Intraperitoneal Cisplatin plus Intravenous Cyclophosphamide versus Intravenous Cisplatin plus Intravenous Cyclophosphamide for Stage III Ovarian Cancer
David S. Alberts, M.D., P.Y. Liu, Ph.D., Edward V. Hannigan, M.D., Robert O'Toole, M.D., Stephen D. Williams, M.D., James A. Young, M.D., Ernest W. Franklin, M.D., Daniel L. Clarke-Pearson, M.D., Vinay K. Malviya, M.D., Brent DuBeshter, M.D., Mark D. Adelson, M.D., and William J. Hoskins, M.D.
Background Intravenous platinum-based chemotherapy is the standardprimary therapy for advanced ovarian cancer. We conducted aphase 3 trial to compare the effects of intraperitoneal andintravenous cisplatin on the survival of women with previouslyuntreated, stage III, epithelial ovarian cancer.
Methods The patients underwent an initial exploratory laparotomyand resection of all tumor masses larger than 2 cm. Within fourweeks after surgery, six courses of intravenous cyclophosphamide(600 mg per square meter of body-surface area per course) pluseither intraperitoneal cisplatin (100 mg per square meter) orintravenous cisplatin (100 mg per square meter) were administeredat three-week intervals.
Results Of 654 randomized patients, 546 were eligible for thestudy. The estimated median survival was significantly longerin the group receiving intraperitoneal cisplatin (49 months;95 percent confidence interval, 42 to 56) than in the groupreceiving intravenous cisplatin (41 months; 95 percent confidenceinterval, 34 to 47). The risk of death was lower in the intraperitonealgroup than in the intravenous group (hazard ratio, 0.76; 95percent confidence interval, 0.61 to 0.96; P = 0.02). Moderate-to-severetinnitus, clinical hearing loss, and neuromuscular toxic effectswere significantly more frequent in the intravenous group.
Conclusions As compared with intravenous cisplatin, intraperitonealcisplatin significantly improves survival and has significantlyfewer toxic effects in patients with stage III ovarian cancerand residual tumor masses of 2 cm or less.
Ovarian cancer, the leading cause of death from gynecologiccancer in the United States, is one of the few solid tumorsin which the five-year survival rate for patients has improvedin recent years.1,2 Nevertheless, most women with advanced ovariancancer die of the disease. Even those with stage III cancerand minimal residual intraperitoneal masses (<2 cm in thegreatest dimension) have a median survival of only about 40months.3,4
Standard chemotherapy for advanced ovarian cancer includes aplatinum analogue (either cisplatin or carboplatin). In an attemptto maximize its activity against ovarian cancer, cisplatin hasbeen administered directly into the peritoneal cavity in investigationalstudies.5 This route yields an intraperitoneal concentrationof cisplatin that is 12 to 15 times greater than the plasmaconcentration.6,7 Some phase 2 studies have suggested that survivalis prolonged in patients with small residual masses (<1 cm)who receive salvage intraperitoneal chemotherapy after initialchemotherapy and second-look surgery.8,9 The present phase 3trial compares cisplatin administered intraperitoneally withcisplatin administered intravenously in patients with previouslyuntreated stage III ovarian cancer and residual masses no largerthan 2 cm in the greatest dimension.
Methods
Patients
Within four weeks before enrollment, patients underwent an initialexploratory laparotomy with at least bilateral salpingo-oophorectomy,total abdominal hysterectomy, omentectomy, and debulking ofall tumor nodules to a size of 2 cm or less in the greatestdimension. The Southwest Oncology Group's Gynecologic SurgicalReview Board reviewed the surgical results to confirm eligibilityfor enrollment. Only patients with a histologic diagnosis ofepithelial-type ovarian cancer were eligible.
Eligible patients had stage III disease, a performance statusof 0 to 2 (according to criteria established by the SouthwestOncology Group), normal blood counts, and adequate renal function(serum creatinine, <1.5 mg per deciliter [130 µmolper liter]; creatinine clearance, >40 ml per minute). Allpatients gave informed consent according to institutional andfederal guidelines before enrollment.
