GYNECOLOCIC
ONCOLOGY
46,
357-360 (1992)
Five-Year Survival for Stage IC or Stage I Grade 3 Epithelial Ovarian Cancer Treated with Cisplatin-Based Chemotherapy M. STEVEN PIVER, M.D.,*,’ JOHN MALFETANO, M.D.,t TRUDY R. BAKER, M.D.,* AND RONALD E. HEMPLING, M.D.* *Department
of Gynecologic
Oncology at Roswell Park Cancer Institute, Buffalo, Albany, New York
New York 14263; and TAlbany Medical Center,
Received December 9. 1991
that these two groups of stage I patients were at such
Thirty-two stage IC or stageI grade 3 patients with invasive _._ high risk for recurrence that they should not be randomovarian adenocarcinomaweretreatedwith 6 monthsof adjuvant
cisplatin-basedchemotherapy.With a median follow-up of 60.5 ized to a nontreatment observation arm. Thus, they were months,there have been three (9%) recurrences.The S-yearpro- placed in a separate protocol (7602) which also included gression-freesurvival was 90.5% and the S-year survival was all stage II patients, These patients were randomized to melphalan or intraperitoneal P3’. Although there was no 93.3%. 0 1992 Academic Press, Inc. difference in 5year disease-free survival (80% both groups) and overall survival (81% for melphalan and 78% CASE REPORT for P3’), the survival rate of the stage IC or stage I poorly differentiated tumors (grade 3) were not separated out In 1983 we initiated a prospective trial to treat stage I from the stage II patients. Because of the results of trial (A,B,C) patients with cisplatin-based chemotherapy to 7601 that none of the surgically staged stage IA or IB evaluate if survival was improved by this adjuvant therapy well or moderately differentiated tumors required adjuas compared to earlier trials in which 30-40% of women vant chemotherapy and plus the fact that none of our with stage I ovarian cancer treated by surgery alone died stage IA or IB treated with cisplatin-based chemotherapy of their cancer before 5 years [1,2]. At the time of our recurred, our initial study was changed to include only initial report in 1989, 93% (28/30) were progression-free stage IC (malignant peritoneal cytology or ruptured ovarat a median follow-up of 4 years [3]. However, in 1990 ian tumors) or stage I grade 3 tumors. The purpose of the Gynecologic Oncology Group reported a prospective this paper is to report the results of 32 patients with stage randomized trial (7601) of 81 patients with stage I well IC or stage I grade 3 ovarian adenocarcinoma treated (grade 1) or moderately (grade 2) differentiated cancers with cisplatin-based chemotherapy. confined to the ovary (stage IAi and IBi) who were assigned to melphalan or observation. After a median follow-up of 6 years, there was no significant difference MATERIALS AND METHODS between the patients randomized to observation or melphalan with respect to either 5-year disease-free survival From 1983 through 1991, 32 patients with FIG0 stage (91% versus 98%) or overall survival (94% versus 98%). IC or stage I grade 3 invasive ovarian adenocarcinoma From this study, it appears that patients surgically staged were treated at Roswell Park Cancer Institute (RPCI) and found to have stage IA or IB well or moderately (20) and Albany Medical Center (AMC) (12). Patient differentiated tumors have excellent 5year survivals and characteristics are seen in Table 1. require no therapy other than the initial surgery [4]. As previously described, chemotherapy consisted of inHowever, absent from this study was the fate of patients duction cisplatin given once a week for 4 weeks followed with stage IC or stage I grade 3 tumors. The authors felt by five monthly courses of cisplatin, adriamycin, and cy’ To whom reprint requests should be addressed at Department of clophosphamide (RPCI) or cisplatin and cyclophosphamide (AMC) [3]. Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. One month after the last course of cisplatin-based 357 0090-8258/!92$4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
358
PIVER ET AL.
