Stage III ovarian tumors of low malignant potential treated with cisplatin combination therapy (A Gynecologic Oncology Group Study)

GYNECOLOGIC

ONCOLOGY

41, 230-233

(1991)

Stage III Ovarian Tumors of Low Malignant Potential Treated with Cisplatin Combination Therapy (A Gynecologic Oncology Group Study) GREGORY P. SUTTON, M.D.,*,’ BRIAN N. BUNDY, YORDAN, M.D.,§ JACKSON B. BEECHAM, *Division

PH.D. ,I GEORGE A. OMURA, M.D.,* EDGARDO L. M.D.,]] AND THOMAS BONFIGLIO, M.D.”

of Gynecologic Oncology, Department of Obstetrics and Gynecology, Indiana University Medical School, Indianapolis, Indiana TGynecologic Oncology Group, Roswell Park Memorial Institute, Buffalo, New York; *University of Alabama at Birmingham, Birmingham, Alabama; OSection of Gynecologic Oncology, Rush-Presbyterian St. Luke’s Medical Center, Chicago, Illinois; and Departments of IlGynecologic Oncology and ‘Anatomic Pathology, University of Rochester Medical Center, Rochester, New York I4627

46227;

Received October 10. 1990

By serendipity we have had the opportunity to evaluate cisplatin-basedchemotherapyin ovarian tumors of low malignant potential (LMP). Optimal (lessthan 1 cm residualdisease)FIG0 stageIII ovarian carcinomaswererandomly assignedto treatment with cisplatmpluscyclophosphamide with or without doxorubicin on a prospectiveGynecologicOncology Group Study. On review by the GynecologicOncology Group Pathology Committee, 32 of thesecasesweredeterminedto representlow malignant potential tumors. Mean age of pateints with these lesionswas 48 years (range, 25-75 years). After initial cytoreduction, 19 patientshad residualdisease< 1 cm and 13had no residual.Twenty (62.5%) received cisplatin plus cyclophosphamideand 12 cisplatin, cy clophosphamide,and doxorubicin chemotherapy;75% of patients received six or more courses.Second-looksurgery was done in 15 cases;only six werenegative. However, with a medianfollowup of 31.7 months (range, l-75), only 1 patient has died; no cancer was found at autopsy. The remaining patients are alive without clinical evidenceof diseaseat a median of 30 months. The needfor adjunctive therapy in patientswith advancedLMP tumors remainsspeculative. 0 1991 hdemif press, 1~.

MATERIALS

AND METHODS

Patients with histologically confirmed epithelial ovarian carcinoma were eligible for a prospective Gynecologic Oncology Group (GOG) Study if the tumor was considered FIG0 stage III (confined to the peritoneal cavity, retroperitoneal, or inguinal lymph nodes) with residual masses after surgery no larger than 1 cm in diameter. Tumors of low malignant potential were to be excluded. The Gynecologic Oncology Group Pathology Committee review of 415 entries on this protocol identified 32 cases which in the opinion of that committee had epithelial tumors of low malignant potential. Although these entries

INTRODUCTION

Ovarian epithelial tumors which are neither benign nor malignant and which have a propensity for recurrence or progression have been termed “borderline” neoplasms or tumors of low malignant potential (LMP). The latter designation was accepted by the International Federation of Gynecology and Obstetrics (FIGO) in 1961 [l] and by ’ To whom reprint requests should be addressed at: GOG Administrative Office, Suite 194.5, 1234 Market St., Philadelphia, PA 19107. 230

0090-8258/91$1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.

the World Health Organization in 1972 [2]. Most tumors of low malignant potential are identified in stage I. In a previous study [3] surgical removal of stage I lesions resulted in excellent survival which was not improved by the use of postoperative adjunctive pelvic radiotherapy or chemotherapy. When compared to patients with malignant epithelial tumors of the ovary, relatively few patients with lesions of LMP have stage III or IV disease at the time of diagnosis. Although there is general agreement that surgical resection is beneficial in such cases, there is no consensus regarding the value of postoperative therapy. Recently the opportunity arose in a serendipitous fashion to evaluate, albeit without concurrent controls, the efficacy of postoperative platinum-based chemotherapy in patients with stage III (optimally resected residual disease less than 1 cm) ovarian tumors of low malignant potential.