Treatment Plan
Patients were randomly assigned to receive intraperitoneal cisplatinplus intravenous cyclophosphamide or intravenous cisplatin plusintravenous cyclophosphamide. The randomization procedure incorporatedstratification according to the amount of residual tumor (<0.5cm vs. >0.5 cm to 2 cm), performance status (0 or 1 vs. 2),the timing of enrollment (during vs. after surgery), and thecooperative group (Southwest Oncology Group vs. GynecologicOncology Group vs. Eastern Cooperative Oncology Group).
Patients in both treatment groups received cyclophosphamide(600 mg per square meter of body-surface area in 150 ml of diluent)administered in a 60-to-90-minute intravenous infusion on day1. Patients in the intravenous group received cisplatin (100mg per square meter in 500 to 1000 ml of normal saline) administeredintravenously at a rate of 1 mg per minute, followed by at least1 liter of normal saline with 3 g of magnesium sulfate and 40g of mannitol over a period of one to two hours on day 1. Patientsin the intraperitoneal group received cisplatin (100 mg persquare meter in 2 liters of normal saline) warmed to body temperatureand instilled into the peritoneal cavity as rapidly as possible.Concurrently, these patients received at least 1 liter of normalsaline with 3 g of magnesium sulfate and 40 g of mannitol intravenously.
Courses of cyclophosphamide and cisplatin were repeated everythree weeks for a total of six cycles, provided the serum creatinineconcentration was less than or equal to 1.9 mg per deciliter(170 µmol per liter), the white-cell count was higherthan 3000 per cubic millimeter, and the platelet count was higherthan 100,000 per cubic millimeter. Therapy could be delayedfor a maximum of two weeks to allow for the resolution of toxiceffects. Cisplatin was permanently discontinued and the doseof cyclophosphamide increased to 1 g per square meter (in theabsence of grade 3 or 4 myelosuppression) if peripheral neuropathyof grade 2 or higher developed or the serum creatinine concentrationrose above 1.9 mg per deciliter. Therapy was discontinued altogetherif the serum creatinine level remained higher than 1.9 mg perdeciliter for eight weeks.
Clinical and Pathological Assessments
At base line and after six courses of therapy, a physical examinationwas performed, with a complete blood count, serum CA-125 andblood chemical measurements, and chest radiography. In addition,before each cycle, a physical examination was performed, witha complete blood count and measurement of serum CA-125 and creatinineconcentrations. Blood chemical measurements were performed atthe start of every other course. At the completion of therapy,patients without clinical evidence of ovarian cancer (excludingan elevated serum CA-125 value) underwent a second-look laparotomyto determine whether there had been a pathological response.
A complete pathological response was defined as no pathologicalevidence of disease on second-look surgery and biopsy of theupper abdomen and the para-aortic and retroperitoneal lymphnodes, as well as any other site previously involved with tumor.
Statistical Analysis
In the original study design (before the protocol was amendedto increase enrollment), it was assumed that 215 eligible patientswould be randomly assigned to each treatment group. At a two-sidedP value of 0.05, with the use of a Pearson chi-square approximation,the estimated power was 0.85 to detect a difference of 55 percentversus 40 percent in pathological-response rates in the intraperitonealand intravenous groups, respectively. The power was 0.93 (two-sidedlog-rank test, = 0.05) to detect a difference if the underlyingrisk of death (hazard ratio) in the intraperitoneal group, ascompared with the intravenous group, was 0.67. Survival wasdefined as the time from randomization to death from any cause.
Provisions for subgroup analysis were not included in the originalstudy design. During the study, however, a consensus emergedamong gynecologic oncologists that the patients most likelyto benefit from intraperitoneal chemotherapy were those witha tumor mass that was no larger than 0.5 cm in the greatestdimension. Therefore, in January 1991, with no knowledge ofsubgroup data, we extended accrual for an additional year toachieve a sufficiently large sample for a separate analysisof data from patients with residual tumors that were no largerthan 0.5 cm. All previously eligible patients were includedin the extended sample, which was planned to include 560 eligiblepatients overall and 390 eligible patients with residual tumorsno larger than 0.5 cm. In the analysis of this subgroup, ifthe hazard ratio was 0.67 for the patients receiving intraperitonealtreatment, the power to detect a difference was 0.88.
