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Reexploration after treatment for uterine sarcoma
GYNECOLOGIC
ONCOLOGY
16, l-5 (1983)
Reexploration after Treatment for Uterine Sarcoma EDWARD KAREN
V. HANNIGAN, M.D.,*,’ RALPH S. FREEDMAN, M.D.,* S. ELDER, M.S.,t AND FELIX N. RUTLEDGE, M.D.*
*Department of Gynecology, University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030, and fOfjce of Academic Computing and Biostatistics, University of Texas Medical Branch, Galveston, Texas 77550
Received April 1, 1982 Eleven patients treated with combination chemotherapy and radiotherapy for uterine sarcoma were reexplored after an interval of therapy. In none of the eight patients who were free of persistent sarcoma at the time of reexploration, did tumor recur during the period of follow-up. Two patients had all macroscopically visible residual sarcoma resected at reexploration and remain free of disease. The second-look laparotomy after a period of therapy may provide valuable prognostic information for planning therapy for patients who have metastatic or locally recurrent sarcoma.
Reexploration of the abdomen after therapy, a second-look laparotomy, is an accepted and valuable part of the treatment for patients with ovarian carcinoma [l-3]. The three clear indications for second-look laparotomy in ovarian cancer are (1) to assess the effectiveness of therapy, so that chemotherapy may be discontinued if no residual tumor is found; (2) to resect residual disease if present; and (3) if the residual tumor is not resectable, to accurately map the location and extent of the neoplasm as an aid in treatment planning. For patients with no evidence of malignancy at the second-look laparotomy, the probability of subsequent recurrence of ovarian carcinoma has been found to be less than 10% [l]. For patients with residual tumor at reexploration, total resection has been associated with dramatic improvements in length of survival [ 1,2]. There is some controversy as to whether the techniques that have evolved for the reexploration of patients with ovarian carcinoma can be used to appropriately evaluate patients with uterine sarcomas. The biologic behavior of metastatic sarcoma is believed to be dramatically different from that of the epithelial tumors of the ovary. Early vascular and lymphatic spread, as well as early parenchymal organ involvement, are believed to occur with greater frequency in patients with sarcomatosis than in patients with epithelial ovarian cancer. Until recently, patients with metastatic uterine sarcoma have had such a poor prognosis that the utility of a second-look laparotomy has been moot. Currently, however, a number of ’ To whom reprint requests should be addressed: Department of Gynecology, University of Texas Medical Branch, Galveston, Tex. 77550. 1 0090-8258/83$1.50 Copyright 0 1983 by Academic Press. Inc. All rights of reproduction in any form reserved.
2
HANNIGAN
ET AL.
patients are surviving for an extended period without evidence of persistent or recurrent sarcoma after receiving aggressive radiotherapy and/or chemotherapy. The purpose of this report is to review the clinical course of a group of these patients who were reexplored after therapy for metastatic uterine sarcomas. MATERIALS
AND METHODS
The clinical course of 106 patients treated at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1970 and 1979 was reviewed. All patients were treated for metastatic or locally advanced sarcoma of uterine origin. Of these patients, 47 (44%) were diagnosed as having uterine leiomyosarcoma, 44 (42%) a mixed-mesodermal sarcoma, 13 (12%) an endometrial stromal sarcoma, and 2 (2%) an unclassifiable sarcoma of uterine origin. Not all tumors were graded histologically. No mixed-mesodermal sarcoma was graded. For other histologic types if the only material submitted for evaluation originated in a metastatic site, no grading was performed. Of 39 graded leiomyosarcomas, 14 (36%) were determined to represent a low-grade smooth-muscle tumor on the basis of either mitotic index or nuclear pleiomorphism. Of 11 graded stromal sarcomas, 8 (73%) were classified as low grade. The median age of the 106 patients with advanced sarcoma was 56 years; they ranged from 22 to 89 years old. There was no significant difference between the median ages of any group when compared by histologic type. For patients with leiomyosarcoma and stromal sarcoma there was no apparent relationship between age and grade. Of these 106 patients, 90 received at lease one course of cytotoxic chemotherapy, with or