STAGE

III LMP OVARIAN

TUMORS

were excluded from analysis as ineligible in the original study, follow-up was continued. Thus, there was an opportunity to assess their response to combination chemotherapy, even though their inclusion in the parent study had been inadvertent. These 32 cases make up the group for the present study. Other eligibility requirements for entry into the parent study were a GOG performance status of 3 or better (equivalent to 30-40 on the Karnofsky performance scale), entry on protocol no more than 6 weeks after surgery, and a signed informed consent. Patients with Brenner tumors, prior or concomitant extracutaneous malignancy, prior chemo- or radiotherapy, or renal impairment (BUN greater than 25 mg % and/or creatinine greater than 1.2 mg %) were ineligible. Also ineligible were patients with septicemia, severe infection, acute hepatitis, gastrointestinal bleeding, or a history of congestive heart failure. An absolute granulocyte count of 1500/~1 and platelet count of lOO,OOO/~l were also required for entry. No patient was treated until the study was approved by the Human Subjects Committee of the participating institution. After surgery, patients were randomized to receive 50 mg/m2 cisplatin and 1000 mg/m2 cyclophosphamide or 50 mg/m2 cisplatin, 500 mg/m* cyclophosphamide, and 50 Drugs were administered every 3 mg/m2 doxorubicin. weeks for eight courses. Patients who did not progress during therapy were encouraged to undergo second-look laparotomy with inspection of peritoneal contents and peritoneal cytologic samples from the diaphragms, abdominal gutters, and pelvis. Second-look surgery was done at the discretion of the principal investigator. In addition, removal of residual omentum and biopsies of pelvic and para-aortic lymph nodes and peritoneal surfaces were performed. Patients with progressive disease on chemotherapy or who relapsed following therapy were treated at the discretion of the institutional principal investigator. RESULTS The mean age of the 32 patients with low malignant potential epithelial lesions was 48 years with a range of 25 to 75 years. Presenting symptoms included a mass identified by the physician in 13 patients (40.6%) and a mass identified by the patient in 9 (28.2%). Increasing abdominal girth was also identified in 9 patients and 3 each noted weight loss, vaginal bleeding, or early satiety. Six patients were asymptomatic at the time of diagnosis. Twenty-two patients had a GOG performance status of 0, nine had a performance status of 1, and one had a performance status of 2. In 27 cases (84.3%) the tumors were bilateral; in 4 patients the tumor arose from the left ovary and in 3 of these the right ovary was surgically absent at the time of diagnosis. In 1 patient the tumor

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arose from the right ovary; this patient had previously undergone a left oophorectomy. Five patients had previously undergone hysterectomy. The average largest dimension of the primary tumor was 12.5 + 6 cm (range, 3-30 cm) and the mean weight of the tumor removed was 382 g (range, 4-2040 g). Ascites was present in 12 patients (37.5%). The average volume of ascites was 1704 ml (range, 20-6000 ml). Cytology of peritoneal fluid or washings was positive in 22 cases (68.8%), suspicious in 1 additional case (3.2%), and not performed or not recorded in 2 cases. Thus, only 7 patients (21.9%) had benign peritoneal cytology. At the time of initial surgery, all patients had evidence of intraperitoneal spread of disease. There was uterine serosal involvement in 12 patients (37.5%) and spread to the left or right fallopian tubes in 17 instances each (53.6%). The omentum was involved in 21 cases (65.6%) and disease was identified on the diaphragm in 14 patients (43.8%). There was small bowel involvement in 10 cases (31.3%) and spread to the sigmoid and rectum in 17 (53.1%). Peritoneal implants were found in the pelvis in 18 patients (56.3%) and in the upper abdomen in 12 patients (37.5%). Documented spread to lymph nodes was as follows: Obturator, external iliac, high common iliac, and para-aortic, 5 cases each (15.6%), and low common, 4 cases (12.5%). Thirty patients had serous histology; the other two had mutinous tumors. After primary surgery, 13 patients (40.6%) were clinically disease free and 19 (59.4%) had residual disease less than 1 cm in greatest diameter. Twenty patients received cisplatin and cyclophosphamide and eleven received these drugs plus doxorubicin. One patient was randomized to receive the three-drug regimen, but never received chemotherapy and was lost to follow-up after surgery. The average number of courses of chemotherapy was 7 for all patients (range, O-8) as well as for those who received cisplatin and cyclophosphamide (range, 2-8). Patients who received the threedrug regimen averaged 6 cycles of therapy (range, O-8). The mean leukocyte nadir was 2698 cells/$ (range, 3007400 cells/pi) and the mean granulocyte nadir was 300 cells/PI (mean, O-1600 cells/pi). The mean platelet nadir was 233,000 cells/p1 (range, 39,000-570,000 cells/pi). Although one patient each experienced grade 4 granulocyte and platelet toxicity, no granulocytopenic fever or thrombocytopenic hemorrhage was encountered. No serious nephrotoxicity or cardiotoxicity was observed. Second-look surgery was performed in 14 patients (43.8%). Six patients (42.9% of those undergoing secondlook surgery) had no evidence of disease and the remaining eight patients (57.1%) were found to have persistent low malignant potential tumor. Half of the patients with persistent disease at second-look surgery were rendered disease free by surgical resection. Four of the six

