Cancer Investigation, 10(4), 307-315 (1992)

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New Therapies for Ovarian Cancer Russell J. Schilder, M.D. and Robert F. Ozols, M.D., Ph.D. Department of Medical Oncology Fox Chase Cancer Center 7701 Burholme Avenue Phlladelphia, Pennsylvania 19111

INTRODUCTION

decrease in their relative death xate compared with those patients who did not receive cisplatin. The response rate to cisplatin ranges from 50-801. The clinical complete remission (CCR) rate is approximately 40% while the pathological complete response rate (PCR) rate is about 1/2 the CCR rate. Patients who do achieve a PCR cannot be considered cured as 40-W-6 of these patients are destined to relapse (6). While platinum-based therapy has improved the treatment of ovarian cancer, continued research is needed to maximize the efficacy of chemotherapy while minimizing its toxicity through modifications in drug design, dose, and supportive measures. The problemof disease recumnce focuses attention on the area of prevention or reversal of tumor resistance to platinum compoundsand other chemotherapy agents.

The ovary is one of the three most common sites for the development of a malignant neoplasm in the female genital tract. Unlike cancers of the endometriumand cervix, ovarian cancer presents without early warning signs and thus more often presents as extensivedisease (1). The silent growth contributes to its being the most fatal gynecologic malignancy and the fourth most common cause of cancer death among women in this country. Approximately 20,000 new cases of ovarian cancer are diagnosed per year with nearly 12,000 deaths per year. More than 85% of all ovarian malignancies are of epithelial origin (2). The stage of disease is a critical predictor of survival in patients with ovarian cancer (3). Patients with a pathologically documented early stage cancer have a 5-year survival in excess of 80% (4) while patients with stage III disease have a Syear survival of 15-25% (5a). Over 70% of patients diagnosed with ovarian cancer present with advanced disease, i.e., disease outside the pelvis (3). Chemotherapeutic regimens containing platinum compounds have become the mainstay of treatment following surgical cytoreduction performed during staging laparotomy. A retrospective review of 600 patients by Gynecological Oncology Group (GOG) showed that cisplatin-based chemotherapy was a positive predictor of outcome (5b). Patients treated with cisplatin had a 23%

MAMPULATION OF THE DRUG RESISTANCE PHENOTYPE Ovarian cancer is typical of tumors which usually are initially responsive to chemotherapy but later develop clinical resistance. Multiple mechanisms of drug resistance exist including alterations in drug transport (either increased efflux or decreasedinflux), enhand detoxification mechanisms (increased levels of sulfhydryl molecules, e.g., glutathione and metallathimein and related 307

Copyright 0 1992 by Marcel Defier, Inc.

Schdder and 0201s

308 Table 1 Mechanisms of Drug Resistance Mechanism

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Alterations in drug transpolt decreased intlux increased eflux, e.g., MDR-1

Modifier

Verapamil, quinine

Enhanced detoxification glutathione glutathione-S-transferase metallothionein

Buthionhe sulfoximine Ethacrynic acid

Increased capacity of DNA repair increased thymidine kinase activity increased polymerase activity increased excision enzyme activity

Azidothymidine Aphidicolin

-

-

enzymes) and increased repair capacity of DNA damage (7) (Table 1). The method of transport of cisplatin across the cell membrane is incompletelycharacterized. Evidence exists, however, that cisplatin may enter cells by either passive diffusion, carrier-dependenttransport related to transport of neutral amino acids, or both (8,9). A precise cellular alteration in resistant cells has not been identified. Thus, the clinical relevance of decreased uptake of cisplatin intracellularly as a mechanism of resistance remains undefined. There is no simple correlation between drug transport and degree of cisplatin resistance. Reduced intracellular accumulation of chemotherapeutic agents from natural product origin is mediated in part by the P-170 glycoprotein, a product of the MDR-1 gene (10). Bourhis and colleagues analyzed 50 ovarian carcinoma specimens for MDR-1 expression(1 1). While low levels of transcript were detected in samples obtained from 3 of 10 patients treated with vincristine or doxorubicin, no expression of MDR-1 was apparent in specimensfrom 5 patients treated with cyclophosphamideand cisplatin or from 35 untreated patients. Southern blot analysis did not reveal amplification on the MDR-1 gene in these specimens. Ozols and colleagues treated 8 patients with refractory ovarian cancer with doxorubicin and verapamil which antagonizes the activity of the P-170 efflux pump (12). High concentrations of verapamil were required to achieve this effect in vitro. Clinically, such doses of verapand led to completeheart block and congestiveheart failure. There was no evidence of potentiation of doxorubicin toxicity, however, there were no responses. The