without associated radiotherapy. Sixty-eight patients received some form of radiotherapy; 28 of whom received postoperative radiotherapy given by the abdominal-strip irradiation technique [4] with an additional treatment boost to a pelvic field. The remaining 40 patients who received radiotherapy were treated only through pelvic fields. After a period of therapy, 11 of these 106patients underwent a repeat exploratory laparotomy. The remainder of this report concerns the clinical course of these 11 patients. The specific histologic types of uterine sarcoma encountered in these patients are noted in Table 1. Five patients had leiomyosarcoma, three of whom were considered to have a low-grade smooth-muscle tumor. Three patients had an endometrial stromal sarcoma, two of whom were considered to have a low-grade sarcoma, and three patients had mixed-mesodermal sarcoma. The median age of these 11 patients at the time of diagnosis of uterine sarcoma was 40 years; the range was 26 to 55 years. All patients underwent abdominal hysterectomy. TABLE HISTOLOGIC
I
TYPES OF UTERINE
SARCOMA
Leiomyosarcoma
5
Mixed-mesodermal sarcoma Endometrial stromal sarcoma
3 3
REEXPLORATION
FOR UTERINE
SARCOMA
3
The size and location of metastatic deposits of tumor were documented at this laparotomy. Although attempts were made to resect easily accessible sarcoma, no patient had all tumor completely resected at that time. All patients received external irradiation; two patients received preoperative pelvic irradiation and nine patients received postoperative irradiation. Seven of the nine patients who received postoperative radiotherapy were treated by the abdominal-strip irradiation technique with an additional boost to a pelvic field. While two patients received only pelvic irradiation postoperatively, all known disease was included within the treatment portal. All patients received combination VAC chemotherapy, consisting of weekly vincristine (1.5 mg per square meter of body surface area weekly for 12 weeks), actinomycin D (0.5 mg daily for 5 days every 4 weeks), and cyclophosphamide (300 mg daily for 5 days every 4 weeks). Prior to beginning chemotherapy only two patients had clearly measurable lesions on either physical examination or X ray. In one of these patients, the lesion completely disappeared after two courses of therapy. The other patient had a greater than 50% reduction in the size of a single pulmonary nodule after two courses of therapy; this lung lesion was then treated with 3000 rad external irradiation over 3 weeks, which resulted in complete disappearance of the lesion. Seven patients underwent scheduled reexploration after a minimum of 12 courses of chemotherapy; the remaining four patients were explored at the time of laparotomy for correction of small-bowel obstruction. These four patients had received from 4 to 12 courses of chemotherapy prior to reexploration. The technique for reexploration for the scheduled second-look laparotomy was similar to that described for ovarian carcinoma [I]. Multiple biopsies were obtained from the pelvis, abdominal sidewalls, diaphragm, and the serosal surfaces of the abdominal contents. A selective pelvic lymph node sampling was performed, involving removal of representative nodes from the common iliac and hypogastric nodal groups. In addition, washings for cytologic evaluation were obtained from the pelvis and both paracolic gutters. The patients explored in conjunction with the repair of a small-bowel obstruction received macroscopic inspection of the abdomen; no systematic staging biopsies were obtained. RESULTS
The findings at reexploration are given in Table 2. Eight patients had no evidence of persistent sarcoma at reexploration, four at a scheduled second-look laparotomy, and four at an exploration associated with the treatment of smallbowel obstruction. Chemotherapy was discontinued in all of these patients as a result of the operative findings. Of these eight women, seven remain free of sarcoma after a minimum follow-up of 19 months, and a median follow-up of 72 months. The remaining patient died of metabolic complications associated with small-bowel bypass 6 months after surgery. At her autopsy there was no evidence of residual sarcoma. Three patients had gross sarcoma at the time of the scheduled second look. One patient had multiple small nodules of metastatic mixed-mesodermal sarcoma along the mesentery and the serosal surface of the small bowel, which could not be resected. After comparing these findings with those at her initial lapa-
4
HANNIGAN
ET AL.
