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The second-look celiotomy in ovarian cancer
GYNECOLOGIC
ONCOLOGY
19, 34-45 (1984)
The Second-Look Celiotomy in Ovarian Cancer THOMAS F. ROCERETO, M.D.,“‘, CHARLES E. MANGAN, M.D.,3 ROBERT L. GIUNTOLI, M.D. ,3 THOMAS V. SEDLACEK, M.D., HARRISON J. BALL, M.D. ,4 AND JOHN J. MIKUTA, M.D.’ Department
of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
of
Received May 9, 1983 Thirty-six patients with primary ovarian carcinoma who had 42 second-look procedures performed are reported. Twenty-three patients had no tumor found at the second-look celiotomy and were given no further treatment. Thirteen patients had tumor at the secondlook procedure and were continued on therapy. Six patients have died with disease and all had a positive second-look celiotomy. Two patients have died with leukemia but with no evidence of ovarian cancer, one after a negative second-look and the other a negative third-look. No patient with a negative second-look celiotomy has died with disease. A correlation with respect to the findings at the second-look was found with respect to the stage of disease and the amount of residual tumor at the initial surgery. The use of the second-look celiotomy in patients with disease in the early stages and in patients treated with irradiation is discussed, along with the utilization of the laparoscopy.
Each year approximately 18,000women are diagnosed as having ovarian cancer, and 11,000 die from this disease. Surgery is necessary for the accurate diagnosis and staging of ovarian cancer and for years has been the primary mode of treatment for this tumor. The trend in recent times has been, if possible, to remove all or a large amount of the tumor at the primary operation. The literature does suggest that ovarian cancer patients who have no tumor, or only a small amount of tumor remaining after initial surgery, have a longer period of survival than those patients who have a moderate to large amount of tumor after surgery
~431. It is recognized that almost every patient with epithelial ovarian carcinoma would be given postoperative chemotherapy. Even though some patients can ’ Clinical Fellow, American Cancer Society. 2 Present address: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, UMDNJ/Rutgers Medical School at Camden, Camden, New Jersey and Cooper Hospital/University Medical Center. 3 Junior Faculty Clinical Fellow, American Cancer Society. 4 Present address: Department of Obstetrics and Gynecology, Tufts University Medical School, Boston, Massachusetts 02155. ’ To whom reprint requests should be addressed: 1000 Courtyard Bldg., 3400 Spruce Street, Philadelphia, Pa. 19104. 34 0090-8258184$1SO Copyright All rights
0 1984 by Academic Press, Inc. of reproduction in any form reserved.
SECOND-LOOK
CELIOTOMY
IN
OVARIAN
CANCER
35
tolerate chemotherapy for years, it is felt by many oncologists that the patient who is free of disease may no longer need this therapy. Since being clinically free from disease is not the same as being totally free from disease, the problem arises as to how to decide when to stop the chemotherapy. In 1949, Wangensteen [18] introduced the concept of a “second-look” operation in patients with colon carcinoma. In 1951, Arhelger el al. [l] reported that patients with colorectal cancers who were originally found to have lymph nodes containing tumor and were now asymptomatic and clinically free of disease, were found to have residual cancer at a second-look operation. Santor et al. [ 121used the same plan for the second-look procedure in the management of patients with ovarian malignancies and pseudomyxoma peritonei with some success. Smith et al., [15] have shown that at least 1 year of therapy should be given before a second-look is attempted. METHODS Since July 1974, a second-look celiotomy has been performed on patients being treated for ovarian cancer at the Hospital of the University of Pennsylvania. The purpose of this procedure is (1) to determine the status of tumor in patients who are clinically free from disease and resect tumor which may be present, (2) to resect tumor which was not resectable at the initial operation, but which has had a significant response to therapy, and (3) to decide the necessity for further therapy based on the findings at the second-look celiotomy. PREOPERATIVE EVALUATION Prior to the second-look procedure, the patients were evaluated with the following procedures: Chest X ray, intravenous pyelogram, barium enema, liver scan, cystoscopy, sigmoidoscopy, and CAT scan as indicated. Any abnormalities were followed up with the appropriate study. The operative note from the initial operation was carefully reviewed with respect to the previous findings and degree of tumor resection. SECOND-LOOK PROCEDURE At operation the following steps were performed: 1. A vertical midline or paramedian incision was made in the lower abdominal wall regardless of the type of incision used for the initial surgery. 2. Cytologic evaluations were obtained from any free fluid present in the pelvis and from washings or smears of the pelvis, paracolic gutters, and underside of the diaphragm. The washings or fluids were sent in a heparinized tube. 3. The entire abdominal cavity was explored visually and manually including the undersurface of the diaphragm, the surface of the liver and spleen, the mesentery, the surface of the intestines, and any remaining omentum. Retroperitoneal nodes were palpated. Care was taken to cleanse the gloves prior to the exam. 4. The pelvic cavity was thoroughly explored. 5. The uterus, tubes, ovaries, and omentum, if still present, were removed.
36
ROCERETO ET AL.
6. All areas suspicious for tumor, including lymph nodes, were biopsied or preferably removed in toto. 7. Gross tumor was resected as completely as possible. 8. All areas of unresectable tumor were marked with metallic clips for future localization by X ray. 9. If no gross tumor was found, biopsies were taken from the cul-de-sac, both paracolic gutters, and where tumor had previously been grossly left behind. Selective dissection of the para-aortic, common iliac, and pelvic lymph nodes was performed. PATIENT MATERIAL Forty-two second-look celiotomies were performed on 36 patients since July 1974. The mean age of the patients at initial diagnosis was 50.1 years with a range from 21 to 74 years. Initial Stage and Surgery Nine patients had a Stage I disease, 7 Stage II, 19 Stage III, and 1 Stage IV (Table 1). Thirty-three patients had had a total abdominal hysterectomy and bilateral salpingo-oophorectomy as their initial surgery (Table 2). The uterus was left in situ in three patients. In 2 of these latter patients, the extent of the tumor did not allow for its removal. Five patients had tumor residual with nodules greater than 2 cm at initial surgery. Six other patients had small nodules or sheets of tumor on the peritoneal surface of the abdomen and pelvis and/or the serosa of the intestines. All of these patients with residual had Stage III disease. Histology Histologically, all patients had common epithelial tumors (Table 3). All patients with endometrioid and mutinous tumors were in Stage I. The serous and unTABLE 1 STAGE OF DISEASE I II III IV Total
9 7 19 1 36
TABLE 2 INITIAL SURGERY TAH BSO TAH BSO Om BSO BSO Om
14 19 2 1
SECOND-LOOK CELIOTOMY IN OVARIAN CANCER
37
TABLE 3 HISTOLOGY
19 3 4 1 9
Serous Mutinous Endometrioid Adenosquamous Undifferentiated ’ One borderline tumor.