phamide completing the rest of the monthly courses with just cisplatin. The latter was the only incidence of WHO grade 3 hematologic toxicity. No patient developed sigNumber of Patients 32 nificant nephrotoxicity, cardiotoxicity, or neurotoxicity. Stage and grade Of the 32 women, 25 underwent second-look surgery IC grade 1 or 2 18 IC grade 3 10 (21 second-look laparotomy and 4 second-look laparosIA or B grade 3 4 copy) and 7 refused any type of second look. Only 1 (4%) Histology of the 25 women undergoing second-look surgery had Serous 8 Clear cell 7 disease present. With a median follow-up of 60.5 months, Mutinous 5 there have been three recurrences (9%) (Table 2). Five Endometrioid 5 percent (1 of 20) of the surgically staged patients develAdenocarcinoma 5 oped recurrent cancer. Of the 12 not surgically staged Mixed epithelial (clear cell 2 patients, 2 (16%) developed recurrent cancer. Of the 8 endometrioid/mucinous/endometriod) clear cell histologies (1 mixed), 2 (25%) developed reSurgically staged 20 current cancer. Only 1 (4%) of the nonclear cell histoNot surgically staged 12 Second-look surgery 25 logies developed recurrent cancer. Of all patients, 90.6% Refused second look 6 (29 of 32) remain without evidence of disease with normal Progressed prior to second look 1 CA125 levels, two are dead of ovarian cancer at 8 and 20 months, and one is alive in remission at 83 months. The median survival and the median progression-free survival have not been reached. The j-year survival is 93.3% chemotherapy, patients were to undergo second-look lap- and the j-year progression-free survival is 90.5%. aroscopy or laparotomy as previously described. The Kaplan-Meier method was used for calculating the progression-free survival and survival time curves [5]. The DISCUSSION former curves were computed using the time from surgery to disease progression or death, whichever was less. AnalBecause of the inverse relationship between tumor burysis was as of November 1991. den and curability by chemotherapy, in 1983 we initiated a trial to treat all stage I patients with cisplatin-based chemotherapy based on the premise that if cisplatin-based RESULTS chemotherapy was the most effective treatment for adTwenty-eight patients were stage IC, 10 of which were vanced (stages III and IV) ovarian cancer then such therstage IC grade 3. Four patients had stage IA or B grade apy should be highly effective in preventing recurrences 3 tumors. Histology consisted of serous carcinoma in 8, in stage I disease. However, the Gynecologic Oncology clear cell in 7, mutinous in 5, adenocarcinoma in 5, en- Group and Ovarian Cancer Study Group protocol 7601 dometrioid in 5 and 2 mixed cell adenocarcinomas. demonstrated that surgically staged, stage IA and IB Twenty (62.5%) patients underwent total abdominal hys- grade 1 or grade 2 patients had excellent long-term disterectomy, bilateral salpingo-oophorectomy, and com- ease-free survivals and did not require adjuvant therapy after surgery. plete surgical staging with diaphragmatic evaluation, Unanswered from the Gynecologic Oncology Group omentectomy, paraaortic and pelvic lymph node sampling, and peritoneal washings for cytology prior to cis- and Ovarian Cancer Study Group was the fate of the platin-based chemotherapy. Twelve (37.5%), who at the stage IC or stage I grade 3 patients. We have treated 32 time of initial surgery had no macroscopic evidence of stage IC or stage I grade 3 patients with cisplatin-based cancer beyond the ovary, underwent total abdominal hys- chemotherapy, all of whom have completed therapy, and terectomy, bilateral salpingo-oophorectomy, with or with- have undergone or refused second-look surgery. With a out omentectomy, and peritoneal washings and were con- median follow-up of 5 years, there have been three (9%) sidered not to have undergone complete surgical staging recurrences. It has been reported that clear cell histology, prior to cisplatin-based chemotherapy. All patients com- regardless of cisplatin-based chemotherapy, is associated pleted the prescribed four courses of induction cisplatin with a very poor prognosis. Even in the Gynecologic Oncology Group and Ovarian Cancer Study Group proand five monthly courses of cisplatin-based combination chemotherapy except for 1 patient who developed WHO tocols 7601 and 7602, 12 of the 30 recurrences (40%) [6] grade 3 thrombocytopenia necessitating (1) initial dele- involved this histologic type [4]. Although the numbers tion of adriamycin and (2) after the second course of are small in this series, of the 8 clear cell histologies, 2 cisplatin and cyclophosphamide deletion of cyclophos- (25%) developed recurrence as compared to only 1 of 24 TABLE 1 Patient Characteristics
STAGE I OVARIAN
359
CANCER
TABLE 2 Stage IC or Stage I Grade 3 Ovarian Adenocarcinoma Stage
Grade
Histology
3 3
Clear cell Adenocarcinoma Clear cell Serous Mutinous Mutinous Endometrioid Mutinous Serous Mutinous Serous Clear cell Mutinous Endometrioid Clear cell Endometrioid Endometrioid Clear cell Serous Serous Mutinous Endometrioid Clear cell Serous Serous Adenocarcinoma Clear cell Adenocarcinoma Adenocarcinoma Adenocarcinoma Endometrioid Endometrioid Serous Clear cell
IA IA IA IB IC IC IC IC IC IC IC IC IC
2 2
IC
2
IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC
2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3
3 3 1 1 1 1 1 1 1
Second-look laparoscopy
Second-look Iaparotomy
Recurrence (months)
PFS (months)
No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes
No Neg. Neg. Neg.