232

SUTTON

ET AL.

bone marrow failure and pancytopenia and died of bronchopneumonia and sepsis. At autopsy there was no evidence of persistent tumor. EO-

DISCUSSION

20

o-

i 0

12

24

36

48

60

72

MONTHS

FIG. 1. Survival of patients with stage III ovarian tumors of low malignant potential. Arrow indicates median follow-up.

patients who had negative second-look operations had had no residual neoplasm after the initial operation and two had had less than 1 cm of residual disease. Of those patients with persistent neoplasm at the time of secondlook operation, 2 had had no visible residual after the primary operation and 6 had less than 1 cm of residual disease. At the time of second-look surgery, disease was identified in pelvic, common iliac, and para-aortic lymph nodes in one patient. Two patients had persistent disease in the omentum and small bowel serosa, and the pelvic and abdominal peritoneum were involved in seven and three patients, respectively. Four patients had disease in biopsies of the diaphragm. Although no patient had ascites at second-look surgery, two had positive peritoneal washings and nine had peritoneal cytology considered suspicious. In addition to the patient lost to follow-up after initial surgery, four patients were lost to follow-up at 6.2, 6.9, 13.2, and 48.2 months after surgery. None had clinically apparent disease. The median follow-up interval for all patients was 2.6 years (range, 0.3 months to 6.2 years). All patients except one were alive and clinically free of disease at the latest follow-up period (Fig. 1). One patient died 32 months after diagnosis. She had undergone complete surgical excision of a cystic 5 by 6cm ovarian primary as well as disease involving the contralateral ovary, both fallopian tubes, and the omentum. She received eight courses of chemotherapy with cisplatin and cyclophosphamide and then underwent second-look surgery which disclosed persistent microscopic disease in the pelvic peritoneum, omentum, and peritoneal washings. She then received whole abdomen radiotherapy followed by 18 months of oral melphalan. She developed

The mean age of this group of patients (48 years) is similar to that reported by other authors [4] for patients with tumors of low malignant potential and is less than that of patients with invasive carcinomas (median, 55 years) enrolled in the GOG parent study [5] from which the present group of patients derived. These 32 patients with tumors of low malignant potential represent 8.4% of 415 patients enrolled in the parent study prior to pathologic exclusion. the presence of patients with tumors of low malignant potential in the larger study despite local institutional pathology evaluation emphasizes the critical requirement of pathologic review in studies of ovarian carcinoma. Colgan and Norris [6] estimated that approximately 15% of all ovarian malignancies fulfilled the criteria for low malignant potential, but a lower proportion of these tumors would be expected among patients with stage III disease, since the majority of patients with tumors of low malignant potential have stage I lesions [7]. As has been observed by others [8], the majority of low malignant potential tumors in this study were of serous histology. Because survival among patients with stage I tumors of low malignant potential treated by surgery alone may exceed 95% at 5 years [9] and approximate this rate at 10 years [5], many authors [3,6,7] have advocated surgical excision and careful postoperative monitoring. Postoperative treatment of patients with advanced disease, however, is less well defined. Julian and Woodruff [7] reported 11 patients with stage III and 5 with stage IV tumors “rarely” treated with chemotherapeutic agents or radiotherapy. Three of these patients (27.3%) died of disease, nine were living without disease, and two were living with evidence of tumor. These authors suggested that borderline tumors represent low-grade in situ peritoneal neoplasms and as such require no therapy. Barnhill et al. [8] reported 33 patients with stage III tumors of low malignant potential, 18 of whom received postoperative chemotherapy and 13 of whom were treated with radiotherapy. Two additional patients in their series received both chemotherapy and radiotherapy. Two patients with mutinous tumors who were left with less than 3 cm of residual disease postoperatively died 9 and 12 months after diagnosis. One had disease refractory to melphalan and cisplatin/doxorubicin/cyclophosphamide and the second relapsed following whole abdomen radiotherapy. This represents a mortality rate of 6.1%. In addition to these deaths, 5 patients were alive with disease, 2 of whom had persistent disease postoperatively.