addition of doxorubicin to cyclophosphamideand cisplatin did not improve response rates or survival in four large randomized trials (13- 16). A recent meta analysis of these studies demonstrated a small, but significant benefit in response rate and overall survival of 7 A in patients receiving the doxorubicin-containing regimen (17). In three of the four studies doxorubicin was added to cisplatin and cyclophosphamide.Only the GOG study attempted to correct for dose intensity by increasing the cyclophosphamide dose to equal hematologic toxicity. The improvement seen in patients receiving the doxorubicinantaining regimen may be due to greater dose intensity rather than from a contribution of doxorubicin itself. Thus, the MDR-1 gene product does not appear to be a major mechanism of resistance for the commonly used drugs in the treatment of ovarian cancer, i.e., alkylating agents and platinum compounds. This mechanism may play a role, however, in resistance of ovarian cancer cells to tax01 (18, 19). Glutathione and metallothionein are the predominant cellular nonprotein and protein sulfhydryl compounds, respectively. Experimental evidence has suggested a role for metallothioneins as potential mediators of cisplatin resistance. Kelly et al. (20) reported an elevated metallothionein content in cisplatin-resistanthuman cell lines and in murine cells with a cisplatin-inducedresistance phenotype in expressing a transfected human metallothionein gene. Data from our laboratory failed to show a correlation between cisplatin resistance and metallothionein expression in human ovarian cancer cell lines and in the same transfection model (21). Glutathione(GSH) participates in many important reactions involved in maintaining normal cellular homeostasis. Ovarian cancer cell lines with in vitro-induced resistance to melphalan or cisplatin demonstrated cross resistance to each agent and to irradiation (22). Increased levels of intracellular glutathione have been detected in cells resistant to alkylating agents and cisplatin. Conversely, glutathione depletion in resistant cells enhances sensitivity to certain chemotherapy agents. Glutathionesynthesis can be inhibited by the synthetic amino acid, buthionine sulfoximine (BSO), which binds irreversibly to the glutathione synthetic enzyme, gamma-glutamyl-cysteine synthetase (23). Ovarian cancer cells resistant to melphalan and cisplatin can be sensitized to these agents by pretreatment with BSO (24). Treatment of mice carrying OVCAR-3 tumors (a cisplatin-resistant human ovarian cancer cell line) with BSO and melphalan prolonged their survival compared with melphalan alone and decreased glutathione levels in tumor cells by 90% (25). Currently the combination of BSO and melphalan is being evaluated

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New Therapies for Ovarian Cancer in Phase I trials (26,27). In in vitro experiments, the cytotoxicity of cisplatin and carboplatinare enhanced by BSO-mediated glutathime depletion. In animals, the toxicity of cisplatin but not carboplatin is also enhanced by BSO, presumably due to glutathione depletion in the kidney (28). Tlw combination of BSO and carboplatin is about to enter Phase I trials. Glutathione-related enzymes such as g1utathione-Stransferases (GST)also have been linked to tumor resistance to antineoplastic agents. Glutathione S-transferases along with glutathione are involved in many reactions dealing with metabolism and detoxification of a variety of substances (29). Incmsed GST expression has been demonstrated in cisplahresistant cell lines. Compounds such as ethacrynic acid inhibit the activity of GST. Wang and Tew showed that treatment with ethacrynic acid resulted in a reduction of GST activity in cells resistant to chlorambucil(30). Similar observations were reported by other investigators far a variety of drugs in cell lines and in tissue sanples including ovarian cancer (31). Currently, thio-TEPA and ethacrynicacid are being evaluated in a Phase I trial at Fox Chase Cancer Center (32) and chlorambucil in combination with ethacrynic acid is being tested in patients with chlorambucil-resistantchronic lymphocytic leukemia. DNA is a major target for many of chemotherapeutic agents including platinum compounds. An enhanced mechanism of repair of DNA damage induced by such agents has been demonstrated in resistant cells (33). This increased repair capacity can be manipulated to enhance the cytotoxic properties of platinum drugs and/or reverse resistance. Scanlon and colleagues showed in vitro that the antiviral agent azidothymidine (AZT) potentiated cisplatin cytotoxicityin a cisplatin-resistanthuman ovarian cancer cell line (34). These resistant cells had increased expression of thymidine kinase induced after treatment with cisplatin whereas sensitive cells did not. The enhanced ability to repair cisplatin-induced damage resulted in higher levels of AZT incorporated into DNA leading to more frequentearly chain termination. Azidothymidine currently is being evaluated clinically in combination with carboplatin or with 5-l7U and leucovorin (35,36). Aphidicolin is an inhibitor of DNA polymerase alpha (37). In preclinical studies, aphidicolin in combination with cisplatin enhanced cytotoxicity by 3.5-fold in a cisplatin-resistant human ovarian cancer cell line while having only minimal effects on cisplatin cytotoxicity in the sensitive parental cell line (38). The combination of aphidicolin and cisplatinyielded a survival advantagecompared to cisplatin alone when OVCAR-3 cells were implanted into nude mice (80vs. 20% survival at 129 days,

