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© 2003 American Society for Clinical Oncology Adjuvant Treatment for Early Ovarian Cancer: A Randomized Phase III Trial of Intraperitoneal 32P or Intravenous Cyclophosphamide and Cisplatin—A Gynecologic Oncology Group Study
From the Fox Chase Cancer Center, Philadelphia, PA; Roswell Park Cancer Institute, Buffalo, NY; University of California Los Angeles Medical Center, Los Angeles, CA, Mayo Comprehensive Cancer Center, Rochester, MN; Walter Reed Army Medical Center, Washington, DC; Wake Forest University School of Medicine, Winston-Salem, NC; Indiana University School of Medicine, Indianapolis, IN; and the University of Arizona College of Medicine and Arizona Cancer Center, Tucson, AZ. Address reprint requests to Denise Mackey, Gynecologic Oncology Group, Administrative Office, Four Penn Center, 1600 John F. Kennedy Blvd, Suite 1020, Philadelphia, PA 19103; e-mail: rc_young{at}fccc.edu.
Purpose: To conduct a prospective study of intraperitoneal radioactive chromic phosphate (32P) versus cyclophosphamide-cisplatin (CP) in women with early ovarian cancer at high risk for recurrence (International Federation of Gynecology and Obstetrics stage Ia or Ib grade 3 or Ic or stage II, no macroscopic residual disease) and to compare cumulative incidence of recurrence, overall survival, and relative toxicity. Materials and Methods: A total of 251 patients were randomly assigned to treatment with 32P or CP. Twenty-two (8.7%) were ineligible following centralized pathology review. Of the 229 patients included in the analysis, 110 received 32P, and 119 received CP. Results: The cumulative incidence of recurrence at 10 years was 35% (95% CI, 27% to 45%) for patients receiving 32P and 28% (95% CI, 21% to 38%) for those receiving CP. Patients receiving CP had a recurrence rate 29% lower than that of those receiving 32P (P = .15, two-tail test). The death rate for patients treated with CP was 17% lower than that for patients treated with 32P (difference not significant). Combining both arms, the 10-year cumulative incidence of recurrence for all stage I patients was 27% (95% CI, 20% to 34%) compared with 44% (95% CI, 32% to 56%) for stage II patients (P = .01). Both regimens were reasonably well tolerated, but problems with inadequate distribution (7%) and small-bowel perforation (3%) make the otherwise less toxic 32P less acceptable. Conclusion: Although there are no statistically significant differences in survival, the lower cumulative recurrence seen with CP and complications of 32P administration make platinum-based combinations the preferred adjuvant therapy for early ovarian cancer patients at high-risk for recurrence.
EACH YEAR in the United States, approximately 23,400 women are diagnosed with ovarian cancer,1 and approximately one third (7,800) have localized disease (stages I and II according to the International Federation of Gynecology and Obstetrics [FIGO], classification).2 Despite the appearance of localized disease and the absence of obvious residual tumor, approximately 20% of stage I and 50% of stage II patients will die as a result of recurrent ovarian cancer.3 Early trials by the Gynecologic Oncology Group (GOG)4 and others5–7 defined subsets of patients with early disease (stage IA and IB, grade 1) who have an excellent (> 90%) chance for long-term survival without additional therapy after definitive surgery. For all other patients with early disease, a series of studies has evaluated whole abdominal irradiation,8,9 intraperitoneal radioactive chromic phosphate (32P)10,11 and both single-agent and combination chemotherapy.12–14 Few of the early trials contained sufficient numbers of patients to clearly establish the benefit of any adjuvant approach. Recently, prospective randomized trials of larger size15,16 have documented a modest benefit of platinum or platinum-containing combinations compared with 32P, but none has been definitive. In 1986, the GOG began a prospective randomized trial of 32P compared with cyclophosphamide-cisplatin (CP) combination chemotherapy in women with early stage ovarian cancer at high risk for recurrence. This article summarizes the mature results of that trial, with a median follow-up of 10 years.
