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Phase III Trial of Standard-Dose Intravenous Cisplatin Plus Paclitaxel Versus Moderately High-Dose Carboplatin Followed by Intravenous Paclitaxel and Intraperitoneal Cisplatin in Small-Volume Stage III Ovarian Carcinoma: An Intergroup Study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group

From the Cleveland Clinic Taussig Cancer Center, Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo; Gastrointestinal Oncology Program, Albert Einstein College of Medicine, Bronx; and Department of Pathology and Laboratory Medicine, Strong Memorial Hospital, University of Rochester, Rochester, NY; Pharmacology and Public Health, College of Medicine, University of Arizona, Tucson, AZ; Ohio State University, James Cancer Hospital and Solove Research Institute, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbus, OH; Duke University School of Medicine, Durham, NC; and Division of Gynecologic Oncology, University of Minnesota, Hennepin County Medical Center, Minneapolis, MN.

Address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market St, Philadelphia, PA 19107. © 2001 by American Society of Clinical Oncology. 0732-183X/01/1904-100

	ABSTRACT

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PURPOSE: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin.

PATIENTS AND METHODS: Patients were randomized to receive either IV paclitaxel 135 mg/m² over 24 hours followed by IV cisplatin 75 mg/m² every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m² over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m² every 3 weeks for six courses.

RESULTS: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P = .01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P = .05, one-tail).

CONCLUSION: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.

	INTRODUCTION

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CURRENT STANDARD managementof advanced ovarian cancer includes the administration of a platinum agent in combination with paclitaxel.^1,2 Despite the demonstrated clinical utility of this combination chemotherapy strategy, the majority of women who present with ovarian cancer in its advanced stages ultimately die of complications of the malignancy. Thus there remains a critical need to examine innovative strategies that may ultimately impact on outcome in this disease.

Preclinical data and phase II clinical studies have suggested the potential utility of giving cisplatin by the intraperitoneal (IP) route, and a recently reported phase III intergroup trial has shown a survival advantage for this approach in the management of small-volume residual ovarian cancer.^3,4

The concept of employing systemically administered cytotoxic agents to chemically debulk residual cancer before regional drug delivery has been hypothesized to optimize the benefits of IP therapy by reducing the size of any residual tumor nodules to less than that which can be accomplished surgically.⁵ To test the potential clinical advantage of combining systemic chemical debulking with IP cisplatin in patients also receiving intravenously (IV) administered paclitaxel, the Gynecologic Oncology Group (GOG), Southwest Oncology Group, and the Eastern Cooperative Oncology Group (ECOG) initiated a randomized, controlled phase III trial of standard-dose IV cisplatin/paclitaxel for six courses,¹ compared with an experimental regimen of two cycles of moderately high-dose single-agent carboplatin, area under curve (AUC) 9, followed by six courses of IP cisplatin and IV paclitaxel. We report here the results of this study.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients considered for entry onto this randomized trial had to meet all of the following eligibility criteria: (1) histologic diagnosis of epithelial ovarian carcinoma, stage III (histologic types permitted: serous, mucinous, clear-cell, and endometrioid adenocarcinoma, undifferentiated carcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner’s tumor, and adenocarcinoma not otherwise specified [NOS]); (2) presence of optimal residual disease (largest residual tumor nodule 1 cm in maximal diameter) at the completion of staging and tumor debulking; (3) entry onto the study within 6 weeks of surgery; (4) adequate bone marrow (WBC 3,000 cells/mm³, platelets 100,000/mm³), renal (creatinine clearance 50 mL/min), and hepatic (bilirubin 1.5 times normal, serum AST three times normal function; (5) GOG performance status of 0, 1, or 2; and (6) signed, approved informed consent document stating they understood the investigational nature of the treatment program before entry onto study.

Patients considered ineligible for entry into this protocol included (1) those with ovarian carcinoma of low malignant potential (borderline tumors); (2) patients with suboptimal residual IP (> 1 cm largest residual tumor nodule) or stage IV disease; (3) patients who had previously received chemotherapy or radiotherapy; (4) patients with septicemia, severe infection, acute hepatitis, or severe gastrointestinal bleeding; (5) GOG performance status of 3 or 4; (6) patients with a past or concomitant malignancy other than skin cancer (excluding melanoma); or (7) patients with a history of congestive heart failure or unstable angina or those who had a myocardial infarction within the past 6 months. Patients who were not expected to tolerate the hemodynamic effects of sinus bradycardia, individuals with evidence of abnormal cardiac conduction, and patients taking medications known to affect the cardiac conduction system were also not eligible.