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respectively) (39). A Phase I study of aphidicolin using doses up to 4500 mg/m* recently was completed in Europe. Local imtation consisting of mild phlebitis and erythema was the only toxicity observed even at the highest dose tested (40). Phase I trials of carboplatin and aphidicolin are planned.

NEW DRUG DEVELOPMENT Cisplatin has been the essential chemotherapeuticagent in the treatment of ovarian cancer. The use of this drug is limited by its emetogenic nature and its nephro-, oto-, and neurotoxicities. Several second-generation platinum compounds (e.g., carboplatin)were developed to decrease these undesirable consequences of therapy. Carboplatin induces less of all these toxicities but is limited by myelosuppression. Carboplatin was found to be active against ovarian cancer in numerous Phase I and 11trials (41). Studies were performed to investigate whether carboplatin could be exchanged for cisplatinas initial therapy for patients with ovarian cancer since carboplatin has a more favorble toxicity profile. A recently reported metaanalysis utilized data from three randomized trials comparing carboplatin (400mg/m2) to cisplatin (100 mg/m2) as single-agent therapy (42). There were no differences in the percentage of patients achieving a PCR, the median duration of PCR or survival in patients receiving either platinum analog. Predictably, cisplatincaused more nonhematologic toxicity while carboplatin treatment resulted in significantly greater myelosuppression. Two randomized trials comparing cisplatin combined with cyclophosphamide to a carboplatinlcyclophosphamide regimen in patients with primarily bulky residual disease were reported with similar results as the aforementioned single agent trials (43,44). Not only can carboplatin-based therapy be used as frontline therapy for ovarian cancer, but with its more favorable toxicity profile can be considered the treatment of choice. The dose of carboplatin cannot be compromised. Inferior results were obtained when low-dose carboplatin was utilized (45). The degree of cross-resistancebetween carboplatin and cisplatin is substantial (46). These agents have the same active intermediate structure after aquation and form the same DNA-platinum shdducts (47). An exciting new platinum compound currently entering clinical trials is ormaplatin (formerly tetraplatin). This agent is another second-generationplatinum analog developed in an effort to decrease toxicity. It too has less nephro- and neurotoxicity compared with cisplatin. Ormaplatin was found to be more potent than cisplatin when tested against

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various human ovarian cancer cell l i m (48-50) and demonstrated partial non-cross resistance with cisplatin and carboplatin in v i m (48,50,51). Phase II trials of taxol m patients with ~fractoryovarian cancer have yielded pranking results. This drug is extracted from the bark of western yew trees. Exposure of cells to taxol causes stabilizationof polymerized tubulin as microtubules. The mechanism of action differs from most cytotoxic drugs that work at the level of microtubules [e.g .,the vinca alkaloidswhich Mibit tubulin polymerization (microtubdar formation)] (52). McGuire et al. observed a 30% response rate m patients with cisplatin refractory ovarian cancer (53). A response rate of 37% was generated in a similar study conducted by the GOG (54). Patients with disease not truly refractory to cisplatin had a response rate of 50% to taxol. The notable toxicities of taxol are severe hut transient myelosuppression, primarily leukopenia, peripheral neuropthy ,mucositis, allergic reactions, alopecia, and cardiac dysrhythmias. There was no indication of cumulative effects of any of these toxicities. These toxicitiesof taxol are complementary to those of cisplatin. A Phase I trial of this combination was recently conducted (55). Neutropenia was the dose-limiting toxicity. The clearance of taxol at steady state was slowa when cisplatin was administered prior to taxol. This finding most likely explains why myelosuppression was greater when cisplatin preceded taxol administration. Patients with extensive ethanol consumption had an increased frequency of neuropathy which otherwise was not significant. A Phase 111 study comparing regimens of tax01 and cisplatin to cyclophosphamideand cisplatin as initial chemtherapy is ongoing under the auspices of the GOG. Taxotere is a new semisynthetic analog of taxol whose precursor is isolated from the needles of a related yew species (56). This drug is even slightly more potent as a promoter of tubulin polymerization than taxol, In addition, taxotere exhibits at least partial non-cross-resistance in taxol-resistantcells. Another advantage of taxatere over taxol is that its source is a renewable resource. Phase I trials with taxotere are in progress in Europe, Altretamine (formerlyhexamethylmelamine) has recently been licensed for b treatment of Elapsed ovarian cancer. Manetta et al. treated patients witha l4day course of orally administered drug every 28 days (57). All patients had failed a cisplatin-basedregimenalthough relapse therapy does not necessariof disease after platinumly imply resistawe. The CCR rate was 15%in 52 patients. GI toxicity was the major untoward effect of this agent. The GOG has recently reported its experience with ifosfamide as a treatment for recurrent or refractory