Study Design This phase III randomized trial, begun in 1986, was conducted by the GOG, the North Central Cancer Treatment Group (NCCTG), and the Southwest Oncology Group (SWOG). Women with selected high-risk ovarian cancer (after definitive surgery documented early stage disease and no macroscopic residua) were randomly assigned to receive either a single dose 15 mC intraperitoneal 32P or cyclophosphamide 1 gm/m2 and cisplatin 100 mg/m2 every 21 days for three cycles. Before the administration of 32P, 99m technetium or radio-opaque contrast material was used to evaluate the adequacy of the intraperitoneal distribution. Patients with inadequate distribution were not subsequently treated with 32P. Intraperitoneal 32P was to be given within 10 days and not more than 6 weeks after the laparotomy through a multiperforated peritoneal dialysis catheter. The isotope was administered in 250 mL of normal saline, and wide distribution through the peritoneal cavity was achieved by four quadrant rotations of the patient at 15-minute intervals. Cyclophosphamide 1 gm/m2 IV was administered on day 1 of each cycle in 1000 mL of 1% normal saline. Cisplatin 100 mg/m2 IV on day 1 was administered 1 hour later in 250 mL of normal saline. Cycles of combination chemotherapy were repeated every 3 weeks depending on the time needed for blood counts to recover to pretreatment levels. Dose modifications for hematologic toxicity were based on both the nadir WBC and the delay in treatment cycle due to prolonged myelosuppression. Dose modifications were also employed for genitourinary, renal and neurologic toxicities. Nausea and vomiting resulting from the combination chemotherapy regimen were anticipated, and it was recommended that patients with significant symptoms be treated prophylactically with antiemetics.
Eligibility Criteria
Surgical Staging
Statistical Methods The planned sample size was 200 eligible patients observed until at least 28 deaths were reported among those randomly assigned to the 32P regimen. Assuming a proportional hazards model, this planned size would provide a greater than 80% chance of detecting a true treatment effect, which improves the expected 5-year survival rate from 80% to 90% when the type I error is limited to 0.05 for a one-tail log-rank test. An individual’s time at risk of recurrence or death was measured from the date that she was registered onto the study. The recurrence-free interval was measured to the date of first clinical recurrence, except for three individuals. For one patient, the date of recurrence was set as the date of salvage therapy, which was initiated 2 years after being randomly assigned to 32P as a result of rising CA-125 and no other evidence of recurrence. Also, for one individual in each treatment group, the date of recurrence was set as the date that disease was discovered during reassessment surgery. For those patients alive and recurrence-free, the time at risk is measured to the date of last contact. Survival was measured to the date of death or to the date of last contact if the patient was alive at last contact. The primary treatment comparisons of recurrence-free and overall survival include patients regardless of the amount of treatment received. Adverse effects of treatment are assessed only for those who initiated study treatment. The Kaplan-Meier procedure is used to estimate cumulative survival function.17 A proportional hazards model is used to estimate the crude and adjusted hazard ratios.18 The cumulative or marginal incidence of recurrence is used to estimate the probability of recurrence in the presence of competing risks.19 This method is preferred when there are competing risks, because those methods that treat noncancer deaths as censored survival times tend to over-estimate the probability of recurrence. All P values are two-sided.
Between 1986 and 1994, 251 patients were enrolled onto the study, with 124 randomly assigned to receive 32P and 127 to receive CP combination chemotherapy. Forty-six (18%) of the patients did not fulfill all eligibility criteria because of incomplete staging surgery (24 patients), inappropriate FIGO stage (eight patients), tumor of low malignant potential (seven patients), nonepithelial cancer (three patients), second primary cancer(two patients), colon cancer with metastasis to the ovary (one patient), and atypical hyperplasia (one patient). The reasons for 24 patients’ (twelve from each treatment group) not meeting the protocol’s surgical staging eligibility criteria were either not performing or not providing the proper documentation for all pelvic, peritoneal or node biopsies required by the protocol. The 5-year probability of recurrence was only 8.9% (95% CI, 2.4 to 27.4%) among the 24 patients excluded for incomplete or incompletely documented surgical staging, but it was 27.5% (95% CI, 21.9 to 34.1%) among those considered to have had a complete surgical staging procedure. In order to promote internal validity, the analyses presented here include these patients unless otherwise explicitly indicated. These analyses exclude those 22 patients for whom there is pathologic evidence of ineligibility. Therefore, the primary analysis includes 110 patients randomly assigned to receive 32P and 119 randomly assigned to receive CP.
