GYNECOLOGIC ONCOLOGY 34, 334-338 (1989)

Secondary Cytoreductive Surgery for Recurrent Epithelial Ovarian Cancer’

MITCHELL MORRIS, M.D. ,’ DAVID M. GERSHENSON, M.D., J. TAYLOR WHARTON, M.D., LARRY J. COPELAND, M.D., CREIGHTON L. EDWARDS, M.D., AND C. ALLEN STRINGER, M.D.

Department of Gynecology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 67, Houston, Texas 77030

Received November 21, 1988

Thirty patients with recurrent epithelial ovarian carcinoma who underwent secondary tumor-reductive surgery at M. D. Anderson Cancer Center were studied retrospectively. All had been initially treated by primary reductive surgery and postoperative chemo- therapy and had a period of clinical remission of at least 6 months thereafter. Ninety percent of patients had grade 2 or 3 tumors. In 17 (57%), residual tumor volume was reduced to less than 2 cm. There were no postoperative deaths, but 40% of patients suffered postoperative morbidity, mostly prolonged ileus. Median survival after second surgery was 16.3-18 months for patients with residual tumor volume less than 2 cm and 13.3 months for those with residual volume greater than 2 cm (nonsignificant). When the second surgery followed the first by less than 18 months, survival was a median of 13.5 months after the second operation as compared with 19 months when the interval was 18 months or longer (nonsignificant). Twenty-two patients received post- surgical chemotherapy; only 11% of those who were evaluable responded. Although secondary tumor-reductive surgery for re- current ovarian cancer is technically feasible, in the absence of an efficacious second-line medical therapy, its value is limited. 8 1989 Academic F’ms, Inc.

INTRODUCTION

The initial management of epithelial ovarian cancer has become relatively standardized in the last decade. Pri- mary surgery includes an aggressive cytoreductive effort, the goal of which is to leave the patient with the least amount of residual tumor possible [l-4]. This is followed by systemic cisplatin-based combination chemotherapy and, if the patient then has no clinical evidence of dis-

’ Presented at the annual meeting of the Society of Gynecologic Oncologists, Maui, Hawaii, February 5-9, 1989.

’ To whom correspondence should be sent. Supported by American Cancer Society Award 86-529.

ease, a second-look laparotomy [5,6]. Despite a good initial response to therapy, however, many patients ul- timately relapse [7], and treatment of recurrent ovarian cancer remains poorly defined. The absence of an effi- cacious second-line therapy and the clinical heteroge- neity of the patient population are reflected in the wide variety of treatment modalities employed.

Secondary cytoreductive surgery is sometimes per- formed for patients with persistent or recurrent ovarian carcinoma as an accessory to second-line medical ther- apy. Its role, however, is unclear: Does secondary tumor reduction have the same therapeutic benefit as primary reductive surgery? Does residual tumor size affect re- sponse to medical therapy a second time? Published stud- ies [8-141, reporting small numbers of patients and a wide variety of treatment courses, are inconclusive.

Patients who undergo secondary cytoreductive surgery can be grouped according to their clinical presentation: (1) patients who have undergone primary cytoreduction and, while receiving first-line chemotherapy, are clini- cally noted to have stable or progressive disease; (2) patients who have had a disease-free interval after pri- mary therapy and subsequently develop recurrent dis- ease; and (3) patients who have no clinically evident disease after chemotherapy, but at the time of a second- look laparotomy are found to have persistent disease.

The purpose of this study is to evaluate the experience at The University of Texas M. D. Anderson Cancer Cen- ter with secondary cytoreductive surgery for patients in the second of these three categories, that is, those with epithelial ovarian cancer who enjoyed a clinical remis- sion after primary therapy and were subsequently dis- covered to have recurrent disease. The technical feasi- bility of the procedure and subsequent response to second-line medical therapy are discussed.

