Second-look laparotomy in ovarian cancer

GYNECOLOGIC

ONCOLOGY

14, 285-293 (1982)

Second-Look Laparotomy in Ovarian Cancer MAURICE

J. WEBB, M.D., JAMES A. SNYDER, JR., M.D., TIFFANY J. WILLIAMS, M.D.,’ AND DAVID G. DECKER, M.D.

Department

of Obstetrics

and Gynecology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Received December 28, 1981

Second-look laparotomy is confined to patients who have no evidence of disease after appropriate chemotherapy and is recommended in an attempt to determine the need for further treatment. This study involved 59 patients who had previous appropriate surgery for ovarian cancer and had subsequent treatment, with no further clinical evidence of disease. Despite this, 32 (54%) patients had residual malignancy; most were patients with stage III and IV disease. Conversely, patients with grade 1 tumors had a higher proportion of negative findings (71%). The amount of disease remaining after initial surgery correlated well with the second-look findings. Although there have been no major complications, 4 of the 32 patients with “negative” second-look operations subsequently suffered recurrence. However, the survival rates were significant. At 4 years, the survival of patients who had negative second-look operations was 86% compared with 53% for patients who had malignancy diagnosed at second-look operations.

During the last decade, the second-look operation has gained wide acceptance in the management of ovarian cancer. However, in reports on this procedure, the term “second-look laparotomy” is used to describe a wide variety of procedures, including completion of an inadequate initial operation; debulking a mass of tumor after chemotherapeutic treatment; restaging when insufficient information was obtained from the initial operation; and repeat laparotomy in patients with no evidence of disease in order to define the presence or absence of residual neoplasm accurately. The purpose of this paper is to examine a relatively homogeneous group of patients, those who have previously undergone appropriate primary surgical treatment and then either have been observed or have been treated with chemotherapy or radiotherapy for approximately 12 to 18 months and who demonstrate no clinical or laboratory evidence of disease. These patients then underwent repeat laparotomy to ascertain whether disease was or was not present in the peritoneal cavity-and these patients were considered to be undergoing “secondlook laparotomy.” Many other patients with incomplete initial surgery or large ’ To whom all correspondence should be addressed 285 0090-8258/82/060285-09$01.00/O Copyright 0 1982 by Academic Press, Inc. All rights of reproduction in any form reserved.

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masses that required debulking underwent a repeat laparotomy during this period, but by this definition, they are excluded from this report. TECHNIQUE

The operation involves an extensive abdominal-pelvic exploration through an extended midline incision, including collection of peritoneal washings for cytologic study and biopsy specimens of all suspicious areas. In the absence of observable and histologically confirmed (frozen section) residual disease, a systematic biopsy procedure is then followed, including specimens taken from the cul-de-sac, lateral pelvic sidewalls, bladder peritoneum, lateral paracolic gutters, peritoneal surface of the right hemidiaphragm, and high paraaortic lymph nodes. Particular attention is paid to the known sites of residual tumor described at the initial operation. It is not uncommon to obtain 20 to 25 biopsy specimens at each operation. Hysterectomy with omentectomy is performed if this was not done at the original operation. All biopsy specimens initially evaluated by frozen section are subsequently reviewed after permanent fixation before final diagnosis. After completion of the initial operation, and again at the second-look laparotomy, the amount of residual disease is classified as minimal, that is, less than 2 cm in diameter, or maximal, that is, greater than 2 cm in diameter. The underlying purpose of the procedure is to determine if the patient has no disease, and, therefore, the adjunctive treatment can be discontinued, or if disease is still present, whether the treatment should be continued or changed, based on the operative findings and on comparison with the amount of residual disease at the initial operation. MATERIAL