Patient characteristics are summarized in Table 1
The median duration of follow-up for those alive at last contact is 10 years. Ninety-five percent of these patients have been followed for more than 5 years.
Cumulative Incidence of Recurrence and Overall Survival
Overall survival for patients treated with the two therapies is shown in Figure 2  . There is only a modest advantage in overall survival for those treated with CP. The death rate of those randomly assigned to receive CP is 0.83 compared to those randomly assigned to treatment with 32P after adjusting for FIGO stage and grade (P = .43). Thus the death rate is 17% lower for patients randomly assigned to the platinum regimen.
The cumulative incidence of recurrence according to stage is shown in Figure 3 . Although the majority of patients in this trial had stage I disease, the prognostic impact of stage is apparent. The cumulative incidence of recurrence at 10 years is 44% (95% CI, 0.32.9 to 56.6%) for stage II disease but only 27% (95% CI, 20.2 to 34.2%) for stage I. After adjusting for treatment and tumor grade, the recurrence rate is 1.62 times greater for stage II than stage I (P = .05). The probability of surviving 10 years for patients with stage I disease was 70% (95% CI, 77.8 to 63.2%) and, for stage II patients, 62% (95% CI, 74.1 to 49.7%).
Patients randomly assigned to the CP regimen tended to recur less frequently regardless of the stage of their disease. Among those with stage I disease, the 10-year marginal probability of recurrence was 30% (95% CI, 20.8 to 40.9%) for the 32P regimen versus 24% (95% CI, 15.4 to 34.7%) for the CP regimen. Likewise, among those with stage II disease, the 10-year marginal probability of recurrence was 50% (95% CI, 33.2 to 67.8%) for the 32P regimen versus 39% (95% CI, 24.8 to 55.4%) for the CP regimen. In neither instance was the difference significant.
Seventy (30%) of the 229 patients with early ovarian cancer presented with ascites at initial diagnosis. The incidence of recurrence in those with and without ascites is shown in Figure 4
The influence of tumor grade on outcome is shown in Figure 5 . Patients with grade 2 or 3 tumors experienced disease recurrence more often than did patients with either grade 1 or clear-cell histology. The cumulative incidence of recurrence at 10 years is 44% (95% CI, 31.7 to 56.9%) and 40% (95% CI, 28.4 to 53.3%) for grade 2 and 3 tumors, respectively. For grade 1 tumors, the cumulative incidence of recurrence is 22% (95% CI, 12.9 to 34.9%) and for clear-cell histology 20% (95% CI, 11.0 to 32.5%). The somewhat surprising finding for clear-cell tumors may be due to the high frequency of stage I patients in this group. Forty of the 51 patients (78%) with clear-cell histology had stage I disease, a frequency similar to that seen with grade 1, in which 43 (74%) of 58 patients had stage I disease. However, even after adjusting for randomized treatment, FIGO stage, and presence of ascites, the recurrence rate among patients with clear-cell tumor is similar to that of patients with grade 1 tumors (hazard ratio, 0.958, 95% CI, 0.41 to 2.21). The recurrence rates are 2.13 (95% CI, 1.06 to 4.28, P = .335) and 2.10 (95% CI, 1.04 to 4.24, P = .04) greater for patietns with grade 2 or 3 tumors, respectively, relative to grade 1.
Toxicity and Adverse Effects The two therapies used in the trial were relatively well tolerated, but there were different patterns of toxicity depending on type of treatment. Grade 3 and 4 toxicities for all patients who initiated their assigned therapy are summarized in Table 2 . There were eight patients randomly assigned to receive 32P who had inadequate distribution of fluid to allow treatment. Two patients refused 32P treatment, and one refused chemotherapy. These eleven patients are not included in the summary of adverse effects in this table. Of those patients treated with CP, 69% had grade 3 to 4 leukopenia, and 8% experienced thrombocytopenia to the same degree. Grade 3 or 4 gastrointestinal toxicity was seen in 12% of patients treated with CP. Three patients experienced small-bowel perforation during insertion of the intraperitoneal catheter.