differentiated tumors were equally divided among all stages. One patient had a Stage III serous tumor of borderline malignancy. Initial
Treatment
Twenty-eight patients had chemotherapy as their sole treatment after surgery (Table 4). Eight patients had radiotherapy prior to chemotherapy. In six of these latter patients, pelvic irradiation was given for a second primary tumor of the endometrium. Twenty-eight patients were given oral chemotherapy. Twenty-six patients received L-phenylalanine mustard (L-PAM) 1 mg/kg over 5 days every 28 days. One of these patients concurrently received hexamethylmelamine (HMM) 150 mg/M* 14128days and 3 other patients received Corynebacterium parvum (Cparvum) 4 mg/m* intravenously on the seventh day of L-PAM therapy. One patient received cyclophosphamide and one received chlorambucil as their sole chemotherapeutic drug. Therapy was given for at least 17 months. Eight patients with advanced disease were given multiple drug intravenous therapy. Five of the patients received a combination of cis-platinum 50 mg/m2, Adriamycin 50 mg/m*, and cyclophosphamide 500 mg/m’ (CAP) every 3 weeks. Two patients received c&platinum 50 mg/m2 and Adriamycin 30 mg/m* intravenously every 28 days along with cyclophosphamide 150 mg/m’ and HMM 150 mg/m2 p.o. days 2-8 (CHAP). One patient received Adriamycin 50 mg/m* and cyclophosphamide 500 mg/m* every 3 weeks. Seven of these patients had 8-9 courses of chemotherapy prior to the second-look. One patient on CHAP did not have a second-look for 17 months because of neurotoxicity from this regimen. This latter patient received intravenous Cyclophosphamide until the second-look procedure. TABLE 4 THERAPY
Alkylating agent C-Parvum HMM Radiotherapy Adria-Ctx CAP CHAP
28 3 1 8 1 5 2
38
ROCERETO ET AL.
Results
Thirty-six patients underwent a total of 42 second-look celiotomies. All were clinically free of tumor prior to the operation. Preoperative studies for metastatic disease were negative in all patients. The mean length of time from the initial diagnosis to the second-look procedure was 20 months in patients treated with oral agents and 9.4 months in those treated with intravenous agents. The second-look surgery was negative for tumor in 23 out of 36 patients (65%) (Table 5). On this basis, the chemotherapy was stopped in all of these patients. The second-look surgery was positive for tumor in 13 out of 36 patients (35%). Stages Z and ZZ. All 9 patients with Stage I disease had a negative secondlook (Table 6). All are alive and well without evidence of disease and off therapy 30-105 months from diagnosis and 26-77 months from the second-look. All 7 patients with Stage II disease had a negative second-look. Five of these patients are alive and well without evidence of disease 26-107 months from diagnosis and lo-83 months from the second-look. One patient died with leukemia without evidence of ovarian carcinoma 63 months from diagnosis and 33 months from the second-look. This patient received pelvic irradiation prior to chemotherapy. Stages ZZZand IV. The second-look surgery was negative in 7 out of 20 patients (35%) with advanced disease (Table 6). All are alive and well without evidence of disease 30-110 months from diagnosis and 20-83 months from the secondlook. Four had received L-PAM, 2 CAP, and 1 CHAP. The second-look was positive in 13 out of 20 patients (65%) with advanced disease. One of these patients had a borderline tumor. Five of these patients had a third exploration and 2 were negative for tumor. The one patient with a borderline tumor had a fourth exploration which was negative for tumor. Two of the 3 patients who subsequently have had negative exploration are alive and well without evidence of disease 18 and 38 months from their negative celiotomies and 47 and 88 months from diagnosis. The third patient died of leukemia 13 months after her negative operation. She had received L-PAM as her sole treatment. TABLE 5 RESULTS Negative Positive
23 (65%) 13 (35%)
TABLE 6 RESULTS BY STAGE Stage
C-J
(+)
I II III IV
9 7 7 0
0 0 12 1
Total
23
13
SECOND-LOOK
CELIOTOMY
IN OVARIAN
CANCER
39
All of the patients with a positive second-look celiotomy were continued on chemotherapy: Six of these 13 patients have died with disease 20-88 months from diagnosis and 6-65 months from the initial second-look exploration. One patient has died of leukemia without evidence of disease. Two patients have palpable disease and continue on chemotherapy. Four patients are alive without evidence of disease. Two of the latter 4 patients continue on chemotherapy 29 months from diagnosis and 21 months from the second-look celiotomy. The other 2 patients have had a subsequent negative exploration and are off therapy. Surgical
Findings
There were 16 second-look celiotomies in 13 patients in which tumor was present (Table 7). At seven of these celiotomies there were findings suggestive of tumor which were confirmed histologically. One of these patients had an enlarged lymph node which contained tumor. A second patient had a 5-mm nodule in the pelvis and a third patient had two 5-mm nodules on the peritoneum over the right kidney. The other 4 patients had disease greater than 2 cm in multiple areas of the abdominal and pelvic cavity. At nine celiotomies there was no gross evidence of tumor, but tumor was found in the pathology specimen. One of these was a “third-look” in a patient who had a pelvic nodule at the second-look celiotomy. In seven instances microscopic tumor was found in peritoneal biopsies of the pelvic wall. In one instance microscopic tumor was in the normal appearing omentum which had been resected. In the ninth instance a grossly normal para-aortic lymph node had a focus of tumor. Treatment Oral agents. Four of the 12 patients with advanced disease treated with LPAM had a negative second-look celiotomy (Table 8). Two of these patients had obvious tumor left at the initial surgery. All 4 are alive and clinically free of disease. Eight of these 12 patients had a positive second-look. Five of these 8 patients had microscopic tumor in peritoneal biopsies or omentum. One of the 3 patients with macroscopic tumor had an enlarged lymph node, while the other 2 patients had tumor less than 1 cm in diameter. TABLE SURGICAL
FINDINGS
7 AT SECOND-LOOK
Microscopic tumor Tumor <2-cm diam Tumor >2-cm diam
9 3 4
TABLE
8
RESULTS AT SECOND-LOOK
ADVANCED
DISEASE
TX
C-J
(+I
L-PAM cis-Plat
4 3
8 5
ROCERETO ET AL.