The treatment group, size of residual tumor (microscopical vs.<0.5 cm vs. >0.5 cm to 2 cm), age, performance status(0 or 1 vs. 2), race (white vs. other), tumor type (clear cellor mucinous vs. other), tumor grade, participating group (SouthwestOncology Group vs. Gynecologic Oncology Group vs. Eastern CooperativeOncology Group), and timing of enrollment (during vs. aftersurgery) were included as covariates in Cox regression analyses.10Two-sided Fisher's exact tests were used for comparisons oftoxic effects in the two treatment groups. All eligible patientswho received chemotherapy were included in the analysis of toxicity.
Results
Patients
Between June 1986 and July 1992, 654 women were randomly assignedto a study group: 295 from the Southwest Oncology Group, 298from the Gynecologic Oncology Group, and 61 from the EasternCooperative Oncology Group. A total of 108 patients were ineligible(52 in the intravenous group and 56 in the intraperitoneal group)for the following reasons: inadequate surgery (in 54), pathologicalfindings that did not meet the study criteria (31), insufficientdocumentation (20), and miscellaneous clinical factors thatdid not meet the study criteria (3). Table 1 shows the characteristicsof the eligible patients. There were no significant differencesbetween the study groups with respect to important prognosticfactors.
Table 1. Characteristics of 546 Eligible Patients with Stage III Ovarian Cancer Who Were Assigned to Treatment with Intravenous or Intraperitoneal Cisplatin.
Of the 279 eligible patients in the intravenous group, 2 diedbefore treatment, and 1 refused treatment after randomization.There were 20 major protocol violations among the 267 eligiblepatients in the intraperitoneal group: 3 patients died beforetreatment was started, 6 withdrew consent after randomization,8 did not receive the assigned treatment for other reasons (5because of complications related to intraperitoneal catheterizationand 3 because of errors by the local pathologist), 2 receivedtreatment for only one day, and 1 erroneously received intravenouscarboplatin during cycles 2 through 6. All 546 eligible patientswere included in the efficacy analyses (according to the intention-to-treatprinciple), regardless of whether they completed the assignedtreatment. The 20 patients in both groups who did not receiveany treatment were excluded from the toxicity analysis.
Intensity of Cisplatin Dose
In both the intravenous and intraperitoneal groups, 58 percentof all eligible patients completed six courses of cisplatintherapy (Table 2). Among these patients, the average proportionof the initial cisplatin dose administered during cycle 6 (thecourse with the maximal dose reduction) was 96 percent in theintravenous group and 97 percent in the intraperitoneal group.Cisplatin was discontinued because of toxic effects (with aconcomitant increase in the cyclophosphamide dose) in 40 patientsin the intravenous group and 22 in the intraperitoneal group.
Table 2. Percentages of Eligible Patients Receiving Cisplatin and the Dose Received during Each Course of Treatment.
Complete Pathological Responses
Of the 546 eligible patients, 20 never received any study treatment,81 did not complete therapy, and 45 had tumors that progressedbefore the completion of therapy. Second-look surgery was notrequired in these patients. In 103 of the remaining 400 patients,surgery was contraindicated or the patient refused it (70 patients),or the procedure was performed but deemed inadequate by theGynecologic Surgical Review Board (33). Because of the biasassociated with this group of 103 patients who had no clinicalevidence of disease at the completion of therapy but did notundergo second-look surgery or had inadequate surgery, the ratesof pathological responses are given without statistical comparisons.
A total of 297 patients with no clinical evidence of diseaseat the end of chemotherapy underwent adequate second-look surgery.The rate of complete pathological responses was 36 percent inthe intravenous group (complete responses in 57 of 158 patients)and 47 percent in the intraperitoneal group (complete responsesin 66 of 139).
Survival
All eligible patients were included in the primary analysisregardless of whether they completed the assigned treatment.Covariates associated with improved survival included the absenceof gross disease at enrollment (P<0.001), a younger age (P<0.001),a type of tumor other than clear cell or mucinous (P<0.001),and enrollment after surgery (P<0.001). The final Cox modelincluded these four factors and performance status (which wasretained in the model because of its established prognosticimportance).
The results after adjustment for these five factors are shownin Table 3, along with unadjusted median survival in the twogroups. The hazard ratio for the risk of death in the intraperitonealgroup, as compared with the intravenous group, was 0.76 (95percent confidence interval, 0.61 to 0.96; P = 0.02). The mediansurvival was 41 months (95 percent confidence interval, 34 to47) in the intravenous group and 49 months (95 percent confidenceinterval, 42 to 56) in the intraperitoneal group (Figure 1).