From January 1970 to January 1979, 59 patients underwent second-look laparotomy at the Mayo Clinic. Most of the tumors were of serous cell type (41 patients). There were 20 patients with stage I disease, 10 with stage II, 25 with stage II, and 4 with stage IV (Table 1). Thirty-five patients had low-grade tumors (21 with grade 1 and 14 with grade 2, Broders); 15 had grade 3, and 9 had grade 4 tumors. Fifty-four patients (91.5%) had received chemotherapy after their initial operation, and nine (15%) were treated radiotherapeutically with intraperitoneal radioisotopes. Cyclophosphamide was the most commonly utilized chemotherapeutic agent (Table 2). The median dose during the treatment period was 17,600 mg for cyclophosphamide, 770 mg for doxorubicin, 865 mg for c&platinum, and 590 mg for L-phenylalanine mustard. The median age of the patients was 49 years (range 20 to 73 years), and the median time of hospitalization was 7 days (range 5 to 18 days). RESULTS Operative findings. Of the 59 patients undergoing second-look laparotomy, 32 (54%) had negative findings and 27 (46%) had residual ovarian cancer. In 16 cases, the disease was confirmed by biopsy only, in 1 case by cytologic study only, and in 10 cases by both cytologic study and biopsy.

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1

DISTRIBUTION OF 59 PATIENTS ACCORDING TO STAGE OF OVARIAN CANCER

Number of patients

Stage

20 4

I

Ai Aii

8

Bi Bii C

5 1 2 10 4 4 2 25 4 59

II A B C III IV Total

The most frequent site of residual disease was the cul-de-sac, and the least were the paraaortic nodes and diaphragm (Table 3). Time from definitive surgery. The median time from the original surgery to the second-look laparotomy was 521 days (17 months) for patients with negative findings and 430 days (14 months) for patients with positive findings. This difference was not statistically significant. Of the 59 patients in this series, 52 underwent exploration at least 12 months after the original operation (Table 4). In one of the five patients with a negative second-look procedure done less than 12 months after the initial surgery, recurrent ovarian cancer subsequently developed. Likewise, 3 of the 27 (11%) patients with negative findings who were operated on after a 12-month interim had subsequent recurrence. Initial stage versus second-look findings. Negative findings at second-look procedure correlated well with the stage of disease at the initial operation (Table TABLE 2 CHEMOTHERAPY LAPAROTOMY

PRIOR TO SECOND-LOOK FOR OVARIAN CANCER

Drug Cyclophosphamide L-Phenylalanine mustard Cyclophosphamide + other” Doxorubicin None Other combinations Total

Number of patients 24 13 8 6 5 3 59

’ Six patients with cyclophosphamide and cisplatinum.

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TABLE 3 DISEASE SITES AT SECOND-LOOK LAPAROTOMY FOR OVARIAN CANCER IN 27 PATIENTS

Percentage

Site

24 22 14 12 9 7 2 2

Cul-de-sac Pelvic sidewall Bowel mesentery Bowel serosa Omentum Bladder peritoneum Diaphragm Paraaortic nodes

4). Eighty percent of the patients with stage I cancer had negative findings, compared to 60% of patients with stage II and 34.5% with stages III and IV combined. Tumor grade versus second-look findings. There was a close correlation between tumor grade and findings at the second-look operation. Of patients with negative findings, 71% had grade 1 tumors (Broders), 57% had grade 2, 47% had grade 3, and 22% had grade 4 (Table 4). Amount of initial disease versus second-look findings. Of patients with no disease remaining at their initial surgery, 95% had a negative second-look laparotomy. Ten (36%) of the patients who had minimal disease and two (20%) with maximal disease had no evidence of disease at laparotomy (Table 4.). TABLE 4 SECOND-LOOK FINDINGS RELATED TO TIME FROM DEFINITIVE SURGERY, STAGE AND GRADE OF OVARIAN CANCER, AND AMOUNT OF INITIAL DISEASE

Time from definitive surgery ~12 months a12 months Stage I II III and IV Grade 1 2 3 4 Initial residual disease None Minimal’ Maximal’ UOne patient had recurrence. b Three patients had recurrence. ’ Less than 2 cm in diameter. d More than 2 cm in diameter.

Negative (%)

Positive

Total

5”

2 25

7 52

4 4 19

20 10 29

27’ 16 (80)

6 (60) 10 (34.5) 15 (71) 8 (57) 7 (47)

21 14 15 9

2 (22) 20 (95) 10 (36)

2 (20)

1 18 8

21 28 10

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Amount of initial

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disease versus amount of disease at second-look laparotomy.