advanced ovarian cancer (58). The overall response rate in 41 evaluable patients was 20% with 7% of patients achieving a CCR. Neurotoxicity and myelosuppression were the significanttoxicities observed. Hakes et al. obtained a response rate of only 10%using the same dose scheduleof ifosfamide in patients with cisplatin-resistant disease (59).

DOSE INTENSITY AND MODULATORS OF TOXICITY Levin and Hryniuk reviewed the importance of dose intensity in 33 different trials involving patients with ovarian cancer (60). Both clinical r e s p s e and survival of these patients positively correlated with the dose delivered per unit time and the use of combination chemotherapy. The relationship between dose intensity and response was observed for cisplatin (up to 100 mg/m2) but not for the other agents examined. The use of hypertonic saline (61) or sodium thiosulfate (62) allows doses up to 200 mg/m2 of cisplatin to be given without significant renal toxicity (Table 2). While patients responded to second line high-dose cisplatin therapy, neurotoxicity was dose limiting. High-dose carboplatin (800 mg/m2) produced a similar response rate (27 %) with severe myelosuppression (63). Nonhematologic toxicity was minimal. Highdose carboplatin is currently being evaluated as frontline therapy in multiple trials. Table 2

Madulators of Platinwn Toxicity Agent

Toxicity

Hypertonic saline

Nephrotoxicity

Sodium thiosulfate

Nephrotoxicity

Diethyldithiocarbamate

Nephrotoxicity , neurotoxicity myelosuppression, emesis

Colony-stimulating factors f hematopoietic stem cells

.

Myelosuppression

Seratonin H-3 receptor antagonist (ondansctron)

Emesis

ACTH (4-9) analog

Neurotoxicity

WR2721

Neurotoxicity, nephrotoxicity, myelosuppnssion

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New Therapies for Ovarian Cancer Diethyldithiocarbamate (DDTC) is a sulfur nucleophile that has the ability to protect against many of the toxic effects of platinum-based compounds without compromising their antitumor activity in preclinical models. Berry and collaborators using 4 g/m2 of DDTC showed minimal nephrotoxicity after doses of cisplatin up to 160 mg/m2 (64). ototoxicity became dose limiting, especially in patients who had previously received cranial irradiation. Hematological and neurotoxicities were also minimal. In contrast, there was no protective effect afforded to patients with refractory ovarian cancer by DDTC from the toxicities of high-dose carboplatin (800 mg/m2) treatment (65). The patients in Berry’s study represented a mixed population of different diseases and previous treatments (about 25 !% were untreated). Dose and schedule of administration of DDTC may be important parameters to achieving a protective effect. In Berry’s study, DDTC was given 45 minutes after cisplatin while DDTC was given three hours after cisplatin in Rothenberg’s study. Further investigationwith previously untreated patients is warranted. Cisplatin and carboplatin have been administered together, each at standad doses, to attempt to maximize the delivery of platinum while taking advantage of their different toxicities (66-70). The combination was more myelosuppressive when administered concurrently (66). In contrast, nearly full doses of each agent can be tolerated when these drugs are given several days apart (70). The addition of ifosfamide to both platinum compounds resulted in a PCR of 42% (69). Myelosuppression was profound but manageable. Significantnonhematologictoxicity occurred in only 6 96 of patients. Trials involving the combination of cisplatin and high-dose carboplatin in front-line regimens are in progress at the National Cancer Institute and Fox Chase Cancer Center. Reed et al. combined highdose carboplatinwith recornbinant granulocyte-macrophasecolony-stimulatingfactor (GM-CSF) treatment in patients with refractory ovarian cancer (71). The frequency of neutropenic fever was reduced twofold compand to historical oontrols. Thrombocytopenia was not ameliorated by GM-CSF. Other cytokines now entering clinical trials, e.g., interleukins-1, -3, and -6, may d u c e platelet toxicity and allow for more dose-intense therapy. Highdose chemotherapy with autologous bone marrow support has beenlimited to previausly treated patients with persistent or recurrent disease (72-74). In one such study with a group of heavily pretreated patients (median number of prior regimens equals 3) the response rate was 78 !% without any complete remissions and a 23 96 mortality rate (74). In another study where patients received