40
All patients with a positive second-look were continued on chemotherapy. Five of these patients have had six subsequent explorations. Three of these explorations were negative for disease and three were positive for microscopic disease only. Of the 5 patients who have not had a negative re-exploration(s) 2 are alive with evidence of advancing disease and 3 have died, one over 7 years from diagnosis. Intravenous agents. Three of the 8 patients treated with intravenous therapy had a negative second-look celiotomy (Table 8). All three had no residual tumor at the initial surgery and are alive and clinically free of disease off chemotherapy. Five of these 8 patients had a positive second-look. Only one patient had microscopic tumor and this was a normal appearing lymph node. Three of these 5 patients have died with disease. No subsequent exploration has been performed on the other two patients. Deaths
Eight patients have died (Table 9). Two patients died of leukemia after a negative second- and third-look without evidence of disease. Both patients had received L-PAM. One patient received 18 courses of therapy after pelvic irradiation, and the other received 36 courses without irradiation. Six patients died from disease. All had advanced tumor and a positive secondlook. Three patients received L-PAM as their initial therapy and three a cisplatinum regimen. One patient had no residual tumor at the initial surgery, but had an enlarged node at the second-look. The other 5 patients had tumor residual at the initial surgery and 4 of these patients had obvious tumor at the secondlook. Residual
Tumor in Advance Disease
Nine patients with advance disease had no residual tumor at the initial surgery. Five had a negative second-look and 4 had a positive second-look. Two patients with a positive second-look had microscopic disease only and had a subsequent negative exploration. One of these 2 patients died from leukemia while the other is alive and well without evidence of disease. Two patients with a positive secondlook had macroscopic disease and one died with disease 6 months from the second-look, while the other is alive and well without evidence of disease. Eleven patients with advance disease had residual tumor at the initial surgery. Only two had a negative second-look while 9 had a positive second-look. Four had microscopic disease only. One of these 4 has died, 2 have advancing disease, TABLE 9 PATIENT STATUS’ Alive
NED ED
25 3
Dead 2 6
a Ned, no evidence of disease; ED, evidence of disease.
SECOND-LOOK
CELIOTOMY
IN OVARIAN
CANCER
41
and I is alive and well without disease. Four of the other 5 patients who had a positive second-look with macroscopic disease are dead. The fifth patient is alive and well without disease. Five of the 7 patients with a negative second-look had no residual disease at the initial surgery. One of the 2 patients with residual disease had minimal disease. Only 4 of the 13 patients with a positive second-look had no residual disease at the initial surgery. Five of the 6 patients who have died with disease had residual tumor at the initial surgery. All 5 have a positive second-look with only 1 having microscopic disease. Survival
Twenty-two patients are 5 years from diagnosis and 19 are alive (Table 10). At 3 years 27128patients were alive. Three patients died between 3 and 5 years, 2 with disease and 1 without disease. Two patients have died after 5 years, one with and one without disease. Twelve patients are 5 years from their second-look and 11 are alive. At 3 years 18/22 patients were alive. Five of the 6 patients who have died with disease, died less than 2 years from their second-look. The sixth patient died more than 5 years from the second-look. Two patients have survived more than 5 years after a positive second-look. Discussion
In 1976 Smith et al. [15] reported on a large series of second-look procedures in ovarian carcinoma in patients treated with single agents. The results were significantly better in those patients who received 10 or more courses of chemotherapy and in patients with early stage disease as compared to advanced disease. In 1980 Schwartz and Smith [13] reconfirmed that the findings at the second-look and survival of the patients were related to the number of courses of chemotherapy, the stage of the disease, the amount of the tumor resected at the original surgery, and the amount of tumor found at the second-look. Roberts et al. [IO] showed that residual tumor at the second-look also correlated well with histological grade. Twenty-three patients in this series had no evidence of tumor at the secondlook celiotomy and received no further therapy. None of these patients have died from disease. All of the patients with a positive second-look celiotomy TABLE
10
SURVIVAL
Years 2 3 4 5 L?Number
Diagnosis 33/36” 27128 23/25 19/22
Second-look
(92%) (96%) (92%) (86%)
alive/number
evaluable.
26/29 (90%) 18/22 (82%) 17/21 (81%) 11112 (92%)
42
ROCERETO
ET AL.
initially had advanced disease. Five of the 9 patients with advanced disease who had no residual disease after the initial surgery had a negative second-look celiotomy and none have died with disease. Five of the 6 patients who have died with disease had residual tumor after their initial surgery. These findings confirm the experience of other authors [ 10,13,15]. The ultimate survival of these patients is related to the results of the second-look and both are related to the stage of disease and the amount of residual tumor after the initial surgery. No patient should have a second-look until at least 1 year of therapy has been completed. Although it may not be possible to continue drugs such as &-platinum and Adriamycin for 1 year, the accompanying alkylating agent can be and should be continued for the remainder of the year. Some patients who may be clinically free of disease at 6 months may not be so at 1 year. In the present series, all patients with Stage I disease had a negative secondlook. Schwartz and Smith [13] and Roberts er al. [lo] reported 33 and 28% positive second-look procedures, respectively, in patients with Stage I disease. If there is a reason to treat a patient with Stage I disease with chemotherapy, then the authors feel a second-look should be performed prior to stopping that therapy. The cytologic evaluation of peritoneal washings did not correlate with positive findings in this series. All patients whose second-look procedure was histologically negative for tumor had negative peritoneal washings but only 3 patients with a positive second-look had cytology positive for tumor cells. Cytologic evaluation of washings and/or smears of the peritoneal cavity are an essential part of the second-look procedure. These should include the underside of the diaphragm. A patient should not be considered as having a negative second-look unless these washings are performed and contain no tumor ceils. Laparoscopy is being recommended by some physicians in place of, or as part of, the second-look procedure [3,11,14]. Originally, Rosenoff et al. [ 1l] used the laparoscope for the second-look operation without further surgical investigation of those patients with no evidence of disease. Three of their first 5 patients developed recurrences 12-19 months after laparoscopy. They have since suggested that patients with a negative laparoscopy also have an exploratory celiotomy to confirm the negative results. They report that since the change in their policy, 2 to 4 patients with a negative laparoscopy had tumor found at the exploratory celiotomy . 0~01s et al. [6] found a false negative rate of 55% with laparoscopy and were not able to adequately visualize the pelvis in 50% of the cases. Piver et al. [8] found that laparotomy was positive for tumor in 2 of the 10 patients with negative laparoscopies. Schwartz and Smith [13] did not use the laparoscope for the second-look, but noted that there were 24 patients who had no visible tumor, but did have microscopic tumor which would have been missed with the laparoscope. Nine of the 16 positive second-look operations in the present series had microscopic tumors only and would have been misdiagnosed with laparoscopy. The laparoscope can be used to evaluate the underside of the diaphragm, the liver capsule, some intestinal surfaces, and the underside of the visceral peritoneum.
