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Is There a Role for Surgical Cytoreduction in Stage IV Endometrial Cancer?
Gynecologic Oncology 78, 83– 84 (2000) doi:10.1006/gyno.2000.5907, available online at http://www.idealibrary.com on
EDITORIAL Is There a Role for Surgical Cytoreduction in Stage IV Endometrial Cancer? Adnan Munkarah, M.D. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan 48201
Endometrial cancer is the most common malignancy affecting the female genital tract and the fourth most common malignancy affecting women. The American Cancer Society estimates that 36,100 new endometrial cancer cases will be diagnosed in the year 2000 and that 6500 women will die of the disease [1]. Patients with advanced endometrial cancer represent only 10 –15% of all newly diagnosed cases, but account for up to 54% of all deaths attributed to the disease [2, 3]. There is no standard approach to the treatment of women with stage IV endometrial cancer. Recent retrospective studies have examined the role of cytoreductive surgery in those patients. In 1968, Munnell was the first to introduce the concept of surgical cytoreduction in the management of women with advanced epithelial ovarian cancer. He noted that patients who underwent a “definitive operation” had improved survival. A few years later, Griffiths used a more objective approach to assess the outcome of surgical cytoreduction. In his paper, he noted that there was a direct correlation between the size of residual disease at the completion of surgical cytoreduction and the survival of the patient. Following those two initial reports, a number of publications have supported the role of surgical cytoreduction in the management of advanced epithelial ovarian cancer. A number of theoretical considerations explain the merit of this approach. First, resection of the bulk of the tumor will reduce its adverse metabolic effects and improve the patient’s comfort and performance status. Second, the reduction in the size of the large tumor implants will enhance tumor perfusion and, thus, improve drug delivery. In addition, a better blood supply may increase the proliferating fraction of the tumor, making it more susceptible to chemotherapy. Third, reducing the number of viable tumor cells will decrease the rate of spontaneous mutations associated with drug resistance as proposed in the Goldie–Coldman model. Finally, Morton suggested that tumor cytoreduction may help to enhance the host immune function. Would the same concepts apply to endometrial cancer? In the absence of prospective data that address the role of cytoreduction in endometrial cancer, the next option is to look at the retrospective data correlating size of postsurgical residual tumor and patient survival. In 1983, Greer et al. reviewed
their experience in treating patients with metastatic endometrial adenocarcinoma confined to the abdomen with whole abdominal radiation [4]. They noted that tumor reductive surgery to 2 cm or less residual disease was beneficial. The 5-year disease-free survival for 27 patients left with residual ⱕ2 cm was 80% compared to 0% for 4 women with ⬎2 cm residual disease. A few years later, Martinez et al. looked at the Mayo clinic data using whole abdominal radiation with nodal boost in the treatment of endometrial cancer patients at high risk for intraperitoneal metastases [5]. The size of the postsurgical residual tumor was again a prognostic factor. The 5-year disease-free survival of 37 patients left with no macroscopic residual tumor was 78% compared to 70% for 10 patients with small residual implants ⱕ2 cm. More recently, three retrospective studies, including the one by Bristow et al. [6], reviewed the role of cytoreductive surgery in women with stage IV endometrial cancer. All three studies found a direct correlation between surgical outcome and patient survival. Goff et al. [7] published their review on the outcome of 47 patients with surgical stage IV endometrial cancer. The median survival was 18 months in 29 women who had surgically resectable disease compared to 8 months in 18 women who did not undergo surgical resection (P ⫽ 0.0001). The size of residual tumors in the surgically resected group was not mentioned. In a study by Chi et al. [8] 55 patients with surgical stage IV endometrial cancer were divided into three groups: group I consisted of 24 patients (44%) who underwent optimal cytoreduction (diameter of largest residual tumor ⱕ2 cm); group II had 21 patients (38%) who had suboptimal cytoreduction (⬎2 cm residual nodules); and group III consisted of 10 patients (18%) deemed to have unresectable tumor. The median survival was 31 months for patients in group I, 12 months for group II, and 8 months for group III (P ⬍ 0.01). In this issue of the journal, the study by Bristow et al. [6] is a retrospective review of the surgical management of and outcome in 65 patients with stage IVB endometrial carcinoma. Optimal cytoreduction defined as residual tumor ⱕ1 cm in maximal diameter was accomplished in 36 patients (55.4%), while 29 patients (44.6%) had suboptimal cytoreduction. The median survival rates were 34 and 11 months, respectively 83