Neg. ND Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. -
0 0 0 0 0 0 0 0 0 0 0 0 0
73 54 52 77 62 59 72 82 56 39 87 77
No
ND
ND
3
3
No No Yes Yes Yes Yes Yes Yes Yes Yes No No No No Yes No Yes Yes
No
Neg. Pos. Neg. Neg. ND Neg. ND ND Neg. Neg. Neg. Neg. Neg. Neg. Neg. ND ND
0
42
Surgically staged
No No Neg. No No
8.5
6
6
0 0 0 0 0 0 16 0 0 0 0 0 0 0 0 0
99 92 84 53 25 24 16 72 65 62 54 8 16
16 70 18
Note. ND, not done; Neg., negative; Pos., positive.
(4%) of the nonclear cell histologies. The 5-year progression-free survival is 90.5% and the 5-year survival is 93.3%. Interpretation of these excellent 5-year progression-free survival rates should be interpreted with caution, since this is a nonrandomized trial and 37.5% (12) of the patients did not undergo what would now be considered as complete surgical staging. The latter is true of other recent reports in which 51% [7] and 31% [8] of the presumed stage I patients did not undergo complete surgical staging. However, since the prognosis for stage IC or stage I grade 3 prior to the advent of cisplatin was so poor, we believe these results suggest that all such patients should be treated with cisplatin-based chemotherapy. Patients with clear cell histology should also receive such therapy until and when a better therapy is reported in advanced stage III and IV clear cell histology tumors. The Gynecologic
Oncology Group has initiated a randomized trial comparing cisplatin and cyclophosphamide to intraperitoneal P3’ for stage IC, stage I grade 3, and all stage II patients [4]. Hopefully, this randomized trial will provide further support for the efficacy of cisplatin-based therapy in highrisk stage IC and stage I grade 3 ovarian cancer patients.
REFERENCES Bagley, C. M., Young, R. C., Canellos, G. P., and DeVita, V. Treatment of Ovarian Carcinoma: Possibilities for progress, N. Engl. J. Med. 287, 856 (1972).
Fuks, Z. The role of radiation therapy and the management of ovarian carcinoma, Isr. J. Med. Sci. 13, 815-827(1977). Piver, M. S., Malfetano, J., Baker, T. R., Lele, S. B., and Marchetti, D. L. Adjuvant cisplatin-based chemotherapy for Stage I
360
PIVER ET AL.
ovarian adenocarcinoma: A preliminary report, Gynecol. Oncol. 35, 69-72 (1989). 4. Young, R. C., Walton, L. A., Ellenberg, S. S., etal. Adjuvant therapy in Stage I and II epithelial ovarian cancer: Results of two prospective randomized trials, IV. En@. /. Med. 15, 1021-1027 (1990). 5. Kaplan, E. L., and Meier, P. Non parametric estimation from incomplete observations, /. Am. Stat. Assoc. 53, 457-481 (1958).
6. World Health Organization. Handbookfor reporting results of cancer treatmenr: WHO ofiet publication 48, Den Haag Nijhoff (1979). 7. Lentz, S. S., Cha, S. S., Wieand, H. S., and Podratz, K. C. Stage I ovarian epithelial carcinoma: Survival analysis following definitive treatment, Gynecoi. Oncol. 43, 198-202 (1991). 8. Dottino, P. R., Plaxe, S. C., and Cohen, C. J. A phase II trial of adjuvant cisplatin and doxorubicin in Stage I epithelial ovarian cancer, Gynecol. Oncol. 43, 203-205 (1991).