SECOND-LOOK CELIOTOMY IN OVARIAN CANCER
43
However, the laparoscope cannnot be used well to evaluate under adhesions, the mesentery of the small bowel, the kidneys, or the retroperitoneal nodes. There is also the danger of intestinal perforation with the use of the laparoscope especially where extensive disease was initially present or where omentectomy or radiation has been utilized. The high false negative rate associated with cytologic study of peritoneal washings in these patients would reduce the ability of laparoscopy alone to be an effective second-look tool. When the laparoscope is used as part of the second-look procedure, all patients with negative findings need to have an exploratory celiotomy to confirm the laparoscopic findings. Berek ef al. [3] have suggested laparoscopy every 6 months for tumor followup. Early in their series they had 10 bowel perforations, but since the use of the needlescope was introduced to guide the entrance of the laparoscope, they have had only one bowel perforation. They felt that after 24 months (four laparoscopic procedures), the probability of recurrence is stable at less than 10%. Only 12 of 57 patients had four or more successful laparoscopies. Laparotomy to confirm the negative laparoscopy was not done. One of the purposes of the second-look procedure is to resect tumor which was not resectable at the initial operation but which has had a significant response to therapy. Wallach and Blinick [17] performed the second-look for this purpose and found that only those patients who were clinically free of disease prior to the surgery had a good prognosis for survival. Tepper et al. [16] presented 17 patients with ovarian cancer whose original operation consisted only of abdominal exploration and biopsy. These patients then received abdominopelvic irradiation concomitant with Triethylene Thiophosphoramide. A second-look celiotomy was performed 4-8 weeks after the completion of the radiotherapy on those patients whose tumors showed some response to the therapy. At the second-look operation, 9 patients were able to have complete removal of the tumor but only three of these patients were alive without evidence of disease 4-6 years from diagnosis. Piver et al. [7] have attempted to reduce the size of the tumor mass with chemotherapy in order to perform further debulking at the second-look operation. Their patients were subjected to whole abdomen irradiation after the second procedure. They were able to follow this course of therapy in 8 patients, but 5 patients have since died of recurrence. All 3 living patients had nine or more courses of chemotherapy prior to the second-look, and only one of these patients is free of disease. The authors have attempted the same type of tumor reduction with chemotherapy followed by re-exploration with very little success. Two of the patients in the present series have died of leukemia 62 and 54 months after their diagnosis. One patient had radiotherapy followed by 18 courses of L-PAM for Stage II disease while the second patient had 36 courses of LPAM without radiotherapy. Both had a negative third-look. Another patient has had an episode of pancytopenia which was seen in 9 of the patients in Reimer’s [9] report 1-12 months prior to the diagnosis of leukemia. This latter patient is now 5 years from that episode without further problems. This patient also received pelvic irradiation followed by chemotherapy with an alkylating agent. Two other patients not included in this series have died from acute nonlymphatic leukemia. One patient received chemotherapy and radiotherapy, while the other patient
44
ROCERETO ET AL.
received chemotherapy alone. All the above patients received an alkylating agent as their sole chemotherapeutic drug. While leukemia may be a real threat to patients on alkylating agents, and the risk might be decreased by stopping these agents early, the risk of dying from ovarian cancer, especially in advanced stages, is much higher. Whether these risks can be balanced on the basis of second-look findings is at present impossible to assess. The question arises whether or not patients who have irradiation should have a second-look celiotomy. Eight of the patients in this series had irradiation. Two patients had abdominopelvic therapy, while 6 had pelvic therapy alone. There was obvious evidence of radiation effect on the intestines in these patients and, therefore, the bowel was handled as little as possible. None of these patients have had any complications. The patient who has had only pelvic irradiation will most likely have few, if any problems with a second-look celiotomy. However, the patient who has had her whole abdomen irradiated, either by external beam therapy or by intraperitoneal radioactive isotopes, has had most of her intestine irradiated. Dissection through the adhesions caused by this irradiation may lead to serious bowel complications. If a second-look celiotomy is done following whole abdomen irradiation, the intestine should be treated very delicately with as little dissection as possible. Obviously, this may decrease the value of the second-look in these patients. REFERENCES 1. 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, Lancer 77, 412-417 (1957). 2. Aure, J. C., Hoeg, K., and Kolstad, P. Clinical and histologic studies of ovarian carcinoma: Long-term follow-up of 990 cases, Obstet. Gynecol. 37, l-9 (1971). 3. Berek, J. S., Griffiths, 0. T., and Leventhal, J. M. Laparoscopy for second-look evaluation in ovarian cancer, Obsret. Gynecol. 58, 192-198 (1981). 4. Hreshchyshyn, M. M. Single-drug therapy in ovarian cancer, Gynecol. Oncol. 1,220-232 (1973). 5. Munnell, E. W. The changing prognosis and treatment in cancer of the ovary, Amer. J. Obstet. Gynecol. 108, 790-805 (1968). 6. Ozols, R. F., Fisher, R. I., Anderson, T., Makuch, R., and Young, R. C. Peritoneoscopy in the management of ovarian cancer, Obstet. Gynecol. 140, 611-619 (1981). 7. Piver, S. M., Barlow, J. J., Lee, F. T., and Vongtama, V. Sequential therapy for advanced ovarian adenocarcinoma: Operation, chemotherapy, second-look laparotomy, and radiation therapy, Amer. J. Obstet. Gynecol. 122, 355-357 (1975). 8. Piver, S. M., Lele, S. B., Barlow, J. J., and Gamarra, M. Second-look laparoscopy prior to proposed second-look laparotomy, Obstet. Gynecol. 55, 571-573 (1980). 9. Reimer, R. R., Hoover, R., Fraumeni, Jr., J. F., and Young, R. C. Acute leukemia after alkylating-agent therapy of ovarian cancer, N. Engl. J. Med. 297, 177-181 (1977). 10. Roberts, W. S., Hodel, K., Rich, W. M., and DiSaia, P. J. Second-look laparotomy in the management of gynecologic malignancy, Gynecol. Oncol. 13, 345-3.55 (1982). 11. Rosenoff, S. H., Young, R. C., Anderson, T., Bagley, C., Chabner, B., Schein, P. S., Hubbard, S., and DeVita, V. T. Peritoneoscopy: A valuable staging tool in ovarian carcinoma, Ann. In?. Med. 83, 37-41 (1975). 12. Santor, B. T., Griffen, W. O., and Wangensteen, 0. H. The second-look procedure in the management of ovarian malignancies and piuedomyxoma peritonei, Sup. 50, 354-358 (1961). 13. Schwartz, P. E., and Smith, J. P. Second-look operations in ovarian cancer, Amer. J. Obster. Gynecol. 138, 1124-1130 (1980).
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OVARIAN
CANCER
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14. Smith, W. G., Day, T. G., and Smith, J. P. The use of laparoscopy to determine the results of chemotherapy for ovarian cancer, J. Reprod. Med. 18, 257-260 (1977). 15. Smith, J. P., Delgado, G., and Rutledge, F. Second-look operation in ovarian carcinoma, Cancer 38, 1438-1442 16.
(1976).
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. Roentg. Rad. Ther. Arch. Med. 112, 755-759
(1971).
17. Wallach, R. C., and Blinick, G. The second-look operation for carcinoma of the ovary, Surg. Gynecol.
Obster.
