Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer

GYNECOLOGIC

ONCOLOGY

42, 146-150

(1991)

Neoadjuvant Chemotherapy and Interval Debulking for Advanced Epithelial Ovarian Cancer JOSEPH H. JACOB, M.D., Department

DAVID M. GERSHENSON, M.D. ,l MITCHELL MORRIS, M.D., LARRY J. COPELAND, THOMAS W. BURKE, M.D., AND J. TAYLOR WHARTON, M.D.

of Gynecology,

The University

of Texas M.

D. Anderson

Cancer

Center,

Houston,

M.D.,

Texas 77030

Received January 3, 1991

A retrospectivematched-controlstudy wasconductedto review our experiencewith FIGG stage III and IV epithelial ovarian cancer in patients referred after initial laparotomy and biopsy only. The study group comprised22 patients; plannedtreatment wastwo to four cycles of chemotherapy,interval debulking surgery, six morechemotherapycycles,and second-looklaparotomy. Two control groupswerematchedwith the study group according to FIG0 stage, histologic type, and grade (2 or 3) and patient age +5 years. The first control group (22 patients) had >2 cm residualdiseaseafter initial surgery; their plannedtreatment was a minimum of six cycles of chemotherapyplus second-looklaparotomy. The secondcontrol group (18 patients) was referred after initial laparotomy and biopsy only; their diseasewas immediatelyreexploredand debulked.Subsequentplannedtreatment wasa minimum of six cyclesof chemotherapyplus secondlook laparotomy. All patients received cisplatin-basedchemotherapy. Optimal cytoreduction to ~2 cm wasachievedfor 77% of the study group vs 39% of the immediate-reexplorationgroup (P = 0.02). Median survival timesfor the three groupswere not different (16 vs 19.3 vs 18 months, respectively) (P = 0.58). Within the study group, patients who were optimally debulked survived significantly longer than those who were not (18.1 vs 7.5 months) (P = 0.02). Morbidity of the interval debulking procedure was acceptable.Study findings suggestthat patients with bulky residualdiseasehave a uniformly poor prognosisregardlessof the timing of further surgery. o 19~ AcademicPESS,IN.

Over the past 15 years, the treatment of epithelial ovarian cancer has become relatively standardized. Several investigators have shown that the greatest survival potential for patients with advanced disease is realized when initial cytoreductive surgery yields minimal residual tumor [l-7]. It is unclear whether the ability to debulk epithelial ovarian cancer optimally reflects the skill and aggressive’ To whom reprint requests should be addressed at Department of Gynecology, UT M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 67, Houston, Texas 77030. 146

OGW-8258191$1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved

ness of the surgeon or the biologic characteristics of the tumor [3]. This question becomes pertinent to the gynecologic oncologist when faced with the referral of a patient with ovarian cancer who has previously undergone a laparotomy, only to be deemed “unresectable”; usually a biopsy has been taken and the wound closed. Should the patient undergo immediate reoperation? Should a few cycles of chemotherapy be given so that tumor regression might then make optimal cytoreduction more feasible? Or was the referring surgeon correct in his assessment that additional cytoreduction is not possible and the patient is best served by initiating chemotherapy? The present study was conducted to review our experience at The University of Texas M. D. Anderson Cancer Center with bulky FIG0 stage III and IV epithelial ovarian cancers in patients who were referred to us after undergoing an initial laparotomy and biopsy alone. MATERIALS

AND METHODS

Retrospective review of the medical records of patients with a diagnosis of epithelial ovarian cancer referred to M. D. Anderson Cancer Center between 1977 and the end of 1988 identified the study population. The original treatment plan had been determined according to the preference of the attending physician. Eligibility criteria included histologic evidence of epithelial ovarian cancer, FIG0 stage III or IV disease, histologic grade 2 or 3, and treatment with neoadjuvant chemotherapy and interval debulking surgery. Patients with grade 1 or borderline tumors were excluded from the study. Pathology slides from all patients were reviewed by staff of the Department of Pathology. Histologic typing was performed according to the World Health Organization classification system [8], and histologic grading was performed using the pattern-grading system [9].