STAGE

III LMP OVARIAN

TUMORS

The remaining 3 patients had relapses at 12, 60, and 96 months after diagnosis. It is difficult to assess the response to therapy from this study, but it should be noted that 1 patient with residual disease after initial surgery was found to have no tumor at second-look surgery. Bostwick et al. [lo] presented 14 patients with stage III borderline tumors. They found that patients with incomplete excision of disease at the time of diagnosis were at significantly greater risk of developing persistent or recurrent disease than those whose tumors were completely excised. They identified a similar increased risk for stage III disease compared to stage I or stage II disease (64% versus 12%) and reported one recurrence 19 years after initial therapy. Only 2 patients with stage III tumors died of disease (14.3%) in this series, both following chemotherapy and radiation therapy. O’Quinn and Hannigan [ll] treated seven patients with stage III borderline tumors with postoperative melphalan. Three patients (42.7%) died of disease 27, 48, and 52 months following diagnosis. Five patients had second-look surgery and all were positive. Two had “third-look” operations after additional melphalan and both were still positive. One patient died of acute nonlymphocytic leukemia following melphalan therapy. Survivors were disease free at 38, 61, and 72 months following diagnosis. In the present series, survival is excellent and no patient had clinical evidence of tumor at the time of last evaluation. Although this might reflect a beneficial effect of adjunctive chemotherapy, the absence of recurrences may simply indicate that the relatively brief median follow-up interval of 31.7 months is an insufficient time for relapses to become clinically apparent. Effective therapy should result in resolution of tumor and second-look procedures which are negative. Despite adequate chemotherapy, only two of eight patients with residual disease at the primary operation had no disease at second-look. This represents a 25% surgically documented complete response rate. Conversely, two of six patients with no visible residual tumor after the initial operation had microscopically positive second-look surgery. Also of concern is the finding of malignant cytology in two and suspicious cytology in nine (total, 78.6%) of the patients undergoing secondlook surgery. The modest activity of cisplatin-containing chemotherapy regimens in this group of patients is offset by the very low incidence of serious toxicity. The only major adverse effect among subjects in this study was the pancytopenic death of a patient who, because of persistent disease after combination therapy, received whole abdomen radiotherapy followed by melphalan. It is important to note that this patient had neither symptoms nor clinical evidence of disease and that autopsy revealed no

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evidence of the borderline ovarian tumor for which she was so aggressively treated. In order to maximize the benefits and eliminate the risks of therapy, there is a clear need for well-conceived prospective studies in this disease. A prospective Gynecologic Oncology Group Study is underway in such cases. In the meantime, it would appear that cisplatin-based chemotherapy cannot be regarded as routine adjuvant treatment in ovarian tumors of low malignant potential. ACKNOWLEDGMENTS The followifig are participating institutions and the National Cancer Institute grants supporting this study: The Oregon Health Sciences Center University (unfunded), University of Rochester Medical Center (CA 12482), Walter Reed Army Medical Center (CA 23501), University of Minnesota Medical School (CA 23088), University of Southern California Medical Center at Los Angeles (CA 37535), Colorado Foundation for Medical Care (CA 15975), University of Miami School of Medicine (CA 37234), University of North Carolina School of Medicine (Ca 23073), University of Texas Health Science Center at Dallas (Ca 28160), University of California Medical Center at Irvine (CA 23765), Tufts New England Medical Center (CA 37569), Illinois Cancer Council (CA 27806), University of Connecticut Medical Center (unfunded), Eastern Virginia Medical School (CA 40296), Central New York Community Clinical Oncology Program (CA 35092).

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