Seven patients (6%) of those randomly assigned to three courses of therapy did not receive their full three courses. One patient, as mentioned, refused all treatment. Two patients experienced renal toxicity, one had an allergic reaction during her first course of treatment, one refused treatment after grade 2 gastrointestinal toxicity, one had persistent leukopenia that failed to recover within 6 weeks, and one patient declined further treatment after experiencing hearing loss after one course. Treatment may have contributed to the death of two patients, one on each arm of the trial. One patient died 2 months after surgical repair of a small-bowel perforation that occurred during catheter insertion. The second died of cardiac arrest during a period of neutropenia after one course of chemotherapy.
The treatment of patients with stage I and II epithelial ovarian cancer at increased risk for recurrence remains controversial. Although such patients have a 20% to 50% chance of disease recurrence and death after surgery, no existing adjuvant therapy had demonstrated a clear benefit over observation following surgery until the recent publication of the Adjuvant Treatment in Ovarian Neoplasms (ACTION) and International Collaboration on Ovarian Neoplasms (ICON)-1 trials.20–22 In our study, the recurrence rate at 10 years was 29% lower for patients treated with CP than for those treated with 32P (a difference not statistically significant). There is a small difference of 3.8% in 10-year survival favoring the CP arm. Both therapies were reasonably well tolerated, but there were difficulties associated with inadequate distribution (in 7% of patients) and small-bowel perforation (in 3% of patients) that hampered the use of the otherwise less toxic 32P. The 10-year probability of recurrence for stage I patients is relatively low (27%) but, for stage II patients, it is 44%. In a study of this length and maturity, late deaths from causes other than ovarian cancer are increasingly seen. However, the overall 10-year survival rate of all patients on this trial was 68.0%. Although there is no statistically significant difference between the two treatments, the lower cumulative recurrence with CP and difficulties associated with administration of 32P make platinum-based combinations preferable for patients with high-risk limited stage epithelial ovarian cancer who receive adjuvant therapy. In our study, the presence of ascites was associated with a significant increase in the cumulative incidence of recurrence after adjusting for grade and stage. Ascites has been associated with poorer outcome in some studies10 and not in others,7,23 but many studies have not been able to differentiate between those patients with and without cytologically positive peritoneal fluid. One of the most perplexing results from the present trial is the suggestion that clear-cell carcinomas have a relapse incidence similar to that of grade 1 tumors and distinctly better than that of grade 2 or grade 3 tumors. Most authors indicate that the presence of clear-cell histology confers a poorer prognosis.7 Indeed, in our previous trial4 only 17% of patients had clear-cell histology, but 12 (40%) of 20 recurrences had clear-cell features. It was for these reasons that stage I and II clear-cell tumors, regardless of grade, were included in this trial. However, uncertainty exists about whether this histology is more aggressive than other common epithelial tumors.24,25 Several studies have shown that increased mitotic rate, high MIB1 activity,25 or vascular invasion26 are the important prognostic features within clear-cell tumors, rather than the histology itself. Our results are consistent with those of two other prospective trials.15,16 The Norwegian Radium Hospital studied 347 completely resected stage I-III patients treated with either 32P or cisplatin. There was no significant difference in 5-year actuarial disease-free survival rates for either therapy. However, late bowel complications occurred more often in patients treated with 32P compared with the cisplatin group (9% v 2%).15 Those authors concluded that 32P should not be used in subsequent studies. An Italian multicenter group16 compared 32P and cisplatin alone in patients with stage IAii, IBii and IC ovarian cancer. The 5-year disease-free survival rate was better with cisplatin (CP: 85% v 32P: 65%; log-rank test P = .008), although there was no significant survival advantage (CP: 81% v 32P: 79%). Recently, the reports of two large European trials and the combined ACTION and ICON-1 trials have been published.20–22 A total of 923 patients with early stage ovarian cancer were randomly assigned to receive either platinum-based chemotherapy or no initial treatment. The results indicate a statistically significant improvement in both disease-free survival and overall survival with adjuvant platinum-based chemotherapy. However, comprehensiveness of surgical staging was a significant prognostic factor for tumor recurrence in the observation arm. In the one third of patients who had optimal surgical staging, there was no difference in disease-free or overall survival for those who received adjuvant platinum-based chemotherapy. However, this subset of patients was not large enough to reach statistical significance, and the impact of surgical staging on the benefits of adjuvant chemotherapy remains unclear. The collective results of the four trials using platinum-based chemotherapy provide reasonable evidence that platinum-based chemotherapy is now appropriate treatment for patients with stage I and II high-risk ovarian cancer. Whether careful surgical staging and further sub-setting of prognostic factors will allow the expansion of the group of patients who require no adjuvant therapy after surgery awaits further study. Although CP as used in this study was reasonably well-tolerated and slightly better than intraperitoneal 32P, it remains far from optimal. The results from this study at 10 years indicate that only 65% of stage I patients and 52% of stage II patients are expected to be alive and free of recurrent ovarian cancer. Better adjuvant therapy is clearly required. The GOG has recently completed accrual of 457 patients to a prospective randomized trial comparing three courses of carboplatin and paclitaxel with six courses of the same regimen in similar high-risk early disease patients. Whether these regimens reduce cumulative incidence of recurrence, as well as adverse effects, will require further follow-up.