INTERVAL Study Group n=22

(A)

Laparotomyjbiopsy

-/

DEBULKING

147

SURGERY

2-4 cycles .-..-.-w cisplatin-based chemotherapy

Interval debulking

j

Planned 16 cycles cisplatin-based chemotherapy

\ Control Group n=22

(B)

Laparotomy; Residual disease

Control Group n=lS

(C)

Laparotomy/biopsy

>2 cm __)

Planned 26 cycles cisplatin-based chemotherapy

Second-look laparotomy

*

/

FIG.

--+

1.

Reexploration and tumor debulking at referral

-.

Planned 26 cycles cisplatin-based chemotherapy

Treatment schema for study and control groups

The study group (Group A) consisted of 22 patients who were referred to M. D. Anderson Cancer Center after undergoing only laparotomy and biopsy at an outside hospital. After referral, each patient received two to four cycles of cisplatin-based chemotherapy, after which interval debulking was attempted. Thereafter, six or more cycles of chemotherapy and a second-look laparotomy were planned. We compared this group’s clinical course with that of two control groups matched with the study patients according to FIG0 stage, histologic type and grade, and patient age at diagnosis ( + 5 years). All patients received cisplatin-based chemotherapy for a planned minimum of six cycles (Fig. 1). The first control group (Group B) consisted of 22 patients who had undergone an initial laparotomy and suboptimal cytoreduction, leaving bulky residual disease greater than 2 cm. Cisplatin-based chemotherapy was planned for a minimum of six cycles, to be followed by a second-look laparotomy. The second control group (Group C) consisted of 18 patients (four study patients could not be matched) who, like the patients of the study group, were referred to M. D. Anderson Cancer Center after undergoing an initial laparotomy and biopsy at an outside hospital. These patients underwent immediate reexploration in the hope of achieving more complete cytoreduction. Cisplatinbased chemotherapy was then planned for a minimum of six cycles to be followed by a second-look laparotomy. Laparotomies at M. D. Anderson Cancer Center were performed through a vertical midline incision and, in most instances, included abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Cytoreduction was accomplished to the maximum extent deemed safe by the attending surgeon. Optimal debulking was defined as having no residual tumor greater than 2 cm in diameter.

Second-look laparotomy was performed at the completion of the planned number of chemotherapy cycles for patients who had no clinical evidence of disease. Chemotherapy for all patients consisted of a cisplatinbased regimen administered at 4-week intervals. The dose of cisplatin per cycle for each patient was within the range of 50-60 mg/m*. For patients in Group A, interval debulking was performed 4 to 6 weeks after the last of two to four initial chemotherapy cycles; chemotherapy was then resumed 1-2 weeks after the interval debulking. A clinical complete response was defined as the complete disappearance of initially measurable disease for at least 1 month. A clinical partial response was defined as at least a 50% reduction in the sum of the products of perpendicular diameters of initially measurable disease for at least 1 month. No response was defined as stable disease (less than a 25% increase in measurable tumor) or progressive disease (25% or greater increase in measurable tumor). A surgicopathologic complete response was defined as the absence of gross and microscopic tumor at secondlook laparotomy. A surgicopathologic partial response was defined as a 50% or greater reduction in the sum of the products of the perpendicular diameters of measurable lesions at second-look laparotomy as compared with the measurement of residual tumor after initial cytoreductive surgery. Survival rates were analyzed using the life-table methods of Berkson and Gage [lo]. Assessments of statistical significance were made using the Lee-Desu statistic [ll]. RESULTS Characteristics of the patients in the three groups are shown in Table 1. As noted, papillary serous carcinoma

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JACOB ET AL.

TABLE 1 Patient Characteristics Characteristics Median age (years) FIG0 stage III IV Histologic grade 2 3 Histologic type Serous Chemotherapy regimen” DDP/CTX DDP/ADR/CTX DDP/ADR DDP/ALK DDP/HMM/CTX DDP/ALK/HMM/ADR/CTX No. chemotherapy cycles Mean Range

TABLE 3 SurgicopathologicResponseto Chemotherapy

Group A

Group B

Group C

58.5

56.5

56.5

18 4

18 4

16 2

6 16

6 16

5 13

22

22

18

16 4 0 2 0 0

11 10 1 0 0 0

6 0 0 8 1 3

2.8/5.5’ 24/l-11*

7.0 5-12

5.7 3-12

” Abbreviations: DDP, cisplatin; CTX, cyclophosphamide; doxorubicin; ALK, melphalan; HMM, hexamethylmelamine. ’ Before/after interval debulking surgery.