0090-8258/89 $1.50 Copyright 8 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

334

SECONDSURGERYFORRECURRENTOVARIANCANCER 335

PATIENTS AND METHODS

Between January 1,1977, and December 31,1984,1572 patients presented to M. D. Anderson Cancer Center with epithelial cancer of the ovary. Retrospective review identified 115 patients in this category who underwent secondary cytoreductive surgery at this institution. Eighty-five of these patients received a secondary de- bulking at second-look laparotomy or while progressing on chemotherapy. The other 30 patients had a disease- free interval of 6 months or longer after primary therapy and then, when disease recurred, underwent secondary cytoreductive surgery. These 30 are the subject of this report.

The median patient age at diagnosis was 50 years (range, 20-73 years). The majority of patients had ad- vanced disease; only 4 (13.3%) were classified as stage I by the International Federation of Gynecology and Ob- stetrics criteria. Ninety percent of the tumors were grade 2 or 3, 3.3% were grade 1, and 6.7% were ungraded. None of the tumors was of low malignant potential. The histologic types were serous (46.7%), clear cell (16.7%), poorly differentiated (lo%), and endometrioid (6.7%); the remainder (19.9%) were tumors of mixed histologic types.

The primary surgery for 26 patients was performed at an outside institution, but all 30 patients underwent sec- ondary cytoreduction at M. D. Anderson Cancer Center. Accurate information regarding the primary reduction was available for 16 patients. Six had no gross residual tumor after primary surgery, 6 patients had less than 2 cm residual tumor, and 4 had more than 2 cm residual tumor or plaque disease remaining. For 14 patients, re- liable information regarding tumor remaining after pri- mary surgery was not available.

All patients received chemotherapy after primary sur- gery. Seven patients were treated with a cisplatin-based regimen, 11 with a noncisplatin combination, and 12 with melphalan alone. Eleven patients underwent second-look surgery, which showed 2 patients with microscopic dis- ease and 9 with negative biopsies.

The median interval from primary to secondary sur- gery was 42.5 months (range, 6-125 months). Secondary surgery was often quite radical, attempting to resect as much tumor as was technically feasible. The most com- mon procedure (in 17 patients) was tumor debulking- removal of tumor mass(es) without removal of adjacent structures. Thirteen patients underwent a partial colon resection, 8 underwent small bowel resection, and re- sidual omentum was removed from 10 patients. A re- maining ovary was removed from three patients, 3 under- went hysterectomy, one had a pelvic exenteration, and a partial resection of liver and lung was performed in one. Four patients underwent a lymph node dissection,

2 underwent peritoneal stripping, and 2 had a partial resection of the urinary tract. The volume and extent of any tumor remaining following secondary surgery were carefully documented, the former by measuring in cen- timeters the two greatest diameters and the latter by assessing the involvement of other organs or peritoneal surfaces.

Survival was calculated using the Berkson-Gage life- table analysis. Other assessments of statistical signifi- cance were made using the Lee-Desu statistic [151.

RESULTS

Following secondary cytoreductive surgery, 9 patients had no gross residual tumor. Residual tumor in 4 was <l cm; in another 4 patients, 2 1 cm but <2 cm; and in 6 patients, 22 cm. Seven patients had residual plaques of tumor. Thus, optimal debulking, defined as residual tumor of less than 2 cm, was achieved in 57% of patients who underwent secondary cytoreduction. The reasons for suboptimal debulking included parenchymal liver in- volvement (2 patients), extensive intestinal involvement (2 patients), extensive infiltrating bulk disease (1 patient), and unstable medical condition (1 patient). The seven patients with residual tumor plaques had no individual nodules with a diameter greater than 2 cm, but instead had confluent plaques of tumor covering peritoneal or intestinal surfaces that were not resectable. These pa- tients were considered to be suboptimally debulked.

There were two intraoperative complications. One pa- tient suffered a cardiac arrest during the procedure and was successfully resuscitated. The other patient had a ureteral injury that was repaired. Mean operative time was 261 min (range, 70-480 min). The median operative blood loss was 892 ml (range 50-6000 ml), and a median of 2.4 units of blood was replaced intraoperatively.