131, 1085-1089
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18. Wangensteen, 0. H., Lewis, F. J., and Tongen, L. A. The “second-look” Lancer
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in cancer surgery,
ONCOLOGY
19, 34-45 (1984)
The Second-Look Celiotomy in Ovarian Cancer THOMAS F. ROCERETO, M.D.,“‘, CHARLES E. MANGAN, M.D.,3 ROBERT L. GIUNTOLI, M.D. ,3 THOMAS V. SEDLACEK, M.D., HARRISON J. BALL, M.D. ,4 AND JOHN J. MIKUTA, M.D.’ Department
of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
of
Received May 9, 1983 Thirty-six patients with primary ovarian carcinoma who had 42 second-look procedures performed are reported. Twenty-three patients had no tumor found at the second-look celiotomy and were given no further treatment. Thirteen patients had tumor at the secondlook procedure and were continued on therapy. Six patients have died with disease and all had a positive second-look celiotomy. Two patients have died with leukemia but with no evidence of ovarian cancer, one after a negative second-look and the other a negative third-look. No patient with a negative second-look celiotomy has died with disease. A correlation with respect to the findings at the second-look was found with respect to the stage of disease and the amount of residual tumor at the initial surgery. The use of the second-look celiotomy in patients with disease in the early stages and in patients treated with irradiation is discussed, along with the utilization of the laparoscopy.
Each year approximately 18,000women are diagnosed as having ovarian cancer, and 11,000 die from this disease. Surgery is necessary for the accurate diagnosis and staging of ovarian cancer and for years has been the primary mode of treatment for this tumor. The trend in recent times has been, if possible, to remove all or a large amount of the tumor at the primary operation. The literature does suggest that ovarian cancer patients who have no tumor, or only a small amount of tumor remaining after initial surgery, have a longer period of survival than those patients who have a moderate to large amount of tumor after surgery
~431. It is recognized that almost every patient with epithelial ovarian carcinoma would be given postoperative chemotherapy. Even though some patients can ’ Clinical Fellow, American Cancer Society. 2 Present address: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, UMDNJ/Rutgers Medical School at Camden, Camden, New Jersey and Cooper Hospital/University Medical Center. 3 Junior Faculty Clinical Fellow, American Cancer Society. 4 Present address: Department of Obstetrics and Gynecology, Tufts University Medical School, Boston, Massachusetts 02155. ’ To whom reprint requests should be addressed: 1000 Courtyard Bldg., 3400 Spruce Street, Philadelphia, Pa. 19104. 34 0090-8258184$1SO Copyright All rights
0 1984 by Academic Press, Inc. of reproduction in any form reserved.
SECOND-LOOK
CELIOTOMY
IN
OVARIAN
CANCER
35
tolerate chemotherapy for years, it is felt by many oncologists that the patient who is free of disease may no longer need this therapy. Since being clinically free from disease is not the same as being totally free from disease, the problem arises as to how to decide when to stop the chemotherapy. In 1949, Wangensteen [18] introduced the concept of a “second-look” operation in patients with colon carcinoma. In 1951, Arhelger el al. [l] reported that patients with colorectal cancers who were originally found to have lymph nodes containing tumor and were now asymptomatic and clinically free of disease, were found to have residual cancer at a second-look operation. Santor et al. [ 121used the same plan for the second-look procedure in the management of patients with ovarian malignancies and pseudomyxoma peritonei with some success. Smith et al., [15] have shown that at least 1 year of therapy should be given before a second-look is attempted. METHODS Since July 1974, a second-look celiotomy has been performed on patients being treated for ovarian cancer at the Hospital of the University of Pennsylvania. The purpose of this procedure is (1) to determine the status of tumor in patients who are clinically free from disease and resect tumor which may be present, (2) to resect tumor which was not resectable at the initial operation, but which has had a significant response to therapy, and (3) to decide the necessity for further therapy based on the findings at the second-look celiotomy. PREOPERATIVE EVALUATION Prior to the second-look procedure, the patients were evaluated with the following procedures: Chest X ray, intravenous pyelogram, barium enema, liver scan, cystoscopy, sigmoidoscopy, and CAT scan as indicated. Any abnormalities were followed up with the appropriate study. The operative note from the initial operation was carefully reviewed with respect to the previous findings and degree of tumor resection. SECOND-LOOK PROCEDURE At operation the following steps were performed: 1. A vertical midline or paramedian incision was made in the lower abdominal wall regardless of the type of incision used for the initial surgery. 2. Cytologic evaluations were obtained from any free fluid present in the pelvis and from washings or smears of the pelvis, paracolic gutters, and underside of the diaphragm. The washings or fluids were sent in a heparinized tube. 3. The entire abdominal cavity was explored visually and manually including the undersurface of the diaphragm, the surface of the liver and spleen, the mesentery, the surface of the intestines, and any remaining omentum. Retroperitoneal nodes were palpated. Care was taken to cleanse the gloves prior to the exam. 4. The pelvic cavity was thoroughly explored. 5. The uterus, tubes, ovaries, and omentum, if still present, were removed.
36
ROCERETO ET AL.
6. All areas suspicious for tumor, including lymph nodes, were biopsied or preferably removed in toto. 7. Gross tumor was resected as completely as possible. 8. All areas of unresectable tumor were marked with metallic clips for future localization by X ray. 9. If no gross tumor was found, biopsies were taken from the cul-de-sac, both paracolic gutters, and where tumor had previously been grossly left behind. Selective dissection of the para-aortic, common iliac, and pelvic lymph nodes was performed. PATIENT MATERIAL Forty-two second-look celiotomies were performed on 36 patients since July 1974. The mean age of the patients at initial diagnosis was 50.1 years with a range from 21 to 74 years. Initial Stage and Surgery Nine patients had a Stage I disease, 7 Stage II, 19 Stage III, and 1 Stage IV (Table 1). Thirty-three patients had had a total abdominal hysterectomy and bilateral salpingo-oophorectomy as their initial surgery (Table 2). The uterus was left in situ in three patients. In 2 of these latter patients, the extent of the tumor did not allow for its removal. Five patients had tumor residual with nodules greater than 2 cm at initial surgery. Six other patients had small nodules or sheets of tumor on the peritoneal surface of the abdomen and pelvis and/or the serosa of the intestines. All of these patients with residual had Stage III disease. Histology Histologically, all patients had common epithelial tumors (Table 3). All patients with endometrioid and mutinous tumors were in Stage I. The serous and unTABLE 1 STAGE OF DISEASE I II III IV Total
9 7 19 1 36
TABLE 2 INITIAL SURGERY TAH BSO TAH BSO Om BSO BSO Om
14 19 2 1
SECOND-LOOK CELIOTOMY IN OVARIAN CANCER
37
TABLE 3 HISTOLOGY
19 3 4 1 9
Serous Mutinous Endometrioid Adenosquamous Undifferentiated ’ One borderline tumor.