Treatment Regimens
The study was originally designed as a three-arm trial, the third arm being a regimen of cisplatin 75 mg/m² and cyclophosphamide 750 mg/m². When the initial results of GOG Trial #111 became available, in which it was demonstrated that in suboptimal residual ovarian cancer the combination of cisplatin 75 mg/m² plus paclitaxel 135 mg/m² delivered over 24 hours resulted in a superior response rate and progression-free survival compared with the identical cisplatin and cyclophosphamide regimen being used in the current trial,¹ the cisplatin/cyclophosphamide arm of the study was discontinued. Because only 66 patients were enrolled to receive the cisplatin/cyclophosphamide regimen, there are no definitive conclusions regarding efficacy of paclitaxel forthcoming from this part of the trial. Therefore, this study arm will not be discussed further in this report. The two completed study arms included the following: regimen 1, paclitaxel 135 mg/m² by continuous IV infusion for 24 hours on day 1 followed by cisplatin 75 mg/m² IV on day 2, every 21 days for six courses; regimen 2, carboplatin (AUC 9) IV for two courses every 28 days, followed 4 weeks later by paclitaxel 135 mg/m² by continuous IV infusion over 24 hours on day 1, followed by cisplatin 100 mg/m² IP on day 2, every 21 days for six courses. The carboplatin dose was calculated based on the formula of Calvert et al⁶ with the glomerular filtration rate being considered to be equivalent to the creatinine clearance. The creatinine clearance was calculated by the method of Jelliffe.⁷ The IP cisplatin was delivered in 2 L of normal saline through an implantable peritoneal dialysis catheter (ie, Tenckhoff catheter) which was permitted to be connected to an indwelling port. If it was not possible to deliver cisplatin by the IP route because of a malfunction of the catheter, cisplatin was administered IV at a reduced dose of 75 mg/m² to complete the six treatment courses.

Decisions regarding antiemetics and specific hydration programs for cisplatin were left to the discretion of the individual treating physicians. All patients received prophylaxis for the prevention of paclitaxel-associated hypersensitivity reactions (dexamethasone, diphenhydramine, and either cimetidine or ranitidine).

Treatment Modifications
To maintain a consistent dose-intensity in the study, there were no dose reductions in the protocol. Treatment was to be delayed week to week until minimum hematologic, renal, and other parameters were met. Treatment delays were to be kept to a minimum, and every effort was made to maintain the planned schedule. Delays were not permitted other than for documented toxicity.

Subsequent treatments were not to begin until the WBC was 3,000 cells/mm³ and the platelet count was 100,000/mm³. Patients developing grade 3 or 4 peripheral neuropathy were to have treatment interrupted until the adverse effects had resolved to a maximum of grade 1.

Evaluation Criteria
Because all individuals entered onto this protocol had IP disease 1 cm in maximal diameter, no patient had measurable tumor masses. A second-look surgical procedure was planned to be performed in all patients without evidence of progressive disease within 8 weeks after the last course of chemotherapy. Patients who exhibited progression of disease during treatment or before the performance of the second-look laparotomy were not expected to undergo this diagnostic procedure. Negative surgical pathologic findings at second-look surgery were to have been an end point, but the frequency of not having the second-look procedure was sufficiently high and disproportionate between the two treatment groups to render this end point unreliable and likely biased. For this reason, progression-free survival (PFS) and overall survival are the end points of this study. Survival time was defined as the observed length of life from entry into the protocol to death, or, for living patients, date of last contact (regardless of whether this contact was on a subsequent protocol). PFS was defined as the date from entry onto the protocol to the date of appearance of disease (clinically or radiologically detected, not surgically), or PFS was equal to the survival time in the absence of disease.