The treatment given to the patients after their original operation appeared to have been effective. There were 21 patients who initially had no residual disease, while 32 patients had no residual disease at the second-look procedure (Table 5). Also, of the 10 patients with maximal disease initially, only 4 remained with maximal disease at the second-look procedure. Conversely, only one patient with no initial residual disease had a positive finding at the second-look procedure, and one patient with minimal initial residual disease had maximal disease at second look. Adjunctive chemotherapy. Because of the relatively few patients studied and the multiple chemotherapeutic regimens employed, a significant statement cannot be made concerning the effectiveness of any agent in relation to the second-look findings. There were no positive second-look laparotomies in patients who received a total dose of 700 mg or more of L-phenylalanine mustard or a total dose of 930 mg of cis-platinum. However, the patient who received the highest total dose of cyclophosphamide (64,000 mg) and the patient who received the highest total dose of doxorubicin (1050 mg) both had a positive second-look procedure. Complications of second-look laparotomy. There was no major operative morbidity. Febrile morbidity (temperature more than 38°C during two 24-hr periods, not including the first 24-hr postoperative period) occurred in 30% of patients, wound infection in 3%, urinary infection in 3%, and ileus in 2%. Treatment after positive second-look laparotomy. Of the 27 patients who had positive second-look laparotomy, 12 were subsequently treated by irradiation (intraperitoneal 32P), 8 with additional chemotherapy, and 7 with chemotherapy plus irradiation. The 4-year survival rates for each group were 20, 33, and 66%, respectively, but the differences were not statistically significant. Recurrence after negative second-look laparotomy. Of the 32 patients with negative second-look laparotomy, 4 developed recurrence of ovarian cancer (Table 6). However, one of the four (with stage IC cancer) died shortly after she had a negative evaluation at our institution; “recurrent ovarian cancer” was listed as the cause of death, but no autopsy was performed. Another patient (with stage IAi) had her second-look operation only 6 months after the initial definitive surgery, possibly too early for recurrence to be evident. The remaining two patients had stage IIA and III disease and had no and minimal disease present, respectively, after their initial operation. All four patients had received TABLE

5

INITIAL RESIDUAL DISEASE COMPARED WITH AMOUNT OF DISEASE AT SECOND-LOOK LAPAROTOMY

Initial residual disease Second-look finding None Minimal Maximal Total

None

Minimal

Maximal

Total

20 (95%) 1 0 21

10 (36%) 17 I 28

2 (20%) 4 4 10

32 22 5 59

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TABLE 6 CHARACTERISTICS OF FOUR PATIENTS WITH RECURRENCE AFTER NEGATIVE SECOND-LOOK LAPAROTOMY’

Characteristic Stage IAi IC HA III Residual disease None Minimal Cell type Serous Endometrial Other Grade 2 3 4 Initial chemotherapy Cyclophosphamide Doxorubicin

Number of patients 1 1 1 1 3 1 2 1 1 2 1 1 2 2

’ Thirty-two patients had negative operations.

chemotherapy before their second-look procedure; two had received cyclophosphamide and two doxorubicin. Subsequent surgery. Fifteen patients subsequently underwent a further surgical procedure after the second-look laparotomy, and fourteen of these operations were directly related to the ovarian cancer. Survival. Of the 59 patients, 45 are alive, 12 are dead, and the status of 2 is unknown. Of the 12 patients who died, 9 died of ovarian cancer, 1 died of another cause and had no evidence of ovarian cancer, and 2 died of other causes, with the status of the ovarian cancer unknown. At 5 years, the survival rate for patients with stage I malignancies was 71%, stage II 54%, and stages III and IV combined 47%. The relatively low survival rate for patients with stage I disease undoubtedly reflects the fact that only 4 of the 20 stage I patients had stage IAi disease. When no residual disease was present after the initial operation, the 5-year survival was 95% as compared with 41% if disease remained. The difference between the survival rates according to negative and positive second-look findings was statistically significant (Fig. 1). At 4 years, the survival rate for patients with a negative second-look procedure was 86%, compared with 53% if both biopsy and cytologic study were positive and 35% when cytologic study alone was positive. This apparent contradiction may be explained by the