differentiated tumors were equally divided among all stages. One patient had a Stage III serous tumor of borderline malignancy. Initial
Treatment
Twenty-eight patients had chemotherapy as their sole treatment after surgery (Table 4). Eight patients had radiotherapy prior to chemotherapy. In six of these latter patients, pelvic irradiation was given for a second primary tumor of the endometrium. Twenty-eight patients were given oral chemotherapy. Twenty-six patients received L-phenylalanine mustard (L-PAM) 1 mg/kg over 5 days every 28 days. One of these patients concurrently received hexamethylmelamine (HMM) 150 mg/M* 14128days and 3 other patients received Corynebacterium parvum (Cparvum) 4 mg/m* intravenously on the seventh day of L-PAM therapy. One patient received cyclophosphamide and one received chlorambucil as their sole chemotherapeutic drug. Therapy was given for at least 17 months. Eight patients with advanced disease were given multiple drug intravenous therapy. Five of the patients received a combination of cis-platinum 50 mg/m2, Adriamycin 50 mg/m*, and cyclophosphamide 500 mg/m’ (CAP) every 3 weeks. Two patients received c&platinum 50 mg/m2 and Adriamycin 30 mg/m* intravenously every 28 days along with cyclophosphamide 150 mg/m’ and HMM 150 mg/m2 p.o. days 2-8 (CHAP). One patient received Adriamycin 50 mg/m* and cyclophosphamide 500 mg/m* every 3 weeks. Seven of these patients had 8-9 courses of chemotherapy prior to the second-look. One patient on CHAP did not have a second-look for 17 months because of neurotoxicity from this regimen. This latter patient received intravenous Cyclophosphamide until the second-look procedure. TABLE 4 THERAPY
Alkylating agent C-Parvum HMM Radiotherapy Adria-Ctx CAP CHAP
28 3 1 8 1 5 2
38
ROCERETO ET AL.
Results
Thirty-six patients underwent a total of 42 second-look celiotomies. All were clinically free of tumor prior to the operation. Preoperative studies for metastatic disease were negative in all patients. The mean length of time from the initial diagnosis to the second-look procedure was 20 months in patients treated with oral agents and 9.4 months in those treated with intravenous agents. The second-look surgery was negative for tumor in 23 out of 36 patients (65%) (Table 5). On this basis, the chemotherapy was stopped in all of these patients. The second-look surgery was positive for tumor in 13 out of 36 patients (35%). Stages Z and ZZ. All 9 patients with Stage I disease had a negative secondlook (Table 6). All are alive and well without evidence of disease and off therapy 30-105 months from diagnosis and 26-77 months from the second-look. All 7 patients with Stage II disease had a negative second-look. Five of these patients are alive and well without evidence of disease 26-107 months from diagnosis and lo-83 months from the second-look. One patient died with leukemia without evidence of ovarian carcinoma 63 months from diagnosis and 33 months from the second-look. This patient received pelvic irradiation prior to chemotherapy. Stages ZZZand IV. The second-look surgery was negative in 7 out of 20 patients (35%) with advanced disease (Table 6). All are alive and well without evidence of disease 30-110 months from diagnosis and 20-83 months from the secondlook. Four had received L-PAM, 2 CAP, and 1 CHAP. The second-look was positive in 13 out of 20 patients (65%) with advanced disease. One of these patients had a borderline tumor. Five of these patients had a third exploration and 2 were negative for tumor. The one patient with a borderline tumor had a fourth exploration which was negative for tumor. Two of the 3 patients who subsequently have had negative exploration are alive and well without evidence of disease 18 and 38 months from their negative celiotomies and 47 and 88 months from diagnosis. The third patient died of leukemia 13 months after her negative operation. She had received L-PAM as her sole treatment. TABLE 5 RESULTS Negative Positive
23 (65%) 13 (35%)
TABLE 6 RESULTS BY STAGE Stage
C-J
(+)
I II III IV
9 7 7 0
0 0 12 1
Total
23
13
SECOND-LOOK
CELIOTOMY
IN OVARIAN
CANCER
39
All of the patients with a positive second-look celiotomy were continued on chemotherapy: Six of these 13 patients have died with disease 20-88 months from diagnosis and 6-65 months from the initial second-look exploration. One patient has died of leukemia without evidence of disease. Two patients have palpable disease and continue on chemotherapy. Four patients are alive without evidence of disease. Two of the latter 4 patients continue on chemotherapy 29 months from diagnosis and 21 months from the second-look celiotomy. The other 2 patients have had a subsequent negative exploration and are off therapy. Surgical
Findings
There were 16 second-look celiotomies in 13 patients in which tumor was present (Table 7). At seven of these celiotomies there were findings suggestive of tumor which were confirmed histologically. One of these patients had an enlarged lymph node which contained tumor. A second patient had a 5-mm nodule in the pelvis and a third patient had two 5-mm nodules on the peritoneum over the right kidney. The other 4 patients had disease greater than 2 cm in multiple areas of the abdominal and pelvic cavity. At nine celiotomies there was no gross evidence of tumor, but tumor was found in the pathology specimen. One of these was a “third-look” in a patient who had a pelvic nodule at the second-look celiotomy. In seven instances microscopic tumor was found in peritoneal biopsies of the pelvic wall. In one instance microscopic tumor was in the normal appearing omentum which had been resected. In the ninth instance a grossly normal para-aortic lymph node had a focus of tumor. Treatment Oral agents. Four of the 12 patients with advanced disease treated with LPAM had a negative second-look celiotomy (Table 8). Two of these patients had obvious tumor left at the initial surgery. All 4 are alive and clinically free of disease. Eight of these 12 patients had a positive second-look. Five of these 8 patients had microscopic tumor in peritoneal biopsies or omentum. One of the 3 patients with macroscopic tumor had an enlarged lymph node, while the other 2 patients had tumor less than 1 cm in diameter. TABLE SURGICAL
FINDINGS
7 AT SECOND-LOOK
Microscopic tumor Tumor <2-cm diam Tumor >2-cm diam
9 3 4
TABLE
8
RESULTS AT SECOND-LOOK
ADVANCED
DISEASE
TX
C-J
(+I
L-PAM cis-Plat
4 3
8 5
ROCERETO ET AL.