ADR,

was the only histologic type represented in this study. Several different cisplatin-based chemotherapy regimens were employed, with the majority of patients receiving the combination of cisplatin and cyclophosphamide. Group A patients received 2 to 4 cycles (mean, 2.8) before the interval debulking procedure and from 1 to 11 cycles (mean, 5.5) afterward. Group B patients received from 5 to 12 cycles (mean, 7.0) after initial debulking surgery, and Group C patients received from 3 to 12 cycles after reexploration (mean, 5.7). The interval debulking procedure after neoadjuvant chemotherapy left 17 of 22 patients (77%) in Group A with residual disease of less than 2 cm. Immediate reexploration of patients in Group C resulted in residual disease of less than 2 cm in only 7 of the 18 (39%). This difference was statistically significant (P = 0.02). TABLE 2 Clinical Responseto Chemotherapy Group A Response status Complete response Partial response No response No measurable disease a Abbreviations:

Pre-IDS

Post-IDS

Group B

Group C

1 9 10

0 0 3

4 0 5

1 0 6

2

19

13

11

IDS, interval debulking surgery.

Response Complete response Partial response No response No second-look

Group A

Group B

Group C

2 1 4 15

0 8 10 4

1 1 6 10

Intraoperative blood loss exceeding 2 liters occurred in 31% of Group A patients as compared with 44% of Group C patients. Incidental cystotomy occurred in one patient in each of these two groups. There were no injuries to the gastrointestinal tract in either group. Prolonged ileus was the most common postoperative complication in both groups, occurring in three (14%) of the patients in Group A and three (17%) of those in Group C. One patient in each of these two groups had postoperative pneumonia, and one patient in Group A developed a stress gastric ulcer after interval debulking. Two additional patients in Group C experienced other complications: postoperative hemorrhage exceeding 2 liters in one and exacerbation of chronic pulmonary disease necessitating ventilatory support in the other. Clinical response to chemotherapy was assessed in patients with measurable disease (Table 2). Of 20 patients in Group A who had measurable disease before receiving neoadjuvant chemotherapy, 1 (5%) had a complete response and 9 (45%) had a partial response. Among the 3 patients in this group whose measurable disease persisted after interval debulking, none had a response to postoperative chemotherapy. Four of nine patients (44%) in Group B who had measurable disease had a complete response to chemotherapy. One of seven patients (14%) who had measurable disease in Group C had a complete response. In addition, among the patients without measurable disease, clinical progression during chemotherapy was observed in 11 of 19 patients in Group A (postinterval debulking), in none of 13 in Group B, and in 4 of 11 in Group C. Table 3 summarizes the surgicopathologic response data. Fifteen patients in Group A, four in Group B, and ten in Group C did not undergo a second-look laparotomy. Among those who did, complete surgicopathologic responses were identified in two patients (9%) in Group A, in none in Group B, and in one patient (6%) in Group C. Partial surgicopathologic responses occurred in one patient (5%) in Group A, in eight (36%) in Group B, and in one (6%) in Group C. Comparing the survival data of the three groups revealed no statistically significant differences (P = 0.58). The median survival time was 16.0 months for patients in Group A, 19.3 months for those in Group B, and 18.0

INTERVAL

DEBULKING

months for those in Group C. Although no statistically significant differences in survival results among the three groups were found, an examination of 95% confidence intervals for the proportion surviving at 24 months indicates that substantial differences cannot be rejected. Therefore, clinically meaningful differences may not have been detected because of the small sample size. Within Group A, patients who were optimally debulked at the interval procedure had a median survival time significantly longer than that of those who were not (18.1 vs 7.5 months; P = 0.02). Within Group C, optimal cytoreduction at immediate reexploration had no influence on median survival time (17.3 vs 18.6 months; P = 0.89). Furthermore, when optimally debulked patients in Group A were compared with those in Group C, the median survival times were not different. At the time of analysis, one patient each in Groups A and B was alive with disease. One patient in Group A has been lost to follow-up. All others have succumbed to their cancer.