Statistical Considerations
Randomization with equal probability of assignment to each treatment regimen was carried out by a block arrangement balancing the treatment assignment within gross residual disease status (categories: Yes and No) and major GOG institutions. The accrual goal was set at 440 eligible patients and follow-up until 150 deaths occur. This sample size would provide a statistical power of 80% to detect a proportional one-third decrease in the hazards rate when testing at .05 level (one-sided test).⁸ This report includes 233 deaths, which far exceeds the original goal, and therefore, provides 80% statistical power to detect a 28% reduction in the hazards rate. This difference is on par with the mortality reduction observed in SWOG 8501 (GOG 104) for the entire study group of 24%.

Life tables were computed by using the method of Kaplan and Meier.⁹ Differences in PFS and survival by treatment were evaluated by using the log-rank test¹⁰ according to the intent-to-treat principle of eligible patients. Treatment effect on PFS and survival while adjusting for prognostic factors was accomplished by using the Cox model.¹¹ Screening for chance imbalances between clinical/pathologic characteristics and treatment assignment was accomplished by using the Pearson’s ² test significance level of .20.¹² The Mann-Whitney U test was used when the characteristic was continuous (eg, age).¹²

	RESULTS

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Patient Characteristics
From August 1992 until April 1995, a total of 523 patients were entered onto the two arms of this randomized trial, of whom 61 (11.7%) were subsequently considered to be ineligible (33 in the platinum/paclitaxel arm, 28 in the carboplatin/IP cisplatin/paclitaxel arm). Reasons for patient exclusion, which did not differ between the study regimens, included wrong stage (n = 18), inadequate surgery (n = 13), low malignant potential tumor (n = 11), gross residual disease more than 1 cm (n = 7), wrong primary (n = 6), second primary cancer (n = 2), wrong cell type (n = 2), and inadequate pathology (n = 2).

Of the 462 eligible patients, the treatment groups were well balanced regarding age, race, GOG performance status, histologic subtype of ovarian cancer, tumor grade, and residual disease status ( Table 1). Table 2 shows the percentage of patients receiving different numbers of treatment cycles. Of note, 6.8% of the patients randomized to the experimental arm did not receive any IP therapy, whereas 18.3% of the patients on this regimen received two courses or less of IP drug delivery, principally because of excessive bone marrow toxicity encountered during the initial cycles of IV carboplatin.

Second-Look Results
The frequency of refusal for the performance of second-look surgical procedures was higher than expected and imbalanced between the two regimens (IV regimen, 15.0% v IP regimen, 22.6%). A treatment comparison of the frequency of pathologically negative findings in the subset of individuals undergoing surgery is likely biased. Therefore, this study end point was not examined further.

PFS
At the time of this report, 56 patients (24.7%) randomized to the control arm have no evidence of disease, compared with 75 individuals (31.9%) on the experimental arm. Nine and 10 of these patients who died without documented disease recurrence were in the standard IV therapy regimen and IP arm, respectively.

PFS was found to be longer in the experimental arm, with a median time to recurrence of 27.9 months compared with 22.2 months in the standard cisplatin/paclitaxel arm (log-rank P = .01, one-tail) ( Fig 1). The relative risk estimate of the experimental arm to the control was 0.78 (90% confidence interval [CI], 0.66 to 0.94). When adjusting for statistically significant prognostic factors, ie, gross residual disease status, cell type (high risk: mucinous, clear-cell, adenocarcinoma-NOS) and histologic grade, the relative risk estimate decreased only slightly (ie, 0.75).

View larger version (14K): [in this window] [in a new window]   Fig 1. Progression-free survival (P = .01).

View larger version (13K): [in this window] [in a new window]   Fig 2. Overall survival (P = .05).

	DISCUSSION

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It had been hypothesized previously that the high local concentrations of cisplatin achievable within the peritoneal cavity after regional administration (10- to 20-fold greater than measured within the systemic compartment) would exert its maximum benefit in patients with microscopic residual disease or very small-volume macroscopic cancer at the time of IP drug delivery.³ Support for this concept comes from preclinical data where the depth of penetration of cytotoxic agents directly into tumor or normal tissue after regional delivery has been measured in millimeters or less from the surface of the peritoneal lining.^13-15 Similarly, a number of phase II efficacy trials of IP therapy examined in the salvage setting in women with ovarian cancer have revealed that responses are almost exclusively observed in individuals with microscopic disease only or in those individuals whose maximal tumor diameter measures less than 0.5 to 1 cm.^3,16-18