40
All patients with a positive second-look were continued on chemotherapy. Five of these patients have had six subsequent explorations. Three of these explorations were negative for disease and three were positive for microscopic disease only. Of the 5 patients who have not had a negative re-exploration(s) 2 are alive with evidence of advancing disease and 3 have died, one over 7 years from diagnosis. Intravenous agents. Three of the 8 patients treated with intravenous therapy had a negative second-look celiotomy (Table 8). All three had no residual tumor at the initial surgery and are alive and clinically free of disease off chemotherapy. Five of these 8 patients had a positive second-look. Only one patient had microscopic tumor and this was a normal appearing lymph node. Three of these 5 patients have died with disease. No subsequent exploration has been performed on the other two patients. Deaths
Eight patients have died (Table 9). Two patients died of leukemia after a negative second- and third-look without evidence of disease. Both patients had received L-PAM. One patient received 18 courses of therapy after pelvic irradiation, and the other received 36 courses without irradiation. Six patients died from disease. All had advanced tumor and a positive secondlook. Three patients received L-PAM as their initial therapy and three a cisplatinum regimen. One patient had no residual tumor at the initial surgery, but had an enlarged node at the second-look. The other 5 patients had tumor residual at the initial surgery and 4 of these patients had obvious tumor at the secondlook. Residual
Tumor in Advance Disease
Nine patients with advance disease had no residual tumor at the initial surgery. Five had a negative second-look and 4 had a positive second-look. Two patients with a positive second-look had microscopic disease only and had a subsequent negative exploration. One of these 2 patients died from leukemia while the other is alive and well without evidence of disease. Two patients with a positive secondlook had macroscopic disease and one died with disease 6 months from the second-look, while the other is alive and well without evidence of disease. Eleven patients with advance disease had residual tumor at the initial surgery. Only two had a negative second-look while 9 had a positive second-look. Four had microscopic disease only. One of these 4 has died, 2 have advancing disease, TABLE 9 PATIENT STATUS’ Alive
NED ED
25 3
Dead 2 6
a Ned, no evidence of disease; ED, evidence of disease.
SECOND-LOOK
CELIOTOMY
IN OVARIAN
CANCER
41
and I is alive and well without disease. Four of the other 5 patients who had a positive second-look with macroscopic disease are dead. The fifth patient is alive and well without disease. Five of the 7 patients with a negative second-look had no residual disease at the initial surgery. One of the 2 patients with residual disease had minimal disease. Only 4 of the 13 patients with a positive second-look had no residual disease at the initial surgery. Five of the 6 patients who have died with disease had residual tumor at the initial surgery. All 5 have a positive second-look with only 1 having microscopic disease. Survival
Twenty-two patients are 5 years from diagnosis and 19 are alive (Table 10). At 3 years 27128patients were alive. Three patients died between 3 and 5 years, 2 with disease and 1 without disease. Two patients have died after 5 years, one with and one without disease. Twelve patients are 5 years from their second-look and 11 are alive. At 3 years 18/22 patients were alive. Five of the 6 patients who have died with disease, died less than 2 years from their second-look. The sixth patient died more than 5 years from the second-look. Two patients have survived more than 5 years after a positive second-look. Discussion
In 1976 Smith et al. [15] reported on a large series of second-look procedures in ovarian carcinoma in patients treated with single agents. The results were significantly better in those patients who received 10 or more courses of chemotherapy and in patients with early stage disease as compared to advanced disease. In 1980 Schwartz and Smith [13] reconfirmed that the findings at the second-look and survival of the patients were related to the number of courses of chemotherapy, the stage of the disease, the amount of the tumor resected at the original surgery, and the amount of tumor found at the second-look. Roberts et al. [IO] showed that residual tumor at the second-look also correlated well with histological grade. Twenty-three patients in this series had no evidence of tumor at the secondlook celiotomy and received no further therapy. None of these patients have died from disease. All of the patients with a positive second-look celiotomy TABLE
10
SURVIVAL
Years 2 3 4 5 L?Number
Diagnosis 33/36” 27128 23/25 19/22
Second-look
(92%) (96%) (92%) (86%)
alive/number
evaluable.
26/29 (90%) 18/22 (82%) 17/21 (81%) 11112 (92%)
42
ROCERETO
ET AL.
initially had advanced disease. Five of the 9 patients with advanced disease who had no residual disease after the initial surgery had a negative second-look celiotomy and none have died with disease. Five of the 6 patients who have died with disease had residual tumor after their initial surgery. These findings confirm the experience of other authors [ 10,13,15]. The ultimate survival of these patients is related to the results of the second-look and both are related to the stage of disease and the amount of residual tumor after the initial surgery. No patient should have a second-look until at least 1 year of therapy has been completed. Although it may not be possible to continue drugs such as &-platinum and Adriamycin for 1 year, the accompanying alkylating agent can be and should be continued for the remainder of the year. Some patients who may be clinically free of disease at 6 months may not be so at 1 year. In the present series, all patients with Stage I disease had a negative secondlook. Schwartz and Smith [13] and Roberts er al. [lo] reported 33 and 28% positive second-look procedures, respectively, in patients with Stage I disease. If there is a reason to treat a patient with Stage I disease with chemotherapy, then the authors feel a second-look should be performed prior to stopping that therapy. The cytologic evaluation of peritoneal washings did not correlate with positive findings in this series. All patients whose second-look procedure was histologically negative for tumor had negative peritoneal washings but only 3 patients with a positive second-look had cytology positive for tumor cells. Cytologic evaluation of washings and/or smears of the peritoneal cavity are an essential part of the second-look procedure. These should include the underside of the diaphragm. A patient should not be considered as having a negative second-look unless these washings are performed and contain no tumor ceils. Laparoscopy is being recommended by some physicians in place of, or as part of, the second-look procedure [3,11,14]. Originally, Rosenoff et al. [ 1l] used the laparoscope for the second-look operation without further surgical investigation of those patients with no evidence of disease. Three of their first 5 patients developed recurrences 12-19 months after laparoscopy. They have since suggested that patients with a negative laparoscopy also have an exploratory celiotomy to confirm the negative results. They report that since the change in their policy, 2 to 4 patients with a negative laparoscopy had tumor found at the exploratory celiotomy . 0~01s et al. [6] found a false negative rate of 55% with laparoscopy and were not able to adequately visualize the pelvis in 50% of the cases. Piver et al. [8] found that laparotomy was positive for tumor in 2 of the 10 patients with negative laparoscopies. Schwartz and Smith [13] did not use the laparoscope for the second-look, but noted that there were 24 patients who had no visible tumor, but did have microscopic tumor which would have been missed with the laparoscope. Nine of the 16 positive second-look operations in the present series had microscopic tumors only and would have been misdiagnosed with laparoscopy. The laparoscope can be used to evaluate the underside of the diaphragm, the liver capsule, some intestinal surfaces, and the underside of the visceral peritoneum.