DISCUSSION The role of primary cytoreductive surgery in the therapy for epithelial ovarian cancer and its relative safety seem firmly established [12,13]. Information in the literature regarding the role of neoadjuvant chemotherapy plus interval debulking as treatment of advanced disease is scant, however. We first became interested in this treatment strategy in the late 1970s when faced with the problem of how to treat a patient referred to our institution after undergoing a laparotomy and biopsy only because of presumed tumor unresectability. We reasoned that, on the one hand, immediate reexploration might incur the wrath of the referring physician, further compromise an already debilitated patient, and ultimately accomplish no greater cytoreduction; it would also even further delay initiation of chemotherapy. On the other hand, chemotherapy before an interval debulking might violate time-honored principles of therapy and potentially compromise curability. In 1972, Griffiths and associates [2] reported their experience with nine patients who received neoadjuvant chemotherapy with doxorubicin and cyclophosphamide before undergoing a definitive attempt at debulking. In each instance the referring surgeon had performed a laparotomy and staged the tumor, but judged it to be unresectable. In seven of the nine (78%), the authors were able to debulk the tumor to less than 1 cm residual. Median survival time for these nine patients at the time of the report was 6+ months, considerably less than the median survival time of 18 + months for 15 patients who,

SURGERY

149

during the same period, underwent primary debulking surgery and postoperative chemotherapy. There seems to have been little further information published on this approach until other reports of its use began to appear in the late 1980s. Wils et al. [14] described a similar strategy employed in a Dutch cooperative-group study. Their study involved 88 previously untreated patients with advanced epithelial cancer whom they treated with a combination of cisplatin, doxorubicin, and cyclophosphamide. Optimal debulking (residual not greater than 1.5 cm) at primary surgery could not be accomplished in 50 of the 88 patients but was achieved in 38. Comparison of the two groups showed a negative secondlook rate of only 20% for those suboptimally debulked vs 70% for those with optimal surgical results; the respective actuarial survival rates at 3 years were 25% vs 60%. A select subgroup of these 50 patients, however, had a much more favorable prognosis. In 17 who were evaluable, response to a median of three cycles of chemotherapy (range, two to six) made secondary optimal debulking surgery possible. These patients had a negative second-look rate of 29% and an actuarial survival rate at 3 years of 50%, which approached the rate of the patients whose initial cytoreductive attempt was successful. Neijt et al. [15], as part of a multicenter prospective randomized trial comparing the combination of cisplatin, hexamethylmelamine, doxorubicin, and cyclophosphamide with the cisplatin/cyclophosphamide regimen, described 47 patients who underwent neoadjuvant chemotherapy and interval debulking. In 63% of these patients, the resultant residual disease was less than 1 cm. Unfortunately, their survival time was no better than that of patients whose interval debulking was unsuccessful. Furthermore, patients whose tumors measured less than 1 cm before chemotherapy survived significantly longer than those whose tumors were debulked to less than 1 cm at the interval procedure. In 1989, Lawton and colleagues [16] reported on 28 patients with bulky residual disease following an initial suboptimal debulking procedure. After three cycles of cisplatin-based chemotherapy, tumors in 89% of these patients could be optimally debulked to less than 2 cm. Morbidity was minimal. In a subsequent study [17], the same group reported that 68 patients whose residual disease was greater than 2 cm after a primary debulking attempt were randomized to receive either chemotherapy alone or chemotherapy combined with interval debulking surgery that was performed after one to three cycles of chemotherapy. Twenty-eight patients actually underwent the interval surgery, which optimally debulked the tumors of 18 (64%). The survival times of this group were not significantly different from those of patients with bulky residual disease treated with chemotherapy alone. Unlike other investigators [2,14,15], we made no at-

150

JACOB ET AL.