The following GOG institutions participated in this study: (National Cancer Institute grant numbers are in parentheses.) University of Alabama at Birmingham (CA 12484), Oregon Health Sciences University, Duke University Medical Center (CA 12534), Abington Memorial Hospital, University of Rochester Medical Center (CA 12482), Walter Reed Army Medical Center (CA 23501), Wayne State University (CA 12477), University of Minnesota Medical School (CA 23088), University of Southern California at Los Angeles (CA 37535), University of Mississippi Medical Center (CA 13633), Colorado Gynecologic Oncology Group, P.C.(CA 15975), University of California at Los Angeles (CA 13630), University of Pennsylvania Cancer Center (CA 15977), University of Miami School of Medicine (CA 37234), Milton S. Hershey Medical Center (CA 16386), Georgetown University Hospital (CA 16938), University of Cincinnati, University of N Carolina School of Medicine (CA 23073), University of Iowa Hospitals and Clinics (Ca 19502), University of Texas/Southwestern Medical Center at Dallas (CA 28160), Indiana University Medical Center (CA 21720), Wake Forest University School of Medicine (CA 21946), Albany Medical College (CA 27469), University of California Medical Center at Irvine (CA 23765), Tufts-New England Medical Center (CA 37569), Rush-Presbyterian-St. Luke’s Medical Center (CA 12485), SUNY Downstate Medical Center (CA 34477), University of Kentucky, Eastern Virginia Medical School (CA 40296), The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, State University of New York at Stony Brook, Eastern Pennsylvania Gyn/Onc Center, P.C., Southwest Oncology Group, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, N Central Cancer Treatment Group (CA 25224), University of Massachusetts Medical Center, Fox Chase Cancer Center, Medical University of S Carolina, Women’s Cancer Center, University of Oklahoma, University of Chicago, and Tacoma General Hospital.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Robert C. Young, Bristol-Myers Squibb. Received more than $2,000 a year from a company for either of the last 2 years: Robert C. Young, Bristol-Myers Squibb.
Supported by National Cancer Institute grants to GOG member institutions participating in this study.