TABLE 2 RESULTS OF REEXPLORATION
Number Scheduled second look-7 patients Grossly positive-stable disease Grossly positive-partial response Grossly negative-microscopically positive Grossly negative-microscopically negative Exploration associated with therapy of small-bowel obstruction Grossly negative-microscopically negative
rotomy l-year earlier, she was felt to have stable sarcoma and received four additional courses of VAC chemotherapy. After these four courses of therapy, however, her disease was observed to be growing; she died 8 months after reexploration. Two patients had multiple foci of leiomyosarcoma on the peritoneal covering of the pelvic sidewalls. These deposits were completely resected at the time of second-look laparotomy. The patients received additional VAC chemotherapy for 12 and 24 months, respectively. One patient then discontinued therapy and is alive and free of sarcoma l&months later. The other patient, after 24 months of chemotherapy, had a microscopically negative third-look laparotomy. She is without evidence of recurrence 26 months after that exploration. DISCUSSION
In several areas, the 11 patients who underwent reexploration were different from our larger group of patients with metastatic uterine sarcoma. A high proportion of these patients (5 of 11 or 46%) had either low-grade leiomyosarcoma or stromal sarcoma. Although clinical experience has confirmed that extrauterine sarcoma, regardless of grade, results in widespread metastases and death, tumors with low-mitotic index or little pleiomorphism have been associated with long periods of clinically stable disease [5]. The median age of these patients is 16 years less than the median age of the larger group of 106 patients with metastatic uterine sarcoma, a factor associated with higher response rates to therapy [6]. All 11 patients received combination chemotherapy and radiotherapy; seven received simultaneous abdominal-strip irradiation and weekly vincristine. Despite the favorable prognostic factors of age and grade, all had advanced extrauterine sarcoma prior to initiation to therapy. In the eight patients who were free of evidence of sarcoma at reexploration, no disease has recurred, thus confirming the prognostic value of a negative second-look laparotomy and justifying the discontinuance of therapy when no sarcoma is discovered. After chemotherapy was discontinued, these patients were observed very closely. It has been our practice to follow patients with ovarian epithelial malignancy with monthly examinations for the first 12 months after a negative second-look laparotomy, bimonthly examinations for the next 12 months, and trimonthly examinations until the fifth postoperative year. These recommendations are currently being followed in patients with uterine sarcoma following a negative second look.
REEXPLORATION
FOR UTERINE
SARCOMA
5
Two patients with residual sarcoma at reexploration had their tumor completely resected, received additional VAC chemotherapy, and are now without evidence of recurrence. Although this is a very small number of patients, it suggests that resection of residual tumor at second-look laparotomy improves the survival rate of patients with sarcoma. Even though the patients are few in number and represent a highly selected group of those with metastatic sarcoma, these results suggest that second-look laparotomy after a period of therapy provides prognostic information useful in planning therapy, that chemotherapy may be discontinued in patients who have no evidence of residual sarcoma at second look, and that laparotomy to remove previously unresectable sarcoma may result in long-term survivals. REFERENCES 1. Smith, J. P., Delgado, G., and Rutledge, F. Second look operation in ovarian carcinoma: Postchemotherapy, Cancer 38, 1438-1442 (1976). 2. Phillips, B. P., Buchsbaum, J. H., and Lipschutz, S. Reexploration after treatment for ovarian carcinoma, Gynecol. Oncol. 8, 339-345 (1979). 3. Curry, S. L., Zambo, M. M., Nahhas, W. A., Jashshan, A. E., Whitney, C. W., and Mortel, R. Second look laparotomy for ovarian cancer, Gynecol. On&. 11, 114-I 18 (1981). 4. Delclos, L., Braun, E. J., Herrera, J. R., Sampier, V. A., and Van Roosenbeck, E. Whole abdominal irradiation by cobalt-60 moving strip technic, Radiology 81, 632-641 (1963). 5. Kempson, R. L., and Bari, W. Uterine sarcomas: Classification, diagnosis, and prognosis, Hum. Pathd. 1, 331-349 (1970). 6. Hannigan, E. V., Freedman, R. S., Elder, K. W., and Rutledge, F. N. Treatment of advanced uterine sarcoma with vincristine, actinomycin-D, and cyclophosphamide, Gynecol. Oncol., 15, 224-229 (1983).