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0.8

0.8

0.5

1.0

1.5

2.0

2.5

3.0

t = year8 from 2nd look FIG. 1. Survival curves for patients with ovarian cancer according to negative and positive secondlook findings.

fact that when the result of biopsy was positive, the area from which the specimen was taken was widely excised, with all residual tumor being removed if possible, whereas with positive cytologic study alone, the site of the tumor shedding the malignant cells was not discovered. DISCUSSION One of the major problems in the management of ovarian cancer is the lack of accurate ways of detecting recurrence while the cancer is still small and localized. Usually, the disease is widespread by the time a clinically palpable mass is present. That our present methods of detection of recurrence are poor is emphasized by this study, in which 46% of patients with no clinical evidence of disease had metastatic ovarian cancer at second-look laparotomy. However, another difficulty arises when trying to assess the usefulness of second-look laparotomy from reports in the literature. Because the definitions vary widely, results are difficult to compare [l-4]. We believe that the term “second-look laparotomy” should be restricted to those instances in which the patient is clinically free of disease and laparotomy is performed to assess more accurately the presence or absence of cancer. This, after all, is basically what Wangensteen suggested when he first proposed “second look” in the management of gastrointestinal cancers [5,6]. Reoperation soon after inadequate initial surgery or later reoperation in an attempt to debulk known disease is hardly a “look,” as one already knows that tumor is present. In our series, laparoscopy was not used before laparotomy. Laparoscopy should be considered in the management of these patients, although one should

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realize that there are some risks with the procedure and negative findings at laparoscopy do not mean that the patient is free of disease. Reports indicate that from 15 to 29% of patients may have positive findings at laparoscopy and thus be spared the necessity of laparotomy to diagnose persistent disease [7, 81. However, false-negative findings (subsequent laparotomy revealed active cancer) occur in 20 to 50% of patients [g-lo]. This is not unexpected, because the most common site of recurrence is the cul-de-sac and, generally, the bowel is adherent to this area after previous hysterectomy, thus making good visualization impossible. This means that if no evidence of malignancy is found at laparoscopy, a laparotomy is mandatory. It is not unexpected to find that most patients in our series had low-grade tumors. Previous reports from this institution have emphasized the importance of grade in the behavior of ovarian malignancy [ll]. These patients with lowgrade tumors are more likely to remain tumor free clinically for longer periods and hence will be selected for a second-look procedure. They are also more likely to be free of disease at second-look laparotomy. The importance of reducing the tumor cell burden at the original operation has been stressed by many investigators [12-141. The findings at second-look laparotomy in our series bear this out-95% of patients with no residual disease initially had no disease at the second-look procedure, compared with only 20% of patients who were initially left with maximal disease. Also, only two of those patients who had a second-look laparotomy had worse disease than after their initial operation. Other authors also have found that the size of the residual lesion after the initial operation was directly related to the findings at secondlook laparotomy [ 151. Although high paraaortic lymph nodes are always sampled at second-look laparotomy, only on one occasion was an involved node found. This is a lower incidence than that noted in other reports [16], but it indicates that attention must be paid to this area when assessing spread of ovarian cancer [17]. Of some concern are the 16 patients in whom biopsy-proven residual cancer was found but peritoneal cytologic study was negative. Most of these patients had minimal recurrence, and some of the recurrent lesions may have been just beneath the peritonel surface and were not shedding cells into the abdominal cavity. Possibly there are errors in collection or interpretation of the peritoneal fluid. Whatever the cause for this discrepancy, it points out the inaccuracies of relying on cytologic study alone (via laparoscopy or culdocentesis) to prove the presence or absence of disease. Although the concept of second-look laparotomy was proposed many years ago, its use in the management of ovarian cancer is still in its infancy. We do not know what percentage of patients with negative findings are permanently “cured” of their disease. One is particularly concerned about stopping all treatment after a negative second-look procedure in patients who had maximal disease remaining after their initial operation (two patients in our series). However, with concerns regarding long-term alkylating agent chemotherapy, close observation without treatment is justified [ 181.Not much valid information is available about appropriate therapy after a positive second-look laparotomy, but in vitro soft

