than that achieved in the patients with smaller tumor masses (%). Second-look laparotomy was performed rou- Table. Clinical response. Complete response Partial response No response b Total Tumor size (cm) before chemotherapy (No. of patients) * In parenthesis: percentage of evaluable patients (n 9). b No response includes stable disease and minimal response. Total 45 (5) (5) 4(8) 9 tinely to assess response in patients who achieved complete responses. In non-responding patients (including those with minimal response or stable disease), objective tumor response to treatment was defined clinically. In the subgroup of 9 patients in whom surgery was not initially attempted the pathological complete response rate was appreciably lower (8%) than that observed in patients in whom surgery was performed before chemotherapy (4%). It is likely that the reduced efficacy of the treatment in these patients reflects the very extensive disease ( patients had tumor masses greater than cm and 6 were stage IV) rather than the delayed surgical debulking. Of the 45 patients with complete clinical responses, thirty-eight were pathologically evaluable and seven refused second-look laparotomy (Table 4). These latter seven patients were all evaluable for clinical response since they had bulky measurable disease after primary laparotomy. Pathological complete responses were documented in 9/8. Thus the overall negative second-look rate was % in the total group of 9. Of the nine positive patients at second-look surgery, two were completely resected and seven had only microscopic residual disease. Of the pathological complete responders, 5 had tumors > cm in diameter at the start of the treatment and 4 had tumors - cm in diameter. Twenty-one of the pathological complete responders presented with stage HI disease and eight with stage IV disease. The median follow-up for the entire group of treated patients (n 9) at the time of analysis (April 99) was 44 months (range -66). Forty-two patients of the series as a whole died of progressive disease. By actuarial analysis of survival for all eligible patients who entered the study, the estimated -year survival rate was approximately 55% (Fig. ). The median survival time of this series was 4 months. Twelve of the patients in pathological complete response are still disease-free. In relapsed patients the Table 4. Second-look and current status in patients who achieved a complete clinical response. Negative (pcr) Positive: Completely resected Microscopic residual disease Subtotal Refused second look (ccr)' Total No. of pucnis Current status NED " Recurrence or progression 5 C 6 Alive Dead * pcr - pathologic complete response. b Patients with no clinically detectable disease following a second-line therapy. ' Patients with progressive disease. i Evaluable for clinical response Downloaded from at Pennsylvania State University on March 6, 6

5 oo 4 Months Fig.. Survival of 9 patients with advanced bulky ovarian cancer. Survival was measured from the start of chemotherapy and calculated using the method of Kaplan and Meier. Alive, patients; dead, 4 patients; median: 4 months. median disease-free interval was months (range, 6-45). Discussion Clinical data on the treatment of advanced ovarian carcinoma suggest that the dose intensity of cisplatin is an important factor in improving the therapeutic results [5]. These data were obtained from retrospective analysis of series in which cisplatin doses were relatively low (i.e., less than mg/m ). The optimal dose of cisplatin has not yet been defined. Similarly, the clinical relevance of a dose intensity effect above standard dose levels (> - mg/mvcourse) remains to be established. Unfortunately, attempts to escalate cisplatin dose above this range were associated with unacceptable toxicity. From the limited information available regarding the use of cisplatin at doses higher than mg/m [,6], it is still unclear whether these intensification approaches provide significant improvement in terms of response and survival of ovarian cancer patients. The severity of side effects from high-dose therapy remains a major obstacle to the wide-spread use of high-dose cisplatin even in short-term induction regimens [4]. Among the various attempts to improve the therapeutic index of cisplatin, toxicity protection with biochemical and/or pharmacological modulators is a promising approach for optimizing cisplatin therapy. The major problem in the use of chemoprotectors is the questionable selectivity of the protective action, since reaction with cisplatin could also inhibit cytotoxic and antitumor activity [5]. Among the proposed and clinically tested chemoprotectors, GSH appears to be the most promising agent for future clinical development [6]. GSH was initially proposed as a chemoprotector against cisplatin-induced renal toxicity [9]. Whereas intracellular (i.e. endogenous) GSH may contribute to tumor cell resistance to alkylating agents and platinum compounds, extracellular (i.e. exogenous) GSH is unlikely to interfere with the cytotoxic activity of these drugs since circulating GSH is not taken up by cells 59 except in tissues with substantial membrane expression of Y-glutamyltransferase []. The cellular pharmacokinetic behavior of extracellular GSH was clearly documented in ovarian cancer cell systems, which express a low level of membrane Y-glutamyltransferase activity [6]. The present study clearly documents the safety of a high-dose cisplatin regimen including