ONCOLOGY
46,
357-360 (1992)
Five-Year Survival for Stage IC or Stage I Grade 3 Epithelial Ovarian Cancer Treated with Cisplatin-Based Chemotherapy M. STEVEN PIVER, M.D.,*,’ JOHN MALFETANO, M.D.,t TRUDY R. BAKER, M.D.,* AND RONALD E. HEMPLING, M.D.* *Department
of Gynecologic
Oncology at Roswell Park Cancer Institute, Buffalo, Albany, New York
New York 14263; and TAlbany Medical Center,
Received December 9. 1991
that these two groups of stage I patients were at such
Thirty-two stage IC or stageI grade 3 patients with invasive _._ high risk for recurrence that they should not be randomovarian adenocarcinomaweretreatedwith 6 monthsof adjuvant
cisplatin-basedchemotherapy.With a median follow-up of 60.5 ized to a nontreatment observation arm. Thus, they were months,there have been three (9%) recurrences.The S-yearpro- placed in a separate protocol (7602) which also included gression-freesurvival was 90.5% and the S-year survival was all stage II patients, These patients were randomized to melphalan or intraperitoneal P3’. Although there was no 93.3%. 0 1992 Academic Press, Inc. difference in 5year disease-free survival (80% both groups) and overall survival (81% for melphalan and 78% CASE REPORT for P3’), the survival rate of the stage IC or stage I poorly differentiated tumors (grade 3) were not separated out In 1983 we initiated a prospective trial to treat stage I from the stage II patients. Because of the results of trial (A,B,C) patients with cisplatin-based chemotherapy to 7601 that none of the surgically staged stage IA or IB evaluate if survival was improved by this adjuvant therapy well or moderately differentiated tumors required adjuas compared to earlier trials in which 30-40% of women vant chemotherapy and plus the fact that none of our with stage I ovarian cancer treated by surgery alone died stage IA or IB treated with cisplatin-based chemotherapy of their cancer before 5 years [1,2]. At the time of our recurred, our initial study was changed to include only initial report in 1989, 93% (28/30) were progression-free stage IC (malignant peritoneal cytology or ruptured ovarat a median follow-up of 4 years [3]. However, in 1990 ian tumors) or stage I grade 3 tumors. The purpose of the Gynecologic Oncology Group reported a prospective this paper is to report the results of 32 patients with stage randomized trial (7601) of 81 patients with stage I well IC or stage I grade 3 ovarian adenocarcinoma treated (grade 1) or moderately (grade 2) differentiated cancers with cisplatin-based chemotherapy. confined to the ovary (stage IAi and IBi) who were assigned to melphalan or observation. After a median follow-up of 6 years, there was no significant difference MATERIALS AND METHODS between the patients randomized to observation or melphalan with respect to either 5-year disease-free survival From 1983 through 1991, 32 patients with FIG0 stage (91% versus 98%) or overall survival (94% versus 98%). IC or stage I grade 3 invasive ovarian adenocarcinoma From this study, it appears that patients surgically staged were treated at Roswell Park Cancer Institute (RPCI) and found to have stage IA or IB well or moderately (20) and Albany Medical Center (AMC) (12). Patient differentiated tumors have excellent 5year survivals and characteristics are seen in Table 1. require no therapy other than the initial surgery [4]. As previously described, chemotherapy consisted of inHowever, absent from this study was the fate of patients duction cisplatin given once a week for 4 weeks followed with stage IC or stage I grade 3 tumors. The authors felt by five monthly courses of cisplatin, adriamycin, and cy’ To whom reprint requests should be addressed at Department of clophosphamide (RPCI) or cisplatin and cyclophosphamide (AMC) [3]. Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. One month after the last course of cisplatin-based 357 0090-8258/!92$4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
358
PIVER ET AL.
