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Survival after multimodality treatment for stage IIIC endometrial cancer
Survival after multimodality treatment for stage IIIC endometrial cancer Laura A. Katz, MD, Stephen J. Andrews, MD, and James Fanning, DO Toledo, Ohio OBJECTIVE: Our purpose was to review our results of multimodality treatment of lymph node metastasis in endometrial cancer (stage IIIC). STUDY DESIGN: All patients underwent surgical staging for endometrial cancer with complete pelvic and aortic lymphadenectomy. All macroscopic nodal metastases were resected. Patients with microscopic nodal metastasis received adjuvant teletherapy, whereas those with macroscopic nodal metastasis received chemotherapy (carboplatin AUC 5 and paclitaxel 135 mg/m2 every 3 weeks for 6 courses) followed by teletherapy. RESULTS: Twenty-one patients had stage IIIC disease, and one had stage IVB (inguinal nodal metastasis). Sixty-four percent of tumors were poorly differentiated. Fifty-five percent of patients had pelvic nodal metastasis only and 41% had macroscopic nodal metastasis. At a median follow-up of 3.8 years, 32% of patients had recurrence, all extrapelvic. Overall mean survival was 48 months and progression-free survival was 40 months. Overall survival for microscopic nodal metastasis was >60 months versus 35 months for macroscopic metastasis. Overall survival for pelvic nodal metastasis was 53 months versus 42 months for aorticinguinal metastasis. There were no complications from lymphadenectomy, a 22% chemotherapeutic toxicity, and a 14% radiation toxicity. CONCLUSION: Our surgical, chemotherapeutic, and radiation treatment protocol for stage IIIC endometrial cancer produced minimal toxicity and good survival. (Am J Obstet Gynecol 2001;184:1071-3.)
Key words: Endometrial cancer, multimodality treatment, survival
Endometrial cancer is the most common gynecologic cancer in the United States, with an estimated 36,100 new cases in 2000.1 Although 88% of endometrial cancer is diagnosed at an early stage, survival has not improved in the last 25 years.1 The most common site of metastatic disease is the pelvic and aortic lymph nodes (stage IIIC).2 In a MEDLINE review from 1966 to 1999, we were unable to locate any prospective randomized trials dealing with adjuvant treatment for patients with nodal metastasis. We recommend adjuvant treatment for stage IIIC endometrial cancer, depending on whether nodal metastases are microscopic or macroscopic. We recommend teletherapy (external beam radiation) for microscopic nodal metastasis, whereas those with macroscopic nodal metastasis received adjuvant chemotherapy followed by teletherapy. We surgically resect all macroscopic nodal metastasis. The purpose of this article is to review the morbidity and survival of this multimodality treatment.
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and the Department of Pathology, Medical College of Ohio. Reprint requests: James Fanning, DO, Department of Obstetrics and Gynecology, Medical College of Ohio, Richard D. Ruppert Health Center, 3130 Glendale Ave, Toledo, OH 43614-5809. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/115225 doi:10.1067/mob.2001.115225
Methods From 1994 to 1998, 22 of 153 consecutive patients who had undergone surgical staging for endometrial cancer were found to have nodal metastasis. Surgical staging consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytologic study, and bilateral pelvic and aortic lymphadenectomy. Pelvic lymphadenectomy consisted of excision of all lymphatic tissue over the external iliac artery and vein, internal iliac artery, and obturator space above the obturator nerve. Aortic lymphadenectomy consisted of excision of all lymphatic tissue over the aorta and inferior vena cava from bifurcation to duodenum. Because the number of lymph nodes reported depends on the technicians and pathologists who perform the gross and microscopic review, the adequacy of lymphadenectomy was ensured by performing the same procedure on all patients rather than by lymph node counting. Although we did not perform lymph node counting, the median number of pelvic lymph nodes reported was 18 and the median number of aortic lymph nodes was 6. All macroscopic nodal metastases were resected, and complete lymphadenectomy was performed in all cases. Patients with microscopic pelvic nodal metastasis received adjuvant teletherapy to the whole pelvis (4500 cGy directed to a 4-field box technique). Patients with microscopically positive aortic nodal metastasis received pelvic 1071
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May 2001 Am J Obstet Gynecol