ONCOLOGY
16, l-5 (1983)
Reexploration after Treatment for Uterine Sarcoma EDWARD KAREN
V. HANNIGAN, M.D.,*,’ RALPH S. FREEDMAN, M.D.,* S. ELDER, M.S.,t AND FELIX N. RUTLEDGE, M.D.*
*Department of Gynecology, University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030, and fOfjce of Academic Computing and Biostatistics, University of Texas Medical Branch, Galveston, Texas 77550
Received April 1, 1982 Eleven patients treated with combination chemotherapy and radiotherapy for uterine sarcoma were reexplored after an interval of therapy. In none of the eight patients who were free of persistent sarcoma at the time of reexploration, did tumor recur during the period of follow-up. Two patients had all macroscopically visible residual sarcoma resected at reexploration and remain free of disease. The second-look laparotomy after a period of therapy may provide valuable prognostic information for planning therapy for patients who have metastatic or locally recurrent sarcoma.
Reexploration of the abdomen after therapy, a second-look laparotomy, is an accepted and valuable part of the treatment for patients with ovarian carcinoma [l-3]. The three clear indications for second-look laparotomy in ovarian cancer are (1) to assess the effectiveness of therapy, so that chemotherapy may be discontinued if no residual tumor is found; (2) to resect residual disease if present; and (3) if the residual tumor is not resectable, to accurately map the location and extent of the neoplasm as an aid in treatment planning. For patients with no evidence of malignancy at the second-look laparotomy, the probability of subsequent recurrence of ovarian carcinoma has been found to be less than 10% [l]. For patients with residual tumor at reexploration, total resection has been associated with dramatic improvements in length of survival [ 1,2]. There is some controversy as to whether the techniques that have evolved for the reexploration of patients with ovarian carcinoma can be used to appropriately evaluate patients with uterine sarcomas. The biologic behavior of metastatic sarcoma is believed to be dramatically different from that of the epithelial tumors of the ovary. Early vascular and lymphatic spread, as well as early parenchymal organ involvement, are believed to occur with greater frequency in patients with sarcomatosis than in patients with epithelial ovarian cancer. Until recently, patients with metastatic uterine sarcoma have had such a poor prognosis that the utility of a second-look laparotomy has been moot. Currently, however, a number of ’ To whom reprint requests should be addressed: Department of Gynecology, University of Texas Medical Branch, Galveston, Tex. 77550. 1 0090-8258/83$1.50 Copyright 0 1983 by Academic Press. Inc. All rights of reproduction in any form reserved.
2
HANNIGAN
ET AL.
patients are surviving for an extended period without evidence of persistent or recurrent sarcoma after receiving aggressive radiotherapy and/or chemotherapy. The purpose of this report is to review the clinical course of a group of these patients who were reexplored after therapy for metastatic uterine sarcomas. MATERIALS
AND METHODS
The clinical course of 106 patients treated at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1970 and 1979 was reviewed. All patients were treated for metastatic or locally advanced sarcoma of uterine origin. Of these patients, 47 (44%) were diagnosed as having uterine leiomyosarcoma, 44 (42%) a mixed-mesodermal sarcoma, 13 (12%) an endometrial stromal sarcoma, and 2 (2%) an unclassifiable sarcoma of uterine origin. Not all tumors were graded histologically. No mixed-mesodermal sarcoma was graded. For other histologic types if the only material submitted for evaluation originated in a metastatic site, no grading was performed. Of 39 graded leiomyosarcomas, 14 (36%) were determined to represent a low-grade smooth-muscle tumor on the basis of either mitotic index or nuclear pleiomorphism. Of 11 graded stromal sarcomas, 8 (73%) were classified as low grade. The median age of the 106 patients with advanced sarcoma was 56 years; they ranged from 22 to 89 years old. There was no significant difference between the median ages of any group when compared by histologic type. For patients with leiomyosarcoma and stromal sarcoma there was no apparent relationship between age and grade. Of these 106 patients, 90 received at lease one course of cytotoxic chemotherapy, with or without associated radiotherapy. Sixty-eight patients received