GSH. The feasibility of this protocol is supported by a lack of significant nephrotoxicity and by the acceptable neurotoxicity. This unexpected finding may have important clinical implications, since neurotoxicity has emerged as the dose-limiting toxicity in high-dose regimens [4]. Although peripheral neuropathy was a frequent cumulative side effect in our experience, the incidence of severe toxic manifestations was minimal, with a median cumulative dose (8 mg/m ) comparable or superior to that of more toxic protocols [, 6]. Following only three courses of high-dose cisplatin ( mg/m ) using a 5-day schedule of 4 mg/m per day, 5% of patients developed grade -4 peripheral neuropathy []. In our series, neurotoxicity was dose-limiting in only three patients and no disabling neuropathy was observed. Although cisplatin-induced neuropathy may be partially schedule-dependent, the strikingly good tolerability of our regimen is likely to be related to the use of GSH as a chemoprotector. The efficacy of this GSH-cisplatin combination, suggested by preliminary results [], appears to be confirmed in a larger series of patients with a longer follow-up. The study was designed to include only patients with advanced extensive/bulky disease at the start of chemotherapy, since this is considered a poorprognosis group of patients. Indeed, the volume of disease prior to the start of chemotherapy is the most important prognostic factor influencing the ability to achieve a complete remission and the relapse rate []. Thus, in studies in which this subset of advanced stage ID/TV has been separately observed [, 6, ], the pathologically complete response rate was generally less than %, with a median survival time ranging from to 5 months. A pathologic response rate of % (comparable to that of previous observations) [] is appreciably higher than that seen with conventional treatments [] and suggests an improved efficacy beyond that expected from dose intensification. The efficacy of the protocol is also supported by the survival analysis. The median survival time of patients in our series (4 months) with extensive disease (5% of patients had primary residual tumors larger than cm) compares favorably with most series of patients treated with cisplatin-based regimens. In most studies which also incorporate patients with optimally debulked disease, the median survival time ranged from to months []. The expected -year survival time in our series is comparable to that reported for patients who underwent optimal debulking surgery [,8]. In an attempt to explore the dose intensity effect of platinum compounds in ovarian cancer, various Downloaded from at Pennsylvania State University on March 6, 6

6 6 approaches have recently been taken including intraperitoneal therapy, weekly cisplatin administration, high-dose carboplatin or high-dose chemotherapy with hematopoietic colony-stimulating factors or autologous bone marrow transplantation support [,9]. The theoretical advantage of intraperitoneal administration, as a form of loco-regional dose-intensification, is represented by an increased tumor drug exposure. Since this approach has limited efficacy in patients with bulky residual disease or as primary therapy, its role may be limited to that of a consolidation procedure following induction therapy in good-prognosis patients [-]. A weekly schedule with cisplatin alone has been used as an effective induction therapy [8, ], which may achieve a greater dose-intensity than conventional schedules in a short period of treatment [4]. It remains to be documented whether this approach will improve the therapeutic outcome. Further exploration of the dose intensity effect is expected to be feasible with the use of carboplatin. High-dose platinum chemotherapy studies are in progress with the combination of cisplatin with carboplatin. The feasibility of this dose-intensive therapy approach is based on the non-overlapping toxic profile of these two platinum complexes [, 4]. The preliminary results are encouraging in some instances [5-], but it remains to be determined whether such an approach can increase the dose intensity enough to provide a therapeutic advantage over conventional regimens. Preliminary studies with highdose carboplatin have been performed in previously treated patients [, 8, 9]. Clearly these approaches, which require adequate support because of hematologic toxicity [], have several drawbacks, including complications and increased costs. The main advantage of the high-dose cisplatin regimen with GSH is that the dosage of 6 mg/m /course can be maintained for five cycles of treatment, thus allowing the % delivery of planned dose in most patients. The tolerability of this protocol and the easy modality of administration may contribute to the positive treatment outcome. The encouraging results of the present study warrant further clinical investigation. The role of this approach in optimizing the use of cisplatin and in improving the current treatment results in the management of advanced ovarian cancer should be documented in randomized trials. Acknowledgements We are grateful to L. Zanesi and B. Johnston for editorial assistance. The study was supported in part by the Associazione Italiana Ricerca sul Cancro. References. Ozols RF, Young RC. Chemotherapy of ovarian cancer. Semin Oncol 99; 8: -.. Friedlander ML, Dembo AJ. Prognostic factors in ovarian cancer. Semin Oncol 99; 8: 5-.. 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