Consideration of these preclinical and clinical data led to the proposal that two courses of moderately dose-intensive systemic chemotherapy (eg, carboplatin [AUC 9]) might be able to rapidly reduce the volume of residual cancer persisting within the abdominal cavity after maximal surgical cytoreduction. This reduction in tumor volume might then improve the chances that additional treatment with cisplatin delivered regionally would favorably influence outcome in this malignancy. This concept of chemical debulking before the regional delivery of cisplatin had previously been examined in a pilot study using cisplatin, rather than carboplatin, as the initial systemic treatment regimen.⁵ It might be tempting to speculate that the favorable results associated with the experimental study arm in this study were due, at least in part, to the two courses of moderately high-dose carboplatin administered before IP cisplatin and IV paclitaxel. Several randomized trials have now definitively established that doubling the dose-intensity of platinum agents in the management of ovarian cancer results in increased toxicity (as observed in our trial) without any evidence of an improvement in response rate or survival.^19-21 However, these studies do not address the benefit in outcome when substantially increasing the total dose. A study by Kaye et al²² that doubled the intensity and the total dose of cisplatin demonstrated a relative death rate of 0.68 (95% CI, 0.46 to 0.99) in favor of the high-dose regimen.

At this juncture, what should we consider the status of IP cisplatin as initial therapy of small-volume residual advanced ovarian cancer? Despite the favorable impact of the regional strategy as demonstrated in this trial, it is not appropriate to suggest that this regimen should be used in standard clinical practice.

The toxicity of the carboplatin regimen, particularly when followed by IP cisplatin and IV paclitaxel, was considerable. In addition, although an improvement in PFS was observed, the impact on overall survival in this clinical setting was only marginal. Given the mature results of this large randomized multi-institutional phase III clinical trial, it is reasonable to draw several conclusions. First, this study has confirmed the previously documented relative safety of administering IP cisplatin to patients with small-volume residual advanced ovarian cancer outside the clinical research center setting.⁴ Second, the results of this study support the conclusions of a previously reported randomized trial examining IP cisplatin in women with stage III ovarian cancer. This previous intergroup phase III trial demonstrated a survival advantage associated with the use of IP cisplatin compared with IV cisplatin delivery, both in combination with systemic cyclophosphamide.⁴ The experimental arm in this trial resulted in an improvement in PFS (relative risk of 0.78) compared with IV administration. Although the survival difference in this trial is only of borderline statistical significance, the relative risk of 0.81 is remarkably consistent with the relative risk of 0.80 for the minimal residual-disease subgroup (ie, 0.5 cm) from the previous intergroup study.

Third, further exploration of a role for IP chemotherapy in the management of this malignancy is indicated by the positive results of this and other studies. It is now known that the administration of cisplatin plus paclitaxel results in a superior outcome (objective response rate, PFS, overall survival) compared with treatment with cisplatin and cyclophosphamide.^1,2 Therefore, it is important to determine whether the regional pharmacokinetic advantage associated with the IP delivery of cisplatin can translate into additional clinical benefit when the drug is combined with paclitaxel.

The GOG has initiated a second IP chemotherapy trial based on the results of this trial and data demonstrating that paclitaxel can be delivered safely into the peritoneal cavity with both a major pharmacokinetic advantage for cavity exposure^23,24 and evidence of considerable activity in individuals with microscopic residual ovarian cancer after initial IV chemotherapy.²⁵ The currently active GOG trial for patients with optimal residual advanced ovarian cancer examines the combination of IP cisplatin and paclitaxel, along with IV paclitaxel, compared with standard IV delivery of the two cytotoxic agents.