some form of radiotherapy; 28 of whom received postoperative radiotherapy given by the abdominal-strip irradiation technique [4] with an additional treatment boost to a pelvic field. The remaining 40 patients who received radiotherapy were treated only through pelvic fields. After a period of therapy, 11 of these 106patients underwent a repeat exploratory laparotomy. The remainder of this report concerns the clinical course of these 11 patients. The specific histologic types of uterine sarcoma encountered in these patients are noted in Table 1. Five patients had leiomyosarcoma, three of whom were considered to have a low-grade smooth-muscle tumor. Three patients had an endometrial stromal sarcoma, two of whom were considered to have a low-grade sarcoma, and three patients had mixed-mesodermal sarcoma. The median age of these 11 patients at the time of diagnosis of uterine sarcoma was 40 years; the range was 26 to 55 years. All patients underwent abdominal hysterectomy. TABLE HISTOLOGIC
I
TYPES OF UTERINE
SARCOMA
Leiomyosarcoma
5
Mixed-mesodermal sarcoma Endometrial stromal sarcoma
3 3
REEXPLORATION
FOR UTERINE
SARCOMA
3
The size and location of metastatic deposits of tumor were documented at this laparotomy. Although attempts were made to resect easily accessible sarcoma, no patient had all tumor completely resected at that time. All patients received external irradiation; two patients received preoperative pelvic irradiation and nine patients received postoperative irradiation. Seven of the nine patients who received postoperative radiotherapy were treated by the abdominal-strip irradiation technique with an additional boost to a pelvic field. While two patients received only pelvic irradiation postoperatively, all known disease was included within the treatment portal. All patients received combination VAC chemotherapy, consisting of weekly vincristine (1.5 mg per square meter of body surface area weekly for 12 weeks), actinomycin D (0.5 mg daily for 5 days every 4 weeks), and cyclophosphamide (300 mg daily for 5 days every 4 weeks). Prior to beginning chemotherapy only two patients had clearly measurable lesions on either physical examination or X ray. In one of these patients, the lesion completely disappeared after two courses of therapy. The other patient had a greater than 50% reduction in the size of a single pulmonary nodule after two courses of therapy; this lung lesion was then treated with 3000 rad external irradiation over 3 weeks, which resulted in complete disappearance of the lesion. Seven patients underwent scheduled reexploration after a minimum of 12 courses of chemotherapy; the remaining four patients were explored at the time of laparotomy for correction of small-bowel obstruction. These four patients had received from 4 to 12 courses of chemotherapy prior to reexploration. The technique for reexploration for the scheduled second-look laparotomy was similar to that described for ovarian carcinoma [I]. Multiple biopsies were obtained from the pelvis, abdominal sidewalls, diaphragm, and the serosal surfaces of the abdominal contents. A selective pelvic lymph node sampling was performed, involving removal of representative nodes from the common iliac and hypogastric nodal groups. In addition, washings for cytologic evaluation were obtained from the pelvis and both paracolic gutters. The patients explored in conjunction with the repair of a small-bowel obstruction received macroscopic inspection of the abdomen; no systematic staging biopsies were obtained. RESULTS
The findings at reexploration are given in Table 2. Eight patients had no evidence of persistent sarcoma at reexploration, four at a scheduled second-look laparotomy, and four at an exploration associated with the treatment of smallbowel obstruction. Chemotherapy was discontinued in all of these patients as a result of the operative findings. Of these eight women, seven remain free of sarcoma after a minimum follow-up of 19 months, and a median follow-up of 72 months. The remaining patient died of metabolic complications associated with small-bowel bypass 6 months after surgery. At her autopsy there was no evidence of residual sarcoma. Three patients had gross sarcoma at the time of the scheduled second look. One patient had multiple small nodules of metastatic mixed-mesodermal sarcoma along the mesentery and the serosal surface of the small bowel, which could not be resected. After comparing these findings with those at her initial lapa-
4
HANNIGAN
ET AL.