0090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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(P ⫽ 0.0001). Interestingly, the main survival advantage was seen in women left with microscopic (no macroscopic) residual tumor; their median survival was 40.6 months compared to 15.4 months in those with macroscopic residual disease ⱕ1 cm (P ⫽ 0.0001). Unfortunately, detailed data regarding postoperative morbidity were not available in any of the three referenced studies. The identification of factors that predict the outcome of surgical cytoreduction and thus help in selecting patients who would benefit from surgery will be extremely valuable in the planning of therapy. In the study by Goff [7], the reasons for a decision against surgical cytoreduction included lung metastases (22.2%), bladder invasion (22.2%), clinical involvement of the pelvic side wall (16.7%), distant bone metastases (11.1%), liver metastases (11.1%), and diffuse peritoneal carcinomatosis (16.7%). Of 29 women who underwent surgical resection, 5 had lung metastases, 1 had liver metastases, and 1 had bone metastases. The site of extra-abdominal metastasis was not a prognostic factor for survival in that study. Interestingly, two of the long-term survivors were women with pulmonary metastases who had undergone primary cytoreduction. In the paper by Chi [8], extra-abdominal metastases were present in 21% of group I patients, 43% of group II, and 40% of group III, a difference that is not statistically significant (P ⫽ 0.29). Extra-abdominal metastasis did not impact survival. In the present study by Bristow et al., extra-abdominal sites of metastases were noted in 13.8% of their patients. Two factors negatively affected the success of the surgical cytoreduction: (1) extension into the pelvis and (2) presence of upper abdominal disease. Only 31.3% of patients with disease in upper abdominal sites achieved optimal surgical status. In addition, the site of extra-abdominal disease seemed important. All patients whose extra-abdominal disease was limited to the pleura were optimally debulked; on the other hand, no patient with another site of extra-abdominal metastasis achieved optimal cytoreduction. A critical question arises in discussing the role of cytoreductive surgery: Is the benefit the result of tumor biology or surgical effort? In the study by Greer and Hamberger [4], the authors noted a survival advantage of the patients with microscopic metastases over those who were cytoreduced to microscopic disease. This suggests that tumor biology is the principal determinant of disease outcome. On the other hand, two findings by Chi lead us to believe that the surgical effort is an important prognostic factor. First, patients who achieved optimal cytoreduction after a more radical surgery including bowel resection or extra-abdominal surgery had a survival similar to
those who did not need these procedures to achieve optimal cytoreduction. Second, there was no statistically significant difference in survival between patients found at laparotomy to have small-volume metastatic disease (ⱕ2 cm) and those who initially had metastatic disease ⬎2 cm and were subsequently cytoreduced to optimal status. The above studies are all retrospective and suffer from the potential for significant selection and reporting biases. In addition, the number of patients included is relatively small. In view of these limitations, one should be cautious not to assume that surgical cytoreduction is a standard therapy in stage IV endometrial cancer. However, those studies provide consistent data suggesting that the size of residual disease after surgery has an important impact on the survival of patients with advanced endometrial cancer. They also introduce new dilemmas and challenges that need to be addressed. First, can we improve our preoperative assessment so that we can select patients who can achieve an optimal cytoreduction and improved overall survival? Second, is there a role for neoadjuvant chemotherapy in patients with advanced endometrial cancer? Third, what is the optimal postoperative treatment after surgical cytoreduction? The relatively low frequency of stage IV endometrial cancer might delay our ability to answer these questions in the near future. However, it might be an opportune time to initiate cooperative, randomized, prospective studies to address these issues. REFERENCES 1. American Cancer Society: Cancer statistics 2000. Cancer 50(1):12, 2000 2. Behbakht K, Yordan EL, Casey C, DeGeest K, Massad LS, Kirschner CV, Wilbanks GD: Gynecol Oncol 55:363–367, 1994 3. Cook AM, Lodge N, Blake P: Stage IV endometrial carcinoma: a 10 year review of patients. Br J Radiol 72:485– 488, 1999 4. Greer BE, Hamberger AD: Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by the whole-abdomen moving-strip technique and pelvic boost irradiation. Gynecol Oncol 16:365–373, 1983 5. Martinez A, Podratz K, Schray M, Malkasian G: Results of whole abdominopelvic irradiation with nodal boost for patients with endometrial cancer at high risk of failure in the peritoneal cavity: A prospective clinical trial at the Mayo Clinic. Hematol/Oncol Clin North Am 2:431– 436, 1988 6. Bristow RE, Zerbe MJ, Rosenshein NB, Grumbine FC, Montz FJ: Stage IV endometrial carcinoma: the role of cytoreductive surgery and determinants of survival. Gynecol Oncol 78:85–91, 2000 7. Goff BA, Goodman A, Muntz HG, Fuller AF Jr, Nikrui N, Rice LW: Surgical stage IV endometrial carcinoma: a study of 47 cases. Gynecol Oncol 52:237–240, 1994 8. Chi DS, Welshinger M, Venkatraman ES, Barakat RR: The role of surgical cytoreduction in stage IV endometrial carcinoma. Gynecol Oncol 67:56 – 60, 1997