phamide completing the rest of the monthly courses with just cisplatin. The latter was the only incidence of WHO grade 3 hematologic toxicity. No patient developed sigNumber of Patients 32 nificant nephrotoxicity, cardiotoxicity, or neurotoxicity. Stage and grade Of the 32 women, 25 underwent second-look surgery IC grade 1 or 2 18 IC grade 3 10 (21 second-look laparotomy and 4 second-look laparosIA or B grade 3 4 copy) and 7 refused any type of second look. Only 1 (4%) Histology of the 25 women undergoing second-look surgery had Serous 8 Clear cell 7 disease present. With a median follow-up of 60.5 months, Mutinous 5 there have been three recurrences (9%) (Table 2). Five Endometrioid 5 percent (1 of 20) of the surgically staged patients develAdenocarcinoma 5 oped recurrent cancer. Of the 12 not surgically staged Mixed epithelial (clear cell 2 patients, 2 (16%) developed recurrent cancer. Of the 8 endometrioid/mucinous/endometriod) clear cell histologies (1 mixed), 2 (25%) developed reSurgically staged 20 current cancer. Only 1 (4%) of the nonclear cell histoNot surgically staged 12 Second-look surgery 25 logies developed recurrent cancer. Of all patients, 90.6% Refused second look 6 (29 of 32) remain without evidence of disease with normal Progressed prior to second look 1 CA125 levels, two are dead of ovarian cancer at 8 and 20 months, and one is alive in remission at 83 months. The median survival and the median progression-free survival have not been reached. The j-year survival is 93.3% chemotherapy, patients were to undergo second-look lap- and the j-year progression-free survival is 90.5%. aroscopy or laparotomy as previously described. The Kaplan-Meier method was used for calculating the progression-free survival and survival time curves [5]. The DISCUSSION former curves were computed using the time from surgery to disease progression or death, whichever was less. AnalBecause of the inverse relationship between tumor burysis was as of November 1991. den and curability by chemotherapy, in 1983 we initiated a trial to treat all stage I patients with cisplatin-based chemotherapy based on the premise that if cisplatin-based RESULTS chemotherapy was the most effective treatment for adTwenty-eight patients were stage IC, 10 of which were vanced (stages III and IV) ovarian cancer then such therstage IC grade 3. Four patients had stage IA or B grade apy should be highly effective in preventing recurrences 3 tumors. Histology consisted of serous carcinoma in 8, in stage I disease. However, the Gynecologic Oncology clear cell in 7, mutinous in 5, adenocarcinoma in 5, en- Group and Ovarian Cancer Study Group protocol 7601 dometrioid in 5 and 2 mixed cell adenocarcinomas. demonstrated that surgically staged, stage IA and IB Twenty (62.5%) patients underwent total abdominal hys- grade 1 or grade 2 patients had excellent long-term disterectomy, bilateral salpingo-oophorectomy, and com- ease-free survivals and did not require adjuvant therapy after surgery. plete surgical staging with diaphragmatic evaluation, Unanswered from the Gynecologic Oncology Group omentectomy, paraaortic and pelvic lymph node sampling, and peritoneal washings for cytology prior to cis- and Ovarian Cancer Study Group was the fate of the platin-based chemotherapy. Twelve (37.5%), who at the stage IC or stage I grade 3 patients. We have treated 32 time of initial surgery had no macroscopic evidence of stage IC or stage I grade 3 patients with cisplatin-based cancer beyond the ovary, underwent total abdominal hys- chemotherapy, all of whom have completed therapy, and terectomy, bilateral salpingo-oophorectomy, with or with- have undergone or refused second-look surgery. With a out omentectomy, and peritoneal washings and were con- median follow-up of 5 years, there have been three (9%) sidered not to have undergone complete surgical staging recurrences. It has been reported that clear cell histology, prior to cisplatin-based chemotherapy. All patients com- regardless of cisplatin-based chemotherapy, is associated pleted the prescribed four courses of induction cisplatin with a very poor prognosis. Even in the Gynecologic Oncology Group and Ovarian Cancer Study Group proand five monthly courses of cisplatin-based combination chemotherapy except for 1 patient who developed WHO tocols 7601 and 7602, 12 of the 30 recurrences (40%) [6] grade 3 thrombocytopenia necessitating (1) initial dele- involved this histologic type [4]. Although the numbers tion of adriamycin and (2) after the second course of are small in this series, of the 8 clear cell histologies, 2 cisplatin and cyclophosphamide deletion of cyclophos- (25%) developed recurrence as compared to only 1 of 24 TABLE 1 Patient Characteristics
STAGE I OVARIAN
359
CANCER
TABLE 2 Stage IC or Stage I Grade 3 Ovarian Adenocarcinoma Stage
Grade
Histology
3 3
Clear cell Adenocarcinoma Clear cell Serous Mutinous Mutinous Endometrioid Mutinous Serous Mutinous Serous Clear cell Mutinous Endometrioid Clear cell Endometrioid Endometrioid Clear cell Serous Serous Mutinous Endometrioid Clear cell Serous Serous Adenocarcinoma Clear cell Adenocarcinoma Adenocarcinoma Adenocarcinoma Endometrioid Endometrioid Serous Clear cell
IA IA IA IB IC IC IC IC IC IC IC IC IC
2 2
IC
2
IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC
2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3
3 3 1 1 1 1 1 1 1
Second-look laparoscopy
Second-look Iaparotomy
Recurrence (months)
PFS (months)
No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes
No Neg. Neg. Neg.