There were no postoperative deaths. Eleven patients (36.7%) had postoperative morbidity, most commonly prolonged ileus (7 patients). Two patients had febrile morbidity of unknown etiology. Myocardial infarction, fungal sepsis, and an enterocutaneous fistula developed in one patient each. Intravenous hyperalimentation was given to 11 patients postoperatively.

Following secondary surgery, 27 of the 30 patients received some type of second-line medical therapy: 22 received chemotherapy, 3 underwent whole-abdomen ra- diation therapy, and 2 were treated with hormones. The results of second-line chemotherapy were disappointing. Two patients (9%) had a partial response, 15 patients (68%) had progressive disease, 1 patient (5%) had stable disease, and 4 patients (18%) were not evaluable. Among 13 patients who received a combination containing cis- platin, disease progressed in all but one patient who showed a partial response. No patient with evaluable

336 MORRIS ET AL.

disease responded to abdominal radiation or hormonal manipulation.

For the entire group the median time of survival from diagnosis was 62 months; however, median survival from the time of secondary cytoreduction was only 16.3 months. At the time of analysis, one patient had been lost to follow-up and one was alive with disease 23 months after secondary surgery. Three patients were alive with no evidence of disease at 24, 38, and 45 months, respectively, following secondary cytoreduc- tion. All three had no gross residual tumor at the com- pletion of secondary surgery. Two received postsurgical whole-abdomen radiation therapy and one declined fur- ther treatment.

Patients who had residual tumor less than 2 cm after secondary cytoreduction survived a median of 18 months (Fig. l), while patients with remaining tumor 2 cm or greater or with plaque disease survived a median of 13.3 months (P not significant). When the interval between primary and secondary surgery was 18 months or longer, patients survived a median of 19 months after the second operation (Fig. 2). When the interval between surgeries was less than 18 months, patients survived 13.5 months after the secondary surgery (P not significant). Those patients who previously had received a “negative” sec- ond-look laparotomy did not differ with respect to time of survival or response to subsequent therapy from those who had either no second-look or had residual tumor found at second-look.

DISCUSSION

Cytoreductive surgery has become a well-accepted tenet in the treatment of epithelial cancer of the ovary. Numerous investigators have documented improved re- sponses to chemotherapy and prolonged survivals for patients who residual tumor is less than 2.0 cm at the completion of primary surgery [l-4]. Whether the results reflect the skills of the surgical team or merely the in- herent biology of the tumor remains unclear. For the patient with progressive or recurrent ovarian cancer, the role of surgical debulking is even more questionable. Few studies exist in the literature concerning secondary cy- toreductive surgery. What reports there are usually de- scribe small numbers of patients with a wide variety of clinical presentations [g-14]. Most often, the patients reported as having secondary cytoreductive surgery were actually undergoing a second-look laparotomy. Many had not received primary cytoreductive surgery and would more accurately be described as undergoing an interval tumor debulking after initial chemotherapy.

Vogl and associates [14], for example, described what they considered to be “second-effort” surgery in patients with advanced ovarian cancer. All 18 patients had more

<2cm >2cm

0 1.0

Mczhs

3.0 4.0

FIG. 1. Survival from the time of secondary tumor reduction based on residual tumor size. The squares (17 patients) indicate a maximum residual tumor volume less than <2 cm; the diamonds (13 patients) indicate residual disease of 2 cm or greater (P < 0.2).

than 2 cm tumor remaining after primary surgery and received six courses of combination chemotherapy con- taining cisplatin. A second-look laparotomy was then performed with the goal of additional cytoreduction if residual tumor were present. Significant residual tumor was found in 12 patients, but only one of these could be optimally resected. The authors concluded that “second- effort” surgery in women with bulky ovarian cancer was not likely to be of benefit.