Figure 1. Survival of 546 Eligible Patients with Stage III Ovarian Cancer Who Were Randomly Assigned to Treatment with Intravenous or Intraperitoneal Cisplatin.
Figure 2 shows the survival curves for all eligible patientsaccording to the extent of residual intraperitoneal disease.The effect of the treatment (intravenous or intraperitonealcisplatin) was not influenced by the extent of residual disease(P = 0.93 for the interaction of treatment and residual disease).Table 3 shows the results of a separate analysis for the subgroupof patients with residual tumors no larger than 0.5 cm. Theanalysis was repeated for all 654 randomized patients, includingthose who were ineligible. The results were equivalent to thoseof the primary analysis (Table 3).
Figure 2. Survival of Eligible Patients According to the Extent of Residual Disease at Enrollment.
Toxic Effects
Two treatment-related deaths occurred in the intraperitonealgroup. One patient died of respiratory failure of unknown cause41 days after the second cycle of chemotherapy (blood countswere adequate at the time of death). The second patient diedof bronchopneumonia during a period of chemotherapy-associatedleukopenia 13 days after the third cycle. No treatment-relateddeaths occurred in the intravenous group.
Significantly more patients in the intravenous group than inthe intraperitoneal group had grade 3 or higher granulocytopenia(P = 0.002) and leukopenia (P = 0.04) (Table 4). Table 5 showsthe frequency of other toxic effects (grade 2 or higher) duringany treatment cycle. Moderate-to-severe tinnitus and hearingloss were more frequent in patients receiving intravenous cisplatinthan in those receiving intraperitoneal cisplatin. In addition,significantly more patients in the intravenous group had grade2 or 3 neuromuscular toxic effects at the completion of chemotherapy(25 percent, vs. 15 percent in the intraperitoneal group; P= 0.02).
Table 5. Frequency of Other Toxic Effects (>Grade 2) during Any Course of Treatment.
As expected, abdominal pain of grade 2 or higher was more commonin the intraperitoneal group (P<0.001); however, the painusually resolved within 24 hours and was controlled with nonopioidor only weak opioid drugs. One patient had grade 4 abdominalpain. Transient dyspnea was infrequent but occurred in a significantlylarger proportion of patients in the intraperitoneal group (3percent, vs. 0.4 percent in the intravenous group; P = 0.002).In the patients receiving intraperitoneal cisplatin, dyspneaprobably resulted from compression of the base of the lung bythe fluid-filled intraperitoneal cavity.
Discussion
In this study we compared intraperitoneal with intravenous cisplatinin women with advanced ovarian cancer. All the patients hadundergone debulking surgery and received intravenous cyclophosphamideconcomitantly with the cisplatin. The median survival of thepatients treated intraperitoneally was 8 months longer thanthat of the patients given intravenous cisplatin (49 vs. 41months), and the hazard ratio in the intraperitoneal group was0.76 (P = 0.02). These results represent a 20 percent improvementin median survival and a 24 percent reduction in the risk ofdeath during the entire follow-up period among the eligiblepatients in the intraperitoneal group.
Neutropenia, tinnitus, hearing loss, and neuromuscular toxiceffects were significantly less frequent in the intraperitonealgroup than in the intravenous group. Abdominal pain was morecommon in the intraperitoneal group, but in most cases it wastransient and not severe (i.e., grade 3 or higher in only 5percent of the patients).
Previous reports have summarized the toxic effects of intraperitonealcisplatin at doses ranging from 50 to 100 mg per square meter.11,12,13Chronic, low-grade inflammation from repeated intraperitonealadministration may cause mild-to-severe abdominal pain and intraabdominaladhesions. These reports have generally focused on patientswho had undergone two exploratory laparotomies before the administrationof intraperitoneal cisplatin. In our study, all the patientshad undergone only one definitive exploratory laparotomy withinfour weeks before the start of chemotherapy. Thus, our patientswere probably less susceptible to the local toxic effects ofintraperitoneal cisplatin.