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less prior treatment, the overall response rate was 75% with 33 96 of patients achieving CCR (73).These studies were of a pilot nature with a small number of patients. Experience from treating patients with lymphoma has shown that the best results are obtained in patients with minimal disease that is still sensitive to chemotherapy. While no data are currently available in ovarian cancer, it seems reasonable to suggest that aggressive chemotherapy and hematopoietic support earlier in the course of disease when patients still have responsive minimal disease may yield a prolonged disease-free and overall survival. Supportivemeasures such as CSF and peripheral blood stem cells should result in a decrease of morbidity and mortality of high-dose chemotherapy. Several compounds without any intrinsic antineoplastic activity have been combined with platinum analogs to decrease various toxicities. Cisplatin possesses significant emetogenic potential. High-dose metoclopramide-based antiemetic regimens have increased patient tolerance of cisplatin therapy but has not completely eliminated this toxicity. Ondansetron, a seratonin H-3 receptor antagonist, recently has been licensed for the control of chemotherapy-inducednausea and emesis. Urinary excretion of 5-hydroxyindolaceticacid, the main metabolite of seratonin, was elevated in all patients 2-6 hours after receiving cisplatin which paralleled the period of frequent emesis (75). Ondansetron has few side effects and was more effective than highdose metaclopramide when compared in a double-blinded placebo-controlled study (76). This new compound appears to virtually eliminate cisplatin-induced nausea and emesis. Neuropathy has become the most frequent dose-limiting toxicity at high doses of cisplatin (200 mg/m2). A recent report demonstratedthat an ACTH analog, Org 2766, had the ability to prevent cisplatin-induced peripheral neuropathy (77). There was no change in threshold of vibration perception in patients receiving six cycles of cisplatin (75 mg/m2). In contrast, there was an eightfold increase in the threshold after treatment in the placebo control group. If the efficacy of such compounds is confirmed, it may be possible to use either more dose intense and/or prolonged cisplatin-based induction programs in patients with responding disease. Mollman and colleagues (78) treated ovarian cancer patients with cisplatin-based chemotherapy and WR272 l. This compound was initially developed as a radioprotector but was shown to protect against various cisplatin toxicities as well. Combiningthis agent with cisplatin allowed a 1.3-1.7-fold increase in the cisplatin dose (79). Neuropathy was less frequent and the mean total dose of cisplatin at the onset of neurological symptoms was

Schilder and Ozols

312

about twofold higher in patients receiving WR2721 (78). These investigators recently reported early results of a Phase I trial of WR2721 and carboplatin (80).WR2721 allowed a 25% escalation of carboplatin (500 mg/m2) to be administered without significant toxicity. A new trial is in progress where patients are treated with carboplatin only followed by carboplatin along with WR2721 in the next cycle to more accurately evaluate the protection offered by W 7 2 1.