Table I. Patient characteristics (N = 22 patients) Age (y, median and range) Weight (lb, median and range) Race White African American Medical comorbidities Stage IIIC IVB Grade 1 2 3
59 (38-77) 194 (108-300) 20 (91%) 2 (9%) 12 (55%) 21 (96%) 1 (4%)
Table II. Lymph node metastasis Location Pelvic Aortic Pelvic/aortic Inguinal Macroscopic Pelvic Aortic Pelvic/aortic–inguinal Positive nodes (No., median and range)
12 (55%) 3 (14%) 6 (27%) 1 (4%) 9 (41%) 5 1 3 2 (1-15)
1 (5%) 7 (31%) 14 (64%)
teletherapy with an aortic chimney (4500 cGy directed to a 4-field box technique). Patients with macroscopic nodal metastasis received chemotherapy consisting of carboplatin AUC 5 and paclitaxel 135 mg/m2 every 3 weeks for 6 courses. This chemotherapy protocol was based on ovarian cancer chemotherapy protocols. One month after chemotherapy, teletherapy was delivered as described. Statistics were analyzed with SPSS for Windows (SPSS, Chicago, Ill). Comparison of survival estimates was by the Kaplan-Meier method. Because of the small number of patients, the small number of recurrences, and the small number of deaths, mean survival was presented rather than median survival. Results Twenty-two consecutive patients were treated with this protocol. No patients were excluded and no patient refused adjuvant postoperative treatment. Patient characteristics are presented in Table I. Median age was 59 years and median weight was 194 pounds; 55% of patients had significant comorbidities (cardiovascular, 9; diabetes, 3; gastrointestinal, 2; endocrine, 2; neurologic, 1; pulmonary, 1). Twenty-one tumors were stage IIIC because of pelvic or aortic nodal metastasis and one was stage IVB because of inguinal nodal metastasis. Sixty-four percent of tumors were poorly differentiated (grade 3). The status of lymph node metastasis is presented in Table II. Fifty-five percent were pelvic nodal metastases only, and 41% were macroscopic nodal metastases. The median number of metastatic nodes was 2 (range, 1-15). At a median follow-up of 3.8 years (range, 1.8-6 years), 7 patients (32%) have had recurrences. Sites of recurrence include distal vagina (n = 1), abdomen (n = 2), distant (lungs, n = 2), and distant and abdomen (lungs, n = 2). At the present time 16 patients (73%) are alive with no evidence of disease. Survival is presented in Table III. Overall mean survival is 48 months, and progression-free survival is 40 months. Overall mean survival with microscopic nodal metastasis is >5 years, which is double the survival for patients with macroscopic nodal metastasis. Both overall and progression-free survival were increased with
pelvic nodal metastasis versus aortic-inguinal nodal metastasis, but the difference was not statistically significant. No patients had malignant cells on pelvic cytologic examination. Three patients had microscopic ovarian metastasis, and all had macroscopic nodal metastasis. Treatment was well tolerated. No patient had a complication from lymphadenectomy. Two of 9 patients (22%) had grade 3/4 toxicity from chemotherapy. Two patients had neutropenia but not neutropenic sepsis. None had thrombocytopenia. One also had temporary peripheral neuropathy. Three of 22 patients (14%) had grade 3/4 radiation complications. Two had symptomatic prolonged proctitis and 1 had significant vulvar desquamation and vaginal stenosis. Comment We present a multimodality approach to stage IIIC endometrial cancer that includes complete lymphadenectomy, resection of macroscopic nodal metastasis, and chemotherapy for macroscopic nodal metastasis. We routinely perform complete lymphadenectomy in all patients with endometrial cancer because (1) nodal status is the most important prognosticator,2 (2) results of lymphadenectomy allow tailoring of postoperative adjuvant treatment (pelvic teletherapy is withheld for stage I/II),3 (3) there is an apparent small survival advantage after lymphadenectomy,4 (4) there is no increased morbidity with lymphadenectomy,5 and (5) there is cost-effectiveness of lymphadenectomy and tailored treatment.6 We resect macroscopic nodal metastasis because of reports of increased survival after resection versus 0% without resection.7 We have adopted the strategy of giving postoperative adjuvant chemotherapy for macroscopic nodal metastasis because of the high rate of distant recurrence. In the Gynecologic Oncology Group’s (GOG) prospective surgical staging study, >75% of recurrences were distant2 in this subset of patients. Because we were attempting to treat microscopic distant metastasis, we gave adjuvant chemotherapy before radiation rather than delivering low-dose radiation-sensitizing chemotherapy, which is thought not to be effective against distant micrometastasis.