TABLE 2 RESULTS OF REEXPLORATION
Number Scheduled second look-7 patients Grossly positive-stable disease Grossly positive-partial response Grossly negative-microscopically positive Grossly negative-microscopically negative Exploration associated with therapy of small-bowel obstruction Grossly negative-microscopically negative
rotomy l-year earlier, she was felt to have stable sarcoma and received four additional courses of VAC chemotherapy. After these four courses of therapy, however, her disease was observed to be growing; she died 8 months after reexploration. Two patients had multiple foci of leiomyosarcoma on the peritoneal covering of the pelvic sidewalls. These deposits were completely resected at the time of second-look laparotomy. The patients received additional VAC chemotherapy for 12 and 24 months, respectively. One patient then discontinued therapy and is alive and free of sarcoma l&months later. The other patient, after 24 months of chemotherapy, had a microscopically negative third-look laparotomy. She is without evidence of recurrence 26 months after that exploration. DISCUSSION
In several areas, the 11 patients who underwent reexploration were different from our larger group of patients with metastatic uterine sarcoma. A high proportion of these patients (5 of 11 or 46%) had either low-grade leiomyosarcoma or stromal sarcoma. Although clinical experience has confirmed that extrauterine sarcoma, regardless of grade, results in widespread metastases and death, tumors with low-mitotic index or little pleiomorphism have been associated with long periods of clinically stable disease [5]. The median age of these patients is 16 years less than the median age of the larger group of 106 patients with metastatic uterine sarcoma, a factor associated with higher response rates to therapy [6]. All 11 patients received combination chemotherapy and radiotherapy; seven received simultaneous abdominal-strip irradiation and weekly vincristine. Despite the favorable prognostic factors of age and grade, all had advanced extrauterine sarcoma prior to initiation to therapy. In the eight patients who were free of evidence of sarcoma at reexploration, no disease has recurred, thus confirming the prognostic value of a negative second-look laparotomy and justifying the discontinuance of therapy when no sarcoma is discovered. After chemotherapy was discontinued, these patients were observed very closely. It has been our practice to follow patients with ovarian epithelial malignancy with monthly examinations for the first 12 months after a negative second-look laparotomy, bimonthly examinations for the next 12 months, and trimonthly examinations until the fifth postoperative year. These recommendations are currently being followed in patients with uterine sarcoma following a negative second look.
REEXPLORATION
FOR UTERINE
SARCOMA
5
Two patients with residual sarcoma at reexploration had their tumor completely resected, received additional VAC chemotherapy, and are now without evidence of recurrence. Although this is a very small number of patients, it suggests that resection of residual tumor at second-look laparotomy improves the survival rate of patients with sarcoma. Even though the patients are few in number and represent a highly selected group of those with metastatic sarcoma, these results suggest that second-look laparotomy after a period of therapy provides prognostic information useful in planning therapy, that chemotherapy may be discontinued in patients who have no evidence of residual sarcoma at second look, and that laparotomy to remove previously unresectable sarcoma may result in long-term survivals. REFERENCES 1. Smith, J. P., Delgado, G., and Rutledge, F. Second look operation in ovarian carcinoma: Postchemotherapy, Cancer 38, 1438-1442 (1976). 2. Phillips, B. P., Buchsbaum, J. H., and Lipschutz, S. Reexploration after treatment for ovarian carcinoma, Gynecol. Oncol. 8, 339-345 (1979). 3. Curry, S. L., Zambo, M. M., Nahhas, W. A., Jashshan, A. E., Whitney, C. W., and Mortel, R. Second look laparotomy for ovarian cancer, Gynecol. On&. 11, 114-I 18 (1981). 4. Delclos, L., Braun, E. J., Herrera, J. R., Sampier, V. A., and Van Roosenbeck, E. Whole abdominal irradiation by cobalt-60 moving strip technic, Radiology 81, 632-641 (1963). 5. Kempson, R. L., and Bari, W. Uterine sarcomas: Classification, diagnosis, and prognosis, Hum. Pathd. 1, 331-349 (1970). 6. Hannigan, E. V., Freedman, R. S., Elder, K. W., and Rutledge, F. N. Treatment of advanced uterine sarcoma with vincristine, actinomycin-D, and cyclophosphamide, Gynecol. Oncol., 15, 224-229 (1983).