EDITORIAL Is There a Role for Surgical Cytoreduction in Stage IV Endometrial Cancer? Adnan Munkarah, M.D. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan 48201
Endometrial cancer is the most common malignancy affecting the female genital tract and the fourth most common malignancy affecting women. The American Cancer Society estimates that 36,100 new endometrial cancer cases will be diagnosed in the year 2000 and that 6500 women will die of the disease [1]. Patients with advanced endometrial cancer represent only 10 –15% of all newly diagnosed cases, but account for up to 54% of all deaths attributed to the disease [2, 3]. There is no standard approach to the treatment of women with stage IV endometrial cancer. Recent retrospective studies have examined the role of cytoreductive surgery in those patients. In 1968, Munnell was the first to introduce the concept of surgical cytoreduction in the management of women with advanced epithelial ovarian cancer. He noted that patients who underwent a “definitive operation” had improved survival. A few years later, Griffiths used a more objective approach to assess the outcome of surgical cytoreduction. In his paper, he noted that there was a direct correlation between the size of residual disease at the completion of surgical cytoreduction and the survival of the patient. Following those two initial reports, a number of publications have supported the role of surgical cytoreduction in the management of advanced epithelial ovarian cancer. A number of theoretical considerations explain the merit of this approach. First, resection of the bulk of the tumor will reduce its adverse metabolic effects and improve the patient’s comfort and performance status. Second, the reduction in the size of the large tumor implants will enhance tumor perfusion and, thus, improve drug delivery. In addition, a better blood supply may increase the proliferating fraction of the tumor, making it more susceptible to chemotherapy. Third, reducing the number of viable tumor cells will decrease the rate of spontaneous mutations associated with drug resistance as proposed in the Goldie–Coldman model. Finally, Morton suggested that tumor cytoreduction may help to enhance the host immune function. Would the same concepts apply to endometrial cancer? In the absence of prospective data that address the role of cytoreduction in endometrial cancer, the next option is to look at the retrospective data correlating size of postsurgical residual tumor and patient survival. In 1983, Greer et al. reviewed
their experience in treating patients with metastatic endometrial adenocarcinoma confined to the abdomen with whole abdominal radiation [4]. They noted that tumor reductive surgery to 2 cm or less residual disease was beneficial. The 5-year disease-free survival for 27 patients left with residual ⱕ2 cm was 80% compared to 0% for 4 women with ⬎2 cm residual disease. A few years later, Martinez et al. looked at the Mayo clinic data using whole abdominal radiation with nodal boost in the treatment of endometrial cancer patients at high risk for intraperitoneal metastases [5]. The size of the postsurgical residual tumor was again a prognostic factor. The 5-year disease-free survival of 37 patients left with no macroscopic residual tumor was 78% compared to 70% for 10 patients with small residual implants ⱕ2 cm. More recently, three retrospective studies, including the one by Bristow et al. [6], reviewed the role of cytoreductive surgery in women with stage IV endometrial cancer. All three studies found a direct correlation between surgical outcome and patient survival. Goff et al. [7] published their review on the outcome of 47 patients with surgical stage IV endometrial cancer. The median survival was 18 months in 29 women who had surgically resectable disease compared to 8 months in 18 women who did not undergo surgical resection (P ⫽ 0.0001). The size of residual tumors in the surgically resected group was not mentioned. In a study by Chi et al. [8] 55 patients with surgical stage IV endometrial cancer were divided into three groups: group I consisted of 24 patients (44%) who underwent optimal cytoreduction (diameter of largest residual tumor ⱕ2 cm); group II had 21 patients (38%) who had suboptimal cytoreduction (⬎2 cm residual nodules); and group III consisted of 10 patients (18%) deemed to have unresectable tumor. The median survival was 31 months for patients in group I, 12 months for group II, and 8 months for group III (P ⬍ 0.01). In this issue of the journal, the study by Bristow et al. [6] is a retrospective review of the surgical management of and outcome in 65 patients with stage IVB endometrial carcinoma. Optimal cytoreduction defined as residual tumor ⱕ1 cm in maximal diameter was accomplished in 36 patients (55.4%), while 29 patients (44.6%) had suboptimal cytoreduction. The median survival rates were 34 and 11 months, respectively 83
0090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
84
EDITORIAL