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Table III. Survival Overall survival (mo, median and range) All patients Macroscopic Microscopic Pelvic Aortic/inguinal
48 (39-56) 35 (21-50) >60 53 (45-62) 42 (28-57)
Statistical significance
Progression-free survival (mo, median and range) 40 (29-50) 23 (14-32) 49 (38-60) 44 (31-57) 34 (19-48)
P = .01 P = .21
The survival of our patients with microscopic nodal metastasis is high, with mean survival not being reached at 5 years, which is consistent with other reports. In the prospective GOG study2 in a similar group of patients, median survival also has not been reached at 5 years. The results of our treatment for macroscopic and aortic metastasis appear to be favorable. In the GOG study2 of a similar group of patients treated with radiation alone, median survival is 21 months, which is approximately half our survival of 42 months. In a report from Japan,8 a similar aggressive treatment protocol of complete nodal dissection, chemotherapy, and radiation therapy resulted in a 5-year survival rate for patients with aortic nodal metastasis of 75% compared with our 5-year survival rate of 58% and the GOG2 5year survival rate of 38%. In conclusion, our multimodality surgical, chemotherapeutic, and radiation treatment for stage III endometrial cancer produced minimal toxicity and good survival. Because this was not a prospective randomized trial, we are unable to assess the individual benefits of aggressive surgery or chemotherapy as part of this approach.
Statistical significance
P = .05 P = .48
REFERENCES
1. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33. 2. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group Study. Gynecol Oncol 1991;40:55-65. 3. Fanning J, Nanavati PJ, Hilgers RD. Surgical staging and high dose rate brachytherapy for endometrial cancer: limiting external radiotherapy to node-positive tumors. Obstet Gynecol 1996;87:1041-4. 4. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 1995;56:29-33. 5. Fanning J, Firestein S. Prospective evaluation of the morbidity of complete lymphadenectomy in endometrial cancer. Int J Gynecol Cancer 1998;8:270-3. 6. Fanning J. Treatment for early endometrial cancer: cost effective analysis. J Reprod Med 1999;44:719-23. 7. Downey GO, Potish RA, Adcock LL, Prem KA, Twiggs LB. Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 1989;160:1055-61. 8. Onda T, Yoshikawa H, Mizutani K, Mishima M, Yokota H, Nagano H, et al. Treatment of node-positive endometrial cancer with complete node dissection, chemotherapy and radiation therapy. Br J Cancer 1997;75:1836-41.
Key words: Endometrial cancer, multimodality treatment, survival
Endometrial cancer is the most common gynecologic cancer in the United States, with an estimated 36,100 new cases in 2000.1 Although 88% of endometrial cancer is diagnosed at an early stage, survival has not improved in the last 25 years.1 The most common site of metastatic disease is the pelvic and aortic lymph nodes (stage IIIC).2 In a MEDLINE review from 1966 to 1999, we were unable to locate any prospective randomized trials dealing with adjuvant treatment for patients with nodal metastasis. We recommend adjuvant treatment for stage IIIC endometrial cancer, depending on whether nodal metastases are microscopic or macroscopic. We recommend teletherapy (external beam radiation) for microscopic nodal metastasis, whereas those with macroscopic nodal metastasis received adjuvant chemotherapy followed by teletherapy. We surgically resect all macroscopic nodal metastasis. The purpose of this article is to review the morbidity and survival of this multimodality treatment.