1. American Cancer Society: Cancer Facts and Figures. Atlanta, GA, American Cancer Society, 2001 2. Staging announcement: FIGO Cancer Committee. Gynecol Oncol 25:383–384, 1986[CrossRef] 3. Ozols RF, Rubin SC, Thomas GM, et al: Epithelial ovarian cancer, in Hoskins WJ, Perez C, Young RC (eds): Principles and Practice of Gynecologic Oncology. Philadelphia, PA, Lippincott, Williams & Wilkins, 2000, pp 1005–1013 4. Young RC, Walton LA, Ellenberg SS, et al: Adjuvant therapy in stage I and stage II epithelial ovarian cancer: Results of two prospective randomized trials. N Engl J Med 322:1021–1027, 1990[Abstract]
5. Klaasen D, Shelley W, Starreveld A, et al: Early stage ovarian cancer: A randomized clinical trial comparing whole abdominal radiotherapy, melphalan and intraperitoneal chromic phosphate—A National Cancer Institute of Canada Clinical Trials Group report. J Clin Oncol 6:1254–1263, 1988 6. Dembo AJ, Bush RS, Beale FA: Ovarian carcinoma: Improved survival following abdomenopelvic irradiation in patients with a completed pelvic operation. Am J Obstet Gynecol 134:793–800, 1979[Medline] 7. Vergote I, DeBrabanter J, Fyles A, et al: Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 357:176–182, 2001[CrossRef][Medline] 8. Dembo AJ: Radiotherapeutic management of ovarian cancer. Semin Oncol 11:238–250, 1984[Medline] 9. Delclos L, Smith JP: Ovarian cancer: With special regard to types of radiotherapy. NCI Monogr 42:129, 1975 10. Dembo AJ, Davy M, Stenwig AE, et al: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75:263–273, 1990[Medline] 11. Pezner RD, Stevens KRJ, et al: Limited epithelial carcinoma of the ovary treated with curative intent by intraperitoneal instillation of radiocolloids. Cancer 42:2563–26741, 1978[CrossRef][Medline] 12. Hreshchyshyn MM, Park RC, Blessing JA, et al: The role of adjuvant therapy in stage I ovarian cancer. Am J Obstet Gynecol 138:139–144, 1980[Medline] 13. Davy M, Stenwig AE, Kjorstad KE, et al: Early stage ovarian cancer. Acta Obstet Gynecol Scand 64:531–532, 1985[Medline] 14. Chiara S, Mammoliti S, Oliva C, et al: Adjuvant-based chemotherapy for stage I and II ovarian cancer: A 7-year experience. Eur J Cancer 27:1211–1215, 1991[Medline] 15. Vergote IB, Vergote-DeVos LN, Abeler VM, et al: Randomized trial comparing cisplatin with radioactive phosphorous or whole abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69:741–749, 1992[CrossRef][Medline]
16. Bolis G, Colombo N, Pecorelli S, et al: Adjuvant treatment for early epithelial ovarian cancer: Results of two randomized clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P). Ann Oncol 6:887–893, 1995 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 18. Cox DR: Regression model and life tables. J R Statistical Soc B 34:187–220, 1972 19. Gaynor JJ, Fever EJ, Tan CC, et al: On the use of cause-specific failure and conditional failure probabilities: Examples from clinical oncology data. J Am Stat Assn 88:400–409, 1993[CrossRef]
20. Trimbos JB, Parmar M, Vergote I, et al: International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant Chemotherapy in Ovarian Neoplasm Trial: Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95:105–112, 2003
21. International Collaborative Ovarian Neoplasm Trial 1: A Randomized Trial of Adjuvant Chemotherapy in Women with Early Stage Ovarian Cancer. J Natl Cancer Inst 95:125–132, 2003
22. Trimbos, JB, Vergote, I, Bolis, G et al. Impact of adjuvant chemotherapy and surgical staging in early stage ovarian carcinoma: European Organization for Research and Treatment of Ovarian Adjuvant Chemotherapy in Ovarian Neoplasm Trial. J Natl Cancer Inst 95:113–125, 2003 23. Yoshimura S, Scully RE, Tuft PD, et al: Peritoneal fluid cytology in patients with ovarian cancer. Gynecol Oncol 17:161–167, 1984[CrossRef][Medline] 24. Tammela J, Geisler JP, Eskew PNJ: Clear cell carcinoma of the ovary: Poor prognosis compared with serous carcinoma. Eur J Gynaecol Oncol 19:438, 1998[Medline] 25. Morimura V, Hoshi K: Hang XL, et al: Evaluation with MIB1 antibody of proliferative activity in ovarian clear cell adenocarcinoma. Int J Gynecol Pathol 15:315, 1996[Medline] 26. O’Brien MER, Schofield BJ, Tan S, et al: clear cell epithelial ovarian cancer (mesonephroid) bad prognosis only in early stages. Gynecol Oncol 49:250, 1993[CrossRef][Medline] Submitted February 28, 2003; accepted September 2, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