(P ⫽ 0.0001). Interestingly, the main survival advantage was seen in women left with microscopic (no macroscopic) residual tumor; their median survival was 40.6 months compared to 15.4 months in those with macroscopic residual disease ⱕ1 cm (P ⫽ 0.0001). Unfortunately, detailed data regarding postoperative morbidity were not available in any of the three referenced studies. The identification of factors that predict the outcome of surgical cytoreduction and thus help in selecting patients who would benefit from surgery will be extremely valuable in the planning of therapy. In the study by Goff [7], the reasons for a decision against surgical cytoreduction included lung metastases (22.2%), bladder invasion (22.2%), clinical involvement of the pelvic side wall (16.7%), distant bone metastases (11.1%), liver metastases (11.1%), and diffuse peritoneal carcinomatosis (16.7%). Of 29 women who underwent surgical resection, 5 had lung metastases, 1 had liver metastases, and 1 had bone metastases. The site of extra-abdominal metastasis was not a prognostic factor for survival in that study. Interestingly, two of the long-term survivors were women with pulmonary metastases who had undergone primary cytoreduction. In the paper by Chi [8], extra-abdominal metastases were present in 21% of group I patients, 43% of group II, and 40% of group III, a difference that is not statistically significant (P ⫽ 0.29). Extra-abdominal metastasis did not impact survival. In the present study by Bristow et al., extra-abdominal sites of metastases were noted in 13.8% of their patients. Two factors negatively affected the success of the surgical cytoreduction: (1) extension into the pelvis and (2) presence of upper abdominal disease. Only 31.3% of patients with disease in upper abdominal sites achieved optimal surgical status. In addition, the site of extra-abdominal disease seemed important. All patients whose extra-abdominal disease was limited to the pleura were optimally debulked; on the other hand, no patient with another site of extra-abdominal metastasis achieved optimal cytoreduction. A critical question arises in discussing the role of cytoreductive surgery: Is the benefit the result of tumor biology or surgical effort? In the study by Greer and Hamberger [4], the authors noted a survival advantage of the patients with microscopic metastases over those who were cytoreduced to microscopic disease. This suggests that tumor biology is the principal determinant of disease outcome. On the other hand, two findings by Chi lead us to believe that the surgical effort is an important prognostic factor. First, patients who achieved optimal cytoreduction after a more radical surgery including bowel resection or extra-abdominal surgery had a survival similar to
those who did not need these procedures to achieve optimal cytoreduction. Second, there was no statistically significant difference in survival between patients found at laparotomy to have small-volume metastatic disease (ⱕ2 cm) and those who initially had metastatic disease ⬎2 cm and were subsequently cytoreduced to optimal status. The above studies are all retrospective and suffer from the potential for significant selection and reporting biases. In addition, the number of patients included is relatively small. In view of these limitations, one should be cautious not to assume that surgical cytoreduction is a standard therapy in stage IV endometrial cancer. However, those studies provide consistent data suggesting that the size of residual disease after surgery has an important impact on the survival of patients with advanced endometrial cancer. They also introduce new dilemmas and challenges that need to be addressed. First, can we improve our preoperative assessment so that we can select patients who can achieve an optimal cytoreduction and improved overall survival? Second, is there a role for neoadjuvant chemotherapy in patients with advanced endometrial cancer? Third, what is the optimal postoperative treatment after surgical cytoreduction? The relatively low frequency of stage IV endometrial cancer might delay our ability to answer these questions in the near future. However, it might be an opportune time to initiate cooperative, randomized, prospective studies to address these issues. REFERENCES 1. American Cancer Society: Cancer statistics 2000. Cancer 50(1):12, 2000 2. Behbakht K, Yordan EL, Casey C, DeGeest K, Massad LS, Kirschner CV, Wilbanks GD: Gynecol Oncol 55:363–367, 1994 3. Cook AM, Lodge N, Blake P: Stage IV endometrial carcinoma: a 10 year review of patients. Br J Radiol 72:485– 488, 1999 4. Greer BE, Hamberger AD: Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by the whole-abdomen moving-strip technique and pelvic boost irradiation. Gynecol Oncol 16:365–373, 1983 5. Martinez A, Podratz K, Schray M, Malkasian G: Results of whole abdominopelvic irradiation with nodal boost for patients with endometrial cancer at high risk of failure in the peritoneal cavity: A prospective clinical trial at the Mayo Clinic. Hematol/Oncol Clin North Am 2:431– 436, 1988 6. Bristow RE, Zerbe MJ, Rosenshein NB, Grumbine FC, Montz FJ: Stage IV endometrial carcinoma: the role of cytoreductive surgery and determinants of survival. Gynecol Oncol 78:85–91, 2000 7. Goff BA, Goodman A, Muntz HG, Fuller AF Jr, Nikrui N, Rice LW: Surgical stage IV endometrial carcinoma: a study of 47 cases. Gynecol Oncol 52:237–240, 1994 8. Chi DS, Welshinger M, Venkatraman ES, Barakat RR: The role of surgical cytoreduction in stage IV endometrial carcinoma. Gynecol Oncol 67:56 – 60, 1997