In a similar report, Raju and co-workers [13] set out to perform a “debulking procedure” at the time of sec- ond-look laparotomy. Their 65 patients had undergone treatment with cisplatin alone or combined with other agents and had demonstrated tumor regression clinically.

<18 months a18 months

FIG. 2. Survival from the time of secondary tumor reduction ac- cording to the interval between primary tumor reduction and secondary tumor reduction. The squares (5 patients) indicate an interval shorter than 18 months; the diamonds (13 patients) indicate an interval 18 months or longer (P < 0.1).

SECONDSURGERYFORRECURRENTOVARIANCANCER 337

The majority of these patients had not undergone an aggressive primary debulking procedure, and at second- look, residual disease was able to be debulked in only 18%. The authors observed that the survival expectancy of the patients who were able to undergo further tumor reduction was no better than that of the patients whose residual tumor was still present after second-look. They concluded that interval debulking did not seem to lengthen survival.

Podratz and associates [lo] came to the opposite con- clusion when they examined pathologic variables after a second-look laparotomy during which they aggressively attempted to reduce further any remaining tumor. They observed that patients who were left with less than 1 cm residual tumor survived significantly longer than those with more than 1 cm remaining tumor. These patients were treated with a variety of second-line therapies which may have affected their survival durations. The authors stressed that, although secondary cytoreduction may be beneficial for certain groups of patients, only the development of an efficacious second-line medical ther- apy would significantly alter the outcome of patients with persistent disease identified at second-look laparotomy.

In a frequently cited review, Berek and associates [8] examined the outcome of 32 patients who underwent secondary cytoreductive surgery. Their group included patients treated at second-look laparotomy, those who were progressing on chemotherapy, and those with re- current tumor after a disease-free interval. They con- cluded that patients with minimal residual disease after secondary surgery and those who had a long interval between primary and secondary surgery might benefit from an aggressive second surgical effort. Most of the patients who did well, however, were clinically free of disease at the time of secondary surgery, that is, they underwent secondary reduction at second-look laparot- omy. The outcome of patients with progressive disease could not be separated from the outcome of those with remission and subsequent recurrence.

A review of patients from M. D. Anderson Cancer Center [16] who had progressive disease while on first- line chemotherapy and then underwent secondary cy- toreduction showed little benefit for the majority. Except for a small group (21%) whose residual tumor was re- duced to less than 1 cm, patients had a morbid post- operative course and short survival. This finding was not unexpected as there is little hope of salvaging patients who do not respond to first-line medical therapy. Alter- natively, patients who initially had a good response to first-line treatment followed by a period of clinical re- mission might be expected to have a better chance of a second response.

The present study reviews the outcome of patients who

enjoyed a disease-free interval after primary therapy and then underwent a secondary cytoreductive effort at the time of recurrence. The second surgery was technically successful in the majority of patients: 57% had under 2 cm tumor remaining after the procedure. The surgery, although very aggressive in nature, was well tolerated; only three patients showed serious morbidity. Despite the surgical success, however, response to second-line therapy was poor. Since many of the patients had not received cisplatin as a first-line treatment, we believed that a cisplatin combination regimen after secondary cy- toreduction might lengthen their survival time. Unfor- tunately the response to second-line cisplatin was under 10%.

Although this study and others have shown that sec- ondary cytoreductive procedures can be performed with success, the problem of what treatment to use after the surgery remains. The lack of an effective medical salvage therapy negates any potential benefit from cytoreduction. Recently, intraperitoneal chemotherapy has been shown to have some efficacy when residual disease at the time of second-look laparotomy is minimal [ 171. The use of intraperitoneal treatment for recurrent disease, however, is poorly defined. Certain investigational drugs and bi- ological agents may prove to have greater efficacy in the patient with minimal residual tumor, but as of yet none has been very promising as a salvage treatment.