APPENDIX
The following institutions participated in this study: University of Alabama at Birmingham, Oregon Health Sciences University, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Army Medical Center, Wayne State University School of Medicine, University of Minnesota Medical School, University of Southern California Medical Center at Los Angeles, University of Mississippi Medical Center, Colorado Foundation for Medical Care, University of California Medical Center at Los Angeles, University of Washington Medical Center, Hospital of the University of Pennsylvania, University of Miami School of Medicine, The Milton S. Hershey School of Medicine of the Pennsylvania State University, Georgetown University Hospital, University of Cincinnati College of Medicine, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, The Albany Medical College of Union University, University of California Medical Center at Irvine, Tufts New England Medical Center, Rush-Presbyterian-St. Lukes Medical Center, University of Kentucky, Eastern Virginia Medical School, Cleveland Clinic Foundation, The Johns Hopkins Oncology Center, State University of New York at Stony Brook,

APPENDIX (Cont’d)
Pennsylvania Hospital, Southwest Oncology Group, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Columbus Cancer Council, University of Massachusetts Medical Center, Fox Chase Cancer Center, Medical University of South Carolina, Women’s Cancer Center, University of Oklahoma Health Science Center, University of Virginia Health Science Center, University of Chicago, University of Arizona Health Science Center, Tacoma General Hospital, Eastern Collaborative Oncology Group, Thomas Jefferson University Hospital, Case Western Reserve University, and Tampa Bay Cancer Consortium.

	ACKNOWLEDGMENTS

 
Supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469), Gynecologic Oncology Group Statistical Office (CA 37517), Southwest Oncology Group Operations Office Grant (CA 32102), and the Eastern Cooperative Oncology Group Administrative Office Grant (CA 21115) and the Eastern Cooperative Oncology Group Statistical Office Grant (CA 23318).

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17. Markman M, Berek JS, Blessing JA, et al: Characteristics of patients with small-volume residual ovarian cancer unresponsive to cisplatin-based IP chemotherapy: Lessons learned from a Gynecologic Oncology Group phase II trial of IP cisplatin and recombinant alpha-interferon. Gynecol Oncol 45: 3-8, 1992[Medline]

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Submitted May 1, 2000; accepted October 4, 2000.

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				R. J. Morgan Jr., T. W. Synold, B. Xi, D. Lim, S. Shibata, K. Margolin, R. E. Schwarz, L. Leong, G. Somlo, P. Twardowski, et al. Phase I Trial of Intraperitoneal Gemcitabine in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity Clin. Cancer Res., February 15, 2007; 13(4): 1232 - 1237. [Abstract] [Full Text] [PDF]

				A. E. Axtell, M. H. Lee, R. E. Bristow, S. C. Dowdy, W. A. Cliby, S. Raman, J. P. Weaver, M. Gabbay, M. Ngo, S. Lentz, et al. Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer J. Clin. Oncol., February 1, 2007; 25(4): 384 - 389. [Abstract] [Full Text] [PDF]

				L. B. Wenzel, H. Q. Huang, D. K. Armstrong, J. L. Walker, and D. Cella Health-Related Quality of Life During and After Intraperitoneal Versus Intravenous Chemotherapy for Optimally Debulked Ovarian Cancer: A Gynecologic Oncology Group Study J. Clin. Oncol., February 1, 2007; 25(4): 437 - 443. [Abstract] [Full Text] [PDF]

				M. Markman New, Expanded, and Modified Use of Approved Antineoplastic Agents in Ovarian Cancer Oncologist, February 1, 2007; 12(2): 186 - 190. [Abstract] [Full Text] [PDF]

				M. Gore, A. du Bois, and I. Vergote Intraperitoneal Chemotherapy in Ovarian Cancer Remains Experimental J. Clin. Oncol., October 1, 2006; 24(28): 4528 - 4530. [Full Text] [PDF]

				D. M. Gershenson, C. C. Sun, K. H. Lu, R. L. Coleman, A. K. Sood, A. Malpica, M. T. Deavers, E. G. Silva, and D. C. Bodurka Clinical Behavior of Stage II-IV Low-Grade Serous Carcinoma of the Ovary Obstet. Gynecol., August 1, 2006; 108(2): 361 - 368. [Abstract] [Full Text] [PDF]

				S. Bhoola and W. J. Hoskins Diagnosis and management of epithelial ovarian cancer. Obstet. Gynecol., June 1, 2006; 107(6): 1399 - 1410. [Abstract] [Full Text] [PDF]

				C. N. Krasner, M. Roche, N. S. Horowitz, J. G. Supko, S. I. Lee, and E. Oliva Case 11-2006 -- A 54-Year-Old Woman with a Mass in the Pelvis N. Engl. J. Med., April 13, 2006; 354(15): 1615 - 1625. [Full Text] [PDF]