Howell et al. reported that after second-line therapy with intraperitonealcisplatin, rates of surgically established complete responseswere significantly higher among patients with smaller residualintraperitoneal tumor masses (<0.5 cm) than among those withlarger masses (>0.5 cm to 2 cm).8 Consistent with this findingwas the 80 percent rate of a complete pathological responseamong our patients with no gross residual disease who receivedintraperitoneal cisplatin (32 of 40 patients), as compared witha rate of 56 percent among those with no gross residual diseasewho received intravenous cisplatin (24 of 43). Such resultsreflect the fact that the penetration of intraperitoneal cisplatinis limited to a depth of 0.1 to 1 mm from the surface of theperitoneal tumor.14
We found that intraperitoneal cisplatin was associated witha longer survival than was intravenous cisplatin, whether residualintraperitoneal tumor masses were 0.5 cm or less or more than0.5 cm in the greatest dimension. We do not know the reasonfor this result, but several explanations are possible. Allprevious investigations of intraperitoneal cisplatin therapyhave been phase 2 studies, which included mainly patients whohad already received intravenous cisplatin. Our patients hadnever before received chemotherapy, and their tumors may thereforehave been highly sensitive to cisplatin. Moreover, the precisionin measuring intraperitoneal tumor masses during an initialexploratory laparotomy is limited, and the total volume of themass may have more prognostic value than the maximal dimension.
The combination of intravenous paclitaxel plus intraperitonealcisplatin may prove to be more effective than intravenous cyclophosphamideplus intraperitoneal cisplatin in patients with stage III ovariancancer and minimal residual disease. The Gynecologic OncologyGroup recently reported that paclitaxel plus cisplatin significantlyincreased survival (median, 38 months, vs. 24 months with cyclophosphamideplus cisplatin) when administered as primary chemotherapy inwomen with incompletely resected stage III or IV ovarian cancer.15Ongoing phase 3 studies by the Gynecologic Oncology Group andthe Southwest Oncology Group will further define the role ofintraperitoneal cisplatin (and intravenous paclitaxel) in thetreatment of stage III ovarian cancer that has been optimallyresected.
Supported in part by grants from the National Cancer Institute(CA38926, CA32102, CA45450, CA04920, CA42028, CA46441, CA45560,CA13612, CA20319, CA35119, CA35090, CA35281, CA58686, CA28862,CA35431, CA35200, CA45377, CA58861, CA45807, CA35261, CA12644,CA35192, CA37981, CA42777, CA16385, CA12213, CA35128, CA04919,CA35178, CA35176, CA35262, CA32734, CA46282, and CA58415) andBristol-Myers Squibb.
We are indebted to Drs. Renzo Canetta and Mace Rothenberg forscientific advice; to the individual investigators for theirparticipation and support (especially Drs. Ronald Alvarez, AlbertBonebrake, Eric Jenison, William Creasman, Nicola Spirtos, MatthewBurrell, and Mark Crozier); to Dava Garcia for assistance withstudy coordination and manuscript preparation; to Janet O'Sullivan,M.S., for assistance with the statistical analysis; to DanaSparks, M.A.T., for protocol coordination; to Janet Quade, NancyMason-Liddil, and Dianna Garcia for assistance with data management;and to Lois Loescher, R.N., M.S., for editorial assistance.
Source Information
From the University of Arizona, Tucson (D.S.A.); the Southwest Oncology Group Statistical Center, Seattle (P.Y.L.); the University of Texas Medical Branch at Galveston, Galveston (E.V.H.); Ohio State University Health Center, Columbus (R.O.); the Gynecologic Oncology Group, Philadelphia (S.D.W., D.L.C.-P., B.D., M.D.A., W.J.H.); Indiana University School of Medicine, Indianapolis (S.D.W.); the Eastern Cooperative Oncology Group, Boston (J.A.Y.); Cancer Care Associates, Tulsa, Okla. (J.A.Y.); Atlanta Regional Community Clinical Oncology Program, Atlanta (E.W.F.); Wayne State University Medical Center, Detroit (V.K.M.); and the University of Rochester Medical School, Rochester, N.Y. (B.D.).
Address reprint requests to Dr. Alberts at the Southwest Oncology Group (SWOG-8501), Operations Office, 14980 Omicron Dr., San Antonio, TX 78245-3217.
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= 0.05) to detect a difference if the underlying risk of death (hazard ratio) in the intraperitoneal group, as compared with the intravenous group, was 0.67. Survival was defined as the time from randomization to death from any cause. 
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