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and the Department of Pathology, Medical College of Ohio. Reprint requests: James Fanning, DO, Department of Obstetrics and Gynecology, Medical College of Ohio, Richard D. Ruppert Health Center, 3130 Glendale Ave, Toledo, OH 43614-5809. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/115225 doi:10.1067/mob.2001.115225
Methods From 1994 to 1998, 22 of 153 consecutive patients who had undergone surgical staging for endometrial cancer were found to have nodal metastasis. Surgical staging consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytologic study, and bilateral pelvic and aortic lymphadenectomy. Pelvic lymphadenectomy consisted of excision of all lymphatic tissue over the external iliac artery and vein, internal iliac artery, and obturator space above the obturator nerve. Aortic lymphadenectomy consisted of excision of all lymphatic tissue over the aorta and inferior vena cava from bifurcation to duodenum. Because the number of lymph nodes reported depends on the technicians and pathologists who perform the gross and microscopic review, the adequacy of lymphadenectomy was ensured by performing the same procedure on all patients rather than by lymph node counting. Although we did not perform lymph node counting, the median number of pelvic lymph nodes reported was 18 and the median number of aortic lymph nodes was 6. All macroscopic nodal metastases were resected, and complete lymphadenectomy was performed in all cases. Patients with microscopic pelvic nodal metastasis received adjuvant teletherapy to the whole pelvis (4500 cGy directed to a 4-field box technique). Patients with microscopically positive aortic nodal metastasis received pelvic 1071
1072 Katz, Andrews, and Fanning
May 2001 Am J Obstet Gynecol
Table I. Patient characteristics (N = 22 patients) Age (y, median and range) Weight (lb, median and range) Race White African American Medical comorbidities Stage IIIC IVB Grade 1 2 3
59 (38-77) 194 (108-300) 20 (91%) 2 (9%) 12 (55%) 21 (96%) 1 (4%)
Table II. Lymph node metastasis Location Pelvic Aortic Pelvic/aortic Inguinal Macroscopic Pelvic Aortic Pelvic/aortic–inguinal Positive nodes (No., median and range)
12 (55%) 3 (14%) 6 (27%) 1 (4%) 9 (41%) 5 1 3 2 (1-15)
1 (5%) 7 (31%) 14 (64%)
teletherapy with an aortic chimney (4500 cGy directed to a 4-field box technique). Patients with macroscopic nodal metastasis received chemotherapy consisting of carboplatin AUC 5 and paclitaxel 135 mg/m2 every 3 weeks for 6 courses. This chemotherapy protocol was based on ovarian cancer chemotherapy protocols. One month after chemotherapy, teletherapy was delivered as described. Statistics were analyzed with SPSS for Windows (SPSS, Chicago, Ill). Comparison of survival estimates was by the Kaplan-Meier method. Because of the small number of patients, the small number of recurrences, and the small number of deaths, mean survival was presented rather than median survival. Results Twenty-two consecutive patients were treated with this protocol. No patients were excluded and no patient refused adjuvant postoperative treatment. Patient characteristics are presented in Table I. Median age was 59 years and median weight was 194 pounds; 55% of patients had significant comorbidities (cardiovascular, 9; diabetes, 3; gastrointestinal, 2; endocrine, 2; neurologic, 1; pulmonary, 1). Twenty-one tumors were stage IIIC because of pelvic or aortic nodal metastasis and one was stage IVB because of inguinal nodal metastasis. Sixty-four percent of tumors were poorly differentiated (grade 3). The status of lymph node metastasis is presented in Table II. Fifty-five percent were pelvic nodal metastases only, and 41% were macroscopic nodal metastases. The median number of metastatic nodes was 2 (range, 1-15). At a median follow-up of 3.8 years (range, 1.8-6 years), 7 patients (32%) have had recurrences. Sites of recurrence include distal vagina (n = 1), abdomen (n = 2), distant (lungs, n = 2), and distant and abdomen (lungs, n = 2). At the present time 16 patients (73%) are alive with no evidence of disease. Survival is presented in Table III. Overall mean survival is 48 months, and progression-free survival is 40 months. Overall mean survival with microscopic nodal metastasis is >5 years, which is double the survival for patients with macroscopic nodal metastasis. Both overall and progression-free survival were increased with