Neg. ND Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. -
0 0 0 0 0 0 0 0 0 0 0 0 0
73 54 52 77 62 59 72 82 56 39 87 77
No
ND
ND
3
3
No No Yes Yes Yes Yes Yes Yes Yes Yes No No No No Yes No Yes Yes
No
Neg. Pos. Neg. Neg. ND Neg. ND ND Neg. Neg. Neg. Neg. Neg. Neg. Neg. ND ND
0
42
Surgically staged
No No Neg. No No
8.5
6
6
0 0 0 0 0 0 16 0 0 0 0 0 0 0 0 0
99 92 84 53 25 24 16 72 65 62 54 8 16
16 70 18
Note. ND, not done; Neg., negative; Pos., positive.
(4%) of the nonclear cell histologies. The 5-year progression-free survival is 90.5% and the 5-year survival is 93.3%. Interpretation of these excellent 5-year progression-free survival rates should be interpreted with caution, since this is a nonrandomized trial and 37.5% (12) of the patients did not undergo what would now be considered as complete surgical staging. The latter is true of other recent reports in which 51% [7] and 31% [8] of the presumed stage I patients did not undergo complete surgical staging. However, since the prognosis for stage IC or stage I grade 3 prior to the advent of cisplatin was so poor, we believe these results suggest that all such patients should be treated with cisplatin-based chemotherapy. Patients with clear cell histology should also receive such therapy until and when a better therapy is reported in advanced stage III and IV clear cell histology tumors. The Gynecologic
Oncology Group has initiated a randomized trial comparing cisplatin and cyclophosphamide to intraperitoneal P3’ for stage IC, stage I grade 3, and all stage II patients [4]. Hopefully, this randomized trial will provide further support for the efficacy of cisplatin-based therapy in highrisk stage IC and stage I grade 3 ovarian cancer patients.
REFERENCES Bagley, C. M., Young, R. C., Canellos, G. P., and DeVita, V. Treatment of Ovarian Carcinoma: Possibilities for progress, N. Engl. J. Med. 287, 856 (1972).
Fuks, Z. The role of radiation therapy and the management of ovarian carcinoma, Isr. J. Med. Sci. 13, 815-827(1977). Piver, M. S., Malfetano, J., Baker, T. R., Lele, S. B., and Marchetti, D. L. Adjuvant cisplatin-based chemotherapy for Stage I
360
PIVER ET AL.
ovarian adenocarcinoma: A preliminary report, Gynecol. Oncol. 35, 69-72 (1989). 4. Young, R. C., Walton, L. A., Ellenberg, S. S., etal. Adjuvant therapy in Stage I and II epithelial ovarian cancer: Results of two prospective randomized trials, IV. En@. /. Med. 15, 1021-1027 (1990). 5. Kaplan, E. L., and Meier, P. Non parametric estimation from incomplete observations, /. Am. Stat. Assoc. 53, 457-481 (1958).
6. World Health Organization. Handbookfor reporting results of cancer treatmenr: WHO ofiet publication 48, Den Haag Nijhoff (1979). 7. Lentz, S. S., Cha, S. S., Wieand, H. S., and Podratz, K. C. Stage I ovarian epithelial carcinoma: Survival analysis following definitive treatment, Gynecoi. Oncol. 43, 198-202 (1991). 8. Dottino, P. R., Plaxe, S. C., and Cohen, C. J. A phase II trial of adjuvant cisplatin and doxorubicin in Stage I epithelial ovarian cancer, Gynecol. Oncol. 43, 203-205 (1991).