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agar cloning may prove to be useful in this situation. If disease is still present at the second-look laparotomy, every attempt should be made to excise as much tumor as possible. With the combination of aggressive surgery and aggressive chemotherapy, the behavior of this disease can be affected. REFERENCES 1. Phillips, B. P., Buchsbaum, H. J., and Lifshitz, S. Reexploration after treatment for ovarian carcinoma, Gynecol. Oncol. 8, 339-345 (1979). 2. Wallach, R. C., Kabakow, B., Jerez, E., and Blinick, G. The importance of second-look surgical procedures in the staging and treatment of ovarian carcinoma, Semin. Oncol. 2, 243-246 (1975). 3. Tepper, E., Sanfilippo, L. J., Gray, J., and Romney, S. L. Second look surgery after radiation therapy for advanced stages of cancer of the ovary, Amer. J. Roentgenol. Radium Ther. Nucl. Med. 112, 755-759 (1971).

4. Schwartz, P. E., and Smith, J. P. Second-look operations in ovarian cancer, Amer. J. Obstet. Gynecol.

138, 1124-1130 (1980).

5. Wangensteen, 0. H. Cancer of the colon and rectum: With special reference to (1) earlier recognition of alimentary tract malignancy; (2) secondary delayed re-entry of the abdomen in patients exhibiting lymph node involvement; (3) subtotal primary excision of the colon; (4) operation in obstruction, Wis. Med. J. 48, 591-597 (1949). 6. Arhelger, S. W., Jenson, C. B., and Wangensteen, 0. H. Experiences with the “second-look” procedure in the management of cancer of the colon and rectum: With special reference to site of residual cancer, J. Lancet 77, 412-417 (1957). 7. Mangioni, C., Bolis, G., Molteni, P., and Belloni, C. Indications, advantages, and limits of laparoscopy in ovarian cancer, Gynecol. Oncol. 7, 47-55 (1979). 8. Smith, W. G., Day, T. G., Jr., and Smith, J. P. The use of laparoscopy to determine the results of chemotherapy for ovarian cancer, J. Reprod. Med. 18, 257-260 (1977). 9. Piver, M. S., Lele, S. B., Barlow, J. J., and Gamarra, M. Second-look laparoscopy prior to proposed second-look laparotomy, Obstet. Gynecol. 55, 571-573 (1980). 10. Rosenoff, S. H., DeVita, V. T., Jr., Hubbard, S., and Young, R. C. Peritoneoscopy in the staging and follow-up of ovarian cancer, Semin. Oncol. 2, 223-228 (1975). 11. Decker, D. G., Mussey, E., Williams, T. J., and Taylor, W. F. Grading of gynecologic malignancy: Epithelial ovarian cancer, Proc. Nat. Cancer Corzf 7, 223-231 (1973). 12. Webb, M. J., Malkasian, G. D., Jr., and Jorgensen, E. 0. Factors influencing ovarian cancer survival after chemotherapy, Obstet. Gynecol. 44, 564-570 (1974). 13. Griftiths, C. T. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma, Nat. Cancer Inst. Monogr. 42, 101-104 (1975). 14. Smith, J. P., and Day, T. G., Jr. Review of ovarian cancer at the University of Texas Systems Cancer Center, M. D. Anderson Hospital and Tumor Institute, Amer. J. Obstet. Gynecol. 135, 984-990 (1979).

15. Park, R. C., and Hoskins, W. J. Reoperating to assess ovarian cancer treatment, Contemp. Obstet. Gynecol.

17, 159-166 (1981).

16. Knapp, R. C., and Friedman, E. A. Aortic lymph node metastases in early ovarian cancer, Amer. J. Obstet. Gynecol. 119, 1013-1017 (1974). 17. Creasman, W. T., Abu-Ghazaleh, S., and Schmidt, H. J. Retroperitoneal metastatic spread of ovarian cancer, Gynecol. Oncol. 6, 447-450 (1978). 18. Reimer, R. R., Hoover, R., Fraumeni, J. F., Jr., and Young, R. C. Acute leukemia after alkylating-agent therapy of ovarian cancer, N. Engl. J. Med. 297, 177-181 (1977).