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INTRAPERMONEAL THERAPY Ovarian cancer provides an excellent model for the intraperitond (ip) route of chemotherapy administration since this disease disseminates primarily by peritoneal seeding. High drug concentrations are achieved by ip delivery (81). The pharmacologic advantage offered by the ip route is expressed as the ratio of total drug exposure for the peritoneal cavity @c) to that of plasma @) (i.e., area under the concentration versus time curve (AUC),/AUC,). Little information is known about drug levels in the tumor itself. Intraperitoneal administration of cisplatin has been extensively evaluated because of its lack of local toxicity to the peritoneal cavity and its known activity against ovarian cancer. Howell and associates reported a 74% four-year survival rate for a subset of patients with small volume disease ( < 2 cm) treated with cisplatin-based ip therapy (82). Patients with disease > 2 cm had a median survival of only 8 months. Other investigators in various Phase II studies have confirmed that patients with small volume disease seem to do well after ip cisplatin-based treatment (83,84). It is unclear whether patients with small volume disease live longer because of the treatment received or the small volume of disease itself which may be suggestiveof a more favorable biology. Reichman and associates treated patients with refractory or recurrent ovarian cancer with ip cisplatin and etoposide (84). The overall surgically defined response rate was 40% with a PCR rate of 21 %. Responses were independent of residual tumor bulk when the treatment-free interval (TFI) was greater than one year. In patients with refractory disease (TFI < l year) responses were dependent on the amount of residual disease. The median duration of second complete remissions was not reached. While significant nephrotoxicity and myelotoxicity occurred, chemical peritonitis or severe neurotoxicity was not observed. In this study, the results of cisplatin combined with etoposide were similar to those previously obtained with cisplatin alone. Etoposide has been shown to act synergisticallywith cisplatin in animal

models (85)and in the treatment of germ cell tumors (86), small cell lung cancer (87), untreated (88), and refractory ovarian cancer (89)in other studies. Randomized trials with surgical documentation of response will be required to determine the contribution of etoposide when combined with cisplatin and ip chemotherapy. Response rates of first-line ip cisplatin-based-treatedpatients were similar to those reported for standard iv cisplatin-based therapy (90). Failure rates within the abdominal cavity were not different from reported data with iv cisplatin. No survival advantages have yet been demonstrated by this approach. The Intergroup study in progress comparing ip cisplatin versus iv cisplatin with cyclophosphamide administered intravenously for both treatment groups may address some of the issues regarding the role of ip treatment of ovarian cancer. Patients have responded to subsequent treatment with ip carboplatin after a substantial and prolonged response to initial treatment with iv cisplatin. A meta-analysis of results from several ip carboplatin trials yield a PCR rate of 26% in such patients (91). "lese patients may have responded to iv cisplatin or carboplatin as well. Thus, only randomized trials, such as the aforementionedIntergroup study, will determine what role the ip administration of platinum-based cytotoxic agents will have as initial or salvage treatment. The ip administration of alpha-interferon as a single agent has a response rate of 45% in previously treated patients with minimal residual disease of 5 5 mm (92). Synergy between cisplatin and interferon has been demonstrated in vitro (93).Nardi et al. treated patients with an alternating regimen of ip cisplatin and alpha interferon who had residual disease after initial iv cisplatin-based therapy (94). Pathological complete remissions were achieved only in patients with microscopic residual disease. The major toxicity was chemical peritonitisinduced adhesions. This study demonstrates encouraging results with a small highly selected patient population.

EARLY STAGE OVARIAN CANCER Patients with early stage disease established by proper surgical explorationhave a very favorable prognosis (4). Patients with well-differentiated stage LA or IB disease were randomized to receive either oral melphalan or observation. There was no difference in overall and disease-free survival between the two groups of patients. Both sets of patients had a median survival > 90% for more than 6 years of follow up. Patients with poorly differentiated Stage I disease or tumor outside the ovaries

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New Therapies for

Ovarian Cancer

but limited to the pelvis (IC,II) were randomized to receive either oral melphalan or ip 32P.No differences in overall and disease-freesurvival were detected between treatment groups. An overall survival rate of 80% was observed for both arms of the study with a median follow up in excess of 6 years. While these results show a favorable prognosis for these patients, approximately 20 % of them die suggesting that more effective adjuvant therapy still is required. The current GOG trial compares ip 32Pto three cycles of cyclophosphamide (lo00 mg/m2) and cisplatin (100 mg/m2) in patients with poorly differentiated Stage I disease or with lesions outside the ovary but confined to the pelvis since this regimen of combination chemotherapy is known to be effective against advanced disease. Intraperitoneal 32P was chosen as the control arm of this study because there was no difference in efficacy when compared to melphalan, its single dose schedule and its limited toxicity (no increased risk of developing secondary leukemia). The endpoints of this study will be to determine if combination chemotherapy can further improve disease-free survival or overall survival in patients with early stage ovarian cancer

CONCLUSION Developmentof new agents with activity against ovarian cancer such as tax01 continue to generate promising results in treating this disease. Ongoing preclinical studies continue to undercover mechanisms by which cells may become resistant to previously effective agents. New agents capable of blunting toxic side effects of antineoplastic drugs may allow for more dose intense chemotherapy regimens which may impact on survival. Large randomized trials in progress should answer important questionsabout the role of intraperitonealtherapy.

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