SECOND-LOOK CELIOTOMY IN OVARIAN CANCER
43
However, the laparoscope cannnot be used well to evaluate under adhesions, the mesentery of the small bowel, the kidneys, or the retroperitoneal nodes. There is also the danger of intestinal perforation with the use of the laparoscope especially where extensive disease was initially present or where omentectomy or radiation has been utilized. The high false negative rate associated with cytologic study of peritoneal washings in these patients would reduce the ability of laparoscopy alone to be an effective second-look tool. When the laparoscope is used as part of the second-look procedure, all patients with negative findings need to have an exploratory celiotomy to confirm the laparoscopic findings. Berek ef al. [3] have suggested laparoscopy every 6 months for tumor followup. Early in their series they had 10 bowel perforations, but since the use of the needlescope was introduced to guide the entrance of the laparoscope, they have had only one bowel perforation. They felt that after 24 months (four laparoscopic procedures), the probability of recurrence is stable at less than 10%. Only 12 of 57 patients had four or more successful laparoscopies. Laparotomy to confirm the negative laparoscopy was not done. One of the purposes of the second-look procedure is to resect tumor which was not resectable at the initial operation but which has had a significant response to therapy. Wallach and Blinick [17] performed the second-look for this purpose and found that only those patients who were clinically free of disease prior to the surgery had a good prognosis for survival. Tepper et al. [16] presented 17 patients with ovarian cancer whose original operation consisted only of abdominal exploration and biopsy. These patients then received abdominopelvic irradiation concomitant with Triethylene Thiophosphoramide. A second-look celiotomy was performed 4-8 weeks after the completion of the radiotherapy on those patients whose tumors showed some response to the therapy. At the second-look operation, 9 patients were able to have complete removal of the tumor but only three of these patients were alive without evidence of disease 4-6 years from diagnosis. Piver et al. [7] have attempted to reduce the size of the tumor mass with chemotherapy in order to perform further debulking at the second-look operation. Their patients were subjected to whole abdomen irradiation after the second procedure. They were able to follow this course of therapy in 8 patients, but 5 patients have since died of recurrence. All 3 living patients had nine or more courses of chemotherapy prior to the second-look, and only one of these patients is free of disease. The authors have attempted the same type of tumor reduction with chemotherapy followed by re-exploration with very little success. Two of the patients in the present series have died of leukemia 62 and 54 months after their diagnosis. One patient had radiotherapy followed by 18 courses of L-PAM for Stage II disease while the second patient had 36 courses of LPAM without radiotherapy. Both had a negative third-look. Another patient has had an episode of pancytopenia which was seen in 9 of the patients in Reimer’s [9] report 1-12 months prior to the diagnosis of leukemia. This latter patient is now 5 years from that episode without further problems. This patient also received pelvic irradiation followed by chemotherapy with an alkylating agent. Two other patients not included in this series have died from acute nonlymphatic leukemia. One patient received chemotherapy and radiotherapy, while the other patient
44
ROCERETO ET AL.
received chemotherapy alone. All the above patients received an alkylating agent as their sole chemotherapeutic drug. While leukemia may be a real threat to patients on alkylating agents, and the risk might be decreased by stopping these agents early, the risk of dying from ovarian cancer, especially in advanced stages, is much higher. Whether these risks can be balanced on the basis of second-look findings is at present impossible to assess. The question arises whether or not patients who have irradiation should have a second-look celiotomy. Eight of the patients in this series had irradiation. Two patients had abdominopelvic therapy, while 6 had pelvic therapy alone. There was obvious evidence of radiation effect on the intestines in these patients and, therefore, the bowel was handled as little as possible. None of these patients have had any complications. The patient who has had only pelvic irradiation will most likely have few, if any problems with a second-look celiotomy. However, the patient who has had her whole abdomen irradiated, either by external beam therapy or by intraperitoneal radioactive isotopes, has had most of her intestine irradiated. Dissection through the adhesions caused by this irradiation may lead to serious bowel complications. If a second-look celiotomy is done following whole abdomen irradiation, the intestine should be treated very delicately with as little dissection as possible. Obviously, this may decrease the value of the second-look in these patients. REFERENCES 1. 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, Lancer 77, 412-417 (1957). 2. Aure, J. C., Hoeg, K., and Kolstad, P. Clinical and histologic studies of ovarian carcinoma: Long-term follow-up of 990 cases, Obstet. Gynecol. 37, l-9 (1971). 3. Berek, J. S., Griffiths, 0. T., and Leventhal, J. M. Laparoscopy for second-look evaluation in ovarian cancer, Obsret. Gynecol. 58, 192-198 (1981). 4. Hreshchyshyn, M. M. Single-drug therapy in ovarian cancer, Gynecol. Oncol. 1,220-232 (1973). 5. Munnell, E. W. The changing prognosis and treatment in cancer of the ovary, Amer. J. Obstet. Gynecol. 108, 790-805 (1968). 6. Ozols, R. F., Fisher, R. I., Anderson, T., Makuch, R., and Young, R. C. Peritoneoscopy in the management of ovarian cancer, Obstet. Gynecol. 140, 611-619 (1981). 7. Piver, S. M., Barlow, J. J., Lee, F. T., and Vongtama, V. Sequential therapy for advanced ovarian adenocarcinoma: Operation, chemotherapy, second-look laparotomy, and radiation therapy, Amer. J. Obstet. Gynecol. 122, 355-357 (1975). 8. Piver, S. M., Lele, S. B., Barlow, J. J., and Gamarra, M. Second-look laparoscopy prior to proposed second-look laparotomy, Obstet. Gynecol. 55, 571-573 (1980). 9. Reimer, R. R., Hoover, R., Fraumeni, Jr., J. F., and Young, R. C. Acute leukemia after alkylating-agent therapy of ovarian cancer, N. Engl. J. Med. 297, 177-181 (1977). 10. Roberts, W. S., Hodel, K., Rich, W. M., and DiSaia, P. J. Second-look laparotomy in the management of gynecologic malignancy, Gynecol. Oncol. 13, 345-3.55 (1982). 11. Rosenoff, S. H., Young, R. C., Anderson, T., Bagley, C., Chabner, B., Schein, P. S., Hubbard, S., and DeVita, V. T. Peritoneoscopy: A valuable staging tool in ovarian carcinoma, Ann. In?. Med. 83, 37-41 (1975). 12. Santor, B. T., Griffen, W. O., and Wangensteen, 0. H. The second-look procedure in the management of ovarian malignancies and piuedomyxoma peritonei, Sup. 50, 354-358 (1961). 13. Schwartz, P. E., and Smith, J. P. Second-look operations in ovarian cancer, Amer. J. Obster. Gynecol. 138, 1124-1130 (1980).
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CELIOTOMY
IN
OVARIAN
CANCER
45
14. Smith, W. G., Day, T. G., and Smith, J. P. The use of laparoscopy to determine the results of chemotherapy for ovarian cancer, J. Reprod. Med. 18, 257-260 (1977). 15. Smith, J. P., Delgado, G., and Rutledge, F. Second-look operation in ovarian carcinoma, Cancer 38, 1438-1442 16.
(1976).
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. Roentg. Rad. Ther. Arch. Med. 112, 755-759
(1971).
17. Wallach, R. C., and Blinick, G. The second-look operation for carcinoma of the ovary, Surg. Gynecol.
Obster.
131, 1085-1089
(1970).
18. Wangensteen, 0. H., Lewis, F. J., and Tongen, L. A. The “second-look” Lancer
71, 303-307
(1951).
in cancer surgery,