This review, like other retrospective studies, is limited by the heterogeneity of the patient population and the variety of second-line medical therapies given. Never- theless, one can conclude that secondary cytoreductive surgery probably offers little benefit to patients with re- current disease. These procedures should be carefully individualized and probably limited to patients who are candidates for investigational salvage protocols. The de- bate over the effectiveness of secondary cytoreductive surgery will only be resolved by a prospective random- ized trial in conjunction with a proven second-line med- ical therapy.

REFERENCES

Griffiths, C. T. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma, Nutl. Cancer Institute Monogr. 42, 101-104 (1975). Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K., and Elashoff, R. M. Primary cytoreductive surgery for epithelial ovar- ian cancer, Obstet. Gynecof. 61, 413-420 (1983). 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). Munnell, E. W. The changing prognosis and treatment in cancer of the ovary, Amer. J. Obstet. Gynecol. 100, 790-805 (1968).

338 MORRIS ET AL.

5. Gershenson, D. M., Copeland, L. J., Wharton, J. T., Atkinson, E. N., Sneige, N., Edwards, C. L., and Rutledge, F. N. Prognosis of surgically determined complete responders in advanced ovarian cancer, Cancer 55, 1129-l 135 (1985).

6. Phibbs, G. D., Smith, J. P., and Stanhope, C. R. Analysis of sites of persistent cancer at “second-look” laparotomy in patients with ovarian cancer, Amer. J. Obstet. Gynecol. 147, 611-617 (1983).

7. Copeland, L. J., and Gershenson, D. M. Ovarian cancer recur- rence in patients with no macroscopic tumor at second-look lapa- rotomy, Obstet. Gynecol. 68, 873-874 (1986).

8. Berek, J. S., Hacker, N. F., Lagasse, L. D., Nieberg, R. K., and Elashoff, R. M. Survival of patients following secondary cytore- ductive surgery in ovarian cancer, Obstet. Gynecol. 61, 189-193 (1983).

9. Wiltshaw, E., Raju, K. S., and Dawson, I. The role of cytore- ductive surgery in advanced carcinoma of the ovary: An analysis of primary and second surgery, Brit. J. Obstet. Gynaecol. 92,522- 527 (1985).

10. Podratz, K. C., Malkasian, G. D., Jr., Hilton, J. F., Harris, E. A., and Gaffey, T. A. Second-look laparotomy in ovarian cancers: Evaluation of pathologic variables, Amer. J. Obstet. Gynecol. 152, 230-238 (1985).

11. Joyeux, H., Szawlowski, A. W., Saint-Aubert, B., Elashary,

M. M., Solassol, C., and Pujol, H. Aggressive regional surgery for advanced ovarian carcinoma, Cancer 57, 142-147 (1986).

12. Phillips, B. P., Buchsbaum, H. J., and Litshitz, S. Reexploration after treatment for ovarian carcinoma, Gynecol. Oncol. 8, 339-345 (1979).

13. Raju, K. S., Mukinna, J. A., Barker, G. H., Wiltshaw, E., and Jones, J. M. Second-look operations in the planned management of advanced ovarian carcinoma, Amer. J. Obstet. Gynecol. 144, 650-654 (1982).

14. Vogl, S. E., Seltzer, V., Calanog, A., Moukhtar, M., Camacho, F., Kaplan, B., and Greenwald, E. “Second-effort” surgical resection for bulky ovarian cancer, Cancer 54, 2220-2225 (1984).

15. SPSS-X: Statistical package for the social sciences, 3rd ed., McGraw-Hill, New York (1988).

16. Morris, M., Gershenson, D. M., and Wharton, J. T. Secondary cytoreductive surgery in epithelial ovarian cancer: Nonrespondent to first line-therapy, Gynecol. Oncol. 33, l-5 (1989).

17. Howell, S. B., Zimm, S., Markman, M., Abramson, I. S., Cleary, S., Lucas, W. E., and Weiss, R. J. Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy, J. Clin. Oncol. 5, 1607-1612 (1987).