pelvic nodal metastasis versus aortic-inguinal nodal metastasis, but the difference was not statistically significant. No patients had malignant cells on pelvic cytologic examination. Three patients had microscopic ovarian metastasis, and all had macroscopic nodal metastasis. Treatment was well tolerated. No patient had a complication from lymphadenectomy. Two of 9 patients (22%) had grade 3/4 toxicity from chemotherapy. Two patients had neutropenia but not neutropenic sepsis. None had thrombocytopenia. One also had temporary peripheral neuropathy. Three of 22 patients (14%) had grade 3/4 radiation complications. Two had symptomatic prolonged proctitis and 1 had significant vulvar desquamation and vaginal stenosis. Comment We present a multimodality approach to stage IIIC endometrial cancer that includes complete lymphadenectomy, resection of macroscopic nodal metastasis, and chemotherapy for macroscopic nodal metastasis. We routinely perform complete lymphadenectomy in all patients with endometrial cancer because (1) nodal status is the most important prognosticator,2 (2) results of lymphadenectomy allow tailoring of postoperative adjuvant treatment (pelvic teletherapy is withheld for stage I/II),3 (3) there is an apparent small survival advantage after lymphadenectomy,4 (4) there is no increased morbidity with lymphadenectomy,5 and (5) there is cost-effectiveness of lymphadenectomy and tailored treatment.6 We resect macroscopic nodal metastasis because of reports of increased survival after resection versus 0% without resection.7 We have adopted the strategy of giving postoperative adjuvant chemotherapy for macroscopic nodal metastasis because of the high rate of distant recurrence. In the Gynecologic Oncology Group’s (GOG) prospective surgical staging study, >75% of recurrences were distant2 in this subset of patients. Because we were attempting to treat microscopic distant metastasis, we gave adjuvant chemotherapy before radiation rather than delivering low-dose radiation-sensitizing chemotherapy, which is thought not to be effective against distant micrometastasis.
Katz, Andrews, and Fanning 1073
Volume 184, Number 6 Am J Obstet Gynecol
Table III. Survival Overall survival (mo, median and range) All patients Macroscopic Microscopic Pelvic Aortic/inguinal
48 (39-56) 35 (21-50) >60 53 (45-62) 42 (28-57)
Statistical significance
Progression-free survival (mo, median and range) 40 (29-50) 23 (14-32) 49 (38-60) 44 (31-57) 34 (19-48)
P = .01 P = .21
The survival of our patients with microscopic nodal metastasis is high, with mean survival not being reached at 5 years, which is consistent with other reports. In the prospective GOG study2 in a similar group of patients, median survival also has not been reached at 5 years. The results of our treatment for macroscopic and aortic metastasis appear to be favorable. In the GOG study2 of a similar group of patients treated with radiation alone, median survival is 21 months, which is approximately half our survival of 42 months. In a report from Japan,8 a similar aggressive treatment protocol of complete nodal dissection, chemotherapy, and radiation therapy resulted in a 5-year survival rate for patients with aortic nodal metastasis of 75% compared with our 5-year survival rate of 58% and the GOG2 5year survival rate of 38%. In conclusion, our multimodality surgical, chemotherapeutic, and radiation treatment for stage III endometrial cancer produced minimal toxicity and good survival. Because this was not a prospective randomized trial, we are unable to assess the individual benefits of aggressive surgery or chemotherapy as part of this approach.
Statistical significance
P = .05 P = .48
REFERENCES
1. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33. 2. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group Study. Gynecol Oncol 1991;40:55-65. 3. Fanning J, Nanavati PJ, Hilgers RD. Surgical staging and high dose rate brachytherapy for endometrial cancer: limiting external radiotherapy to node-positive tumors. Obstet Gynecol 1996;87:1041-4. 4. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 1995;56:29-33. 5. Fanning J, Firestein S. Prospective evaluation of the morbidity of complete lymphadenectomy in endometrial cancer. Int J Gynecol Cancer 1998;8:270-3. 6. Fanning J. Treatment for early endometrial cancer: cost effective analysis. J Reprod Med 1999;44:719-23. 7. Downey GO, Potish RA, Adcock LL, Prem KA, Twiggs LB. Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 1989;160:1055-61. 8. Onda T, Yoshikawa H, Mizutani K, Mishima M, Yokota H, Nagano H, et al. Treatment of node-positive endometrial cancer with complete node dissection, chemotherapy and radiation therapy. Br J Cancer 1997;75:1836-41.