tempt to compare survival rates of patients who had optimal interval debulking with those of patients whose primary surgery alone achieved optimal cytoreduction. We chose a retrospective matched-control study design to analyze our experience. On the basis of our findings and those of virtually all previous reports, it appears that an interval debulking procedure after neoadjuvant cisplatinbased chemotherapy is feasible and may result in optimal cytoreduction for the majority of patients. The morbidity of the procedure is acceptable. With currently available therapy, however, the prognosis of patients with bulky disease following primary surgery remains uniformly poor, regardless of subsequent surgical intervention. For the gynecological oncologist caring for patients with advanced epithelial ovarian cancer who are referred after an unsuccessful attempt at primary debulking, there appears to be no unequivocal best option. Treatment should be individualized depending on several factors, including the patient’s general condition and the preferences of the patient, the referring physician, and the gynecologic oncologist. REFERENCES 1. Griffiths, C. T. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma, Nutl. Cancer Inst. Monogr. 42, 101-103 (1975). 2. Griffiths, C. T., Parker, L. M., and Fuller, A. F. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer, Cancer Treat. Rep. 63, 235-240 (1979). 3. Wharton, J. T., and Herson, J. Surgery for common epithelial tumors of the ovary, Cancer 48, 582-589 (1981). 4. Delgado, G., Oram, D. H., and Petrilli, E. S. Stage III epithelial ovarian cancer: The role of maximal surgical reduction, Gynecol. Oncol. 18, 293-298 (1984). 5. Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K., and Elashoff, R. M. Primary cytoreductive surgery for epithelial ovarian cancer, Obstet. Gynecol. 61, 413-420 (1983). 6. Wharton, J. T., Edwards, C. L., and Rutledge, F. N. Long-term survival after chemotherapy for advanced epithelial ovarian cancer, Am. J. Obstet. Gynecol. 148, 997-1005 (1984).

7. Gallion, H. H., van Nagel, J. R., Donaldson, E. S., Hanson, M. B., and Kryscio, R. J. Prognostic implications of large volume residual disease in patients with advanced stage epithelial ovarian cancer, Gynecol. Oncol. 27, 220-225 (1987). 8. Serov, S. F., Scully, R. E., and Sobin, L. J. Histological typing of ovarian tumors, in International histological classification of tumors, World Health Organization, Geneva, Switzerland (1973). 9. Day, T. G., Gallager, H. S., and Rutledge, F. N. Epithelial carcinoma of the ovary: Prognostic importance of histologic grade, Natl. Cancer Inst. Monogr. 42, 15-18 (1975). 10. Berkson, J., and Gage, R. P. Survival for cancer patients following treatment, 1. Am. Statist. Assoc. 247, 501-515 (1952). 11. Hull, C. H., and Nie, N. H. SPSS Update 7-9, new procedures and facilities for releases 7-9, McGraw-Hill, New York, Version 9 (1981). 12. Chen, S. S., and Bockner, R. Assessment of morbidity and mortality in primary cytoreductive surgery for advanced ovarian carcinoma, Gynecol. Oncol. 20, 190-195 (1985). 13. Heintz, A. P. M., Hacker, N. F., Berek, J. S., Rose, T. P., Munoz, A. K., and Lagasse, L. Cytoreductive surgery in ovarian carcinoma: Feasibility and morbidity, Obstet. Gynecol. 67, 783-788 (1986). 14. Wils, J., Blijham, G., Naus, A., Belder, C., Boscham, F., Bron, H., Ceelen, Th., Eekhout, A., Erp, J. v., Geelen, P., Geuns, H. v., Haest, J., Hoogland, H., Hiuskes, J., De Koning Gans, H., Kornman, J., Kruyver, G., Lalisang, F., Meulen, J. v. d., Moorman, P., de Pree, N., Stoot, J., Tushuizen, P., Vreeswijk, J., Wals, J., Wetzels, L., and Willebrand, D. Primary or delayed debulking surgery and chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide in stage III-IV epithelial ovarian carcinoma, J. Clin. Oncol. 4, 1068-1073 (1986). 15. Neijt, J. P., ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Willemse, P. H. B., Heintz, A. P. M., van Lent, M., Trimbos, J. B., Bouma, J., Vermorken, J. B., and van Houwelingen, J. C. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma, J. Clin. Oncol. 5, 1157-1168 (1987). 16. Lawton, F. G., Redman, C. W. E., Luesley, D. M., Chan, K. K., and Blackledge, G. Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced, unresected epithelial ovarian cancer, Obstet. Gynecol. 73,6165 (1989). 17. Varma, R., Redman, C. W. E., Blackledge, G., Luesley, D., Chan, K. K., Mould, J., Hull, J., and Lawton, F. Early second surgery in bulky epithelial ovarian cancer (EOC) does not improve survival: Results of a randomized study (Abstract), in Proceedings, Second meeting Ontario,

of the International October 1989, p.

Gynecologic

29.

Cancer

Society,

Toronto,