- Email: [email protected]
Surgical Staging in Endometrial Cancer: Is Excellent Survival Due to Thorough Staging or Patient Selection?
467
LETTERS TO THE EDITOR Pearlman A, Maiman MA, Bell JG: A Phase III randomized study of surgery vs surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG No. 99) Abstract. In: 29th Annual meeting of the Society of Gynecologic Oncologists, Proc Soc Gynecol Oncol, 1998, p. 70 12. Podratz KC, Mariani A, Webb MJ: Staging and therapeutic value of lymphadenectomy in endometrial cancer [editorial]. Gynecol Oncol 70: 163–164, 1998 13. Grigsby PW, Perez CA, Kuten A, Simpson JR, Garcia DM, Camel HM, Kao MS, Galakatos AE: Clinical stage I endometrial cancer: results of adjuvant irradiation and patterns of failure. Int J Radiat Oncol Biol Phys 21:379 –385, 1991 14. Greven KM, Lanciano RM, Herbert SH, Hogan PE: Analysis of complications in patients with endometrial carcinoma receiving adjuvant irradiation. Int J Radiat Oncol Biol Phys 21:919 –923, 1991
15. Petereit D, Greven KM: Surgical staging in endometrial cancer: Is excellent survival due to thorough staging or a patient selection? [letter]. Gynecol Oncol 73:467– 468, 1999
Dasaarahally S. Mohan, M.D. 1 Michael A. Samuels, M.D. Department of Radiation Oncology University Hospitals of Cleveland/CWRU Cleveland, Ohio 44106 Article ID gyno.1999.5450 1
Current address: Department of Radiation Oncology/T28, The Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail: [email protected].
Surgical Staging in Endometrial Cancer: Is Excellent Survival Due to Thorough Staging or Patient Selection? To the Editor: A recent report from Mohan et al. suggested a therapeutic benefit for patients with Stage I endometrial cancer undergoing a therapeutic lymphadenectomy [1]. A supporting editorial by Podratz et al. also appeared in the same issue. As stated by the authors, the purpose of the study was to determine “whether the survival and morbidity of patients treated with therapeutic lymphadenectomy are equal to or better than with these alternative treatments, ”i.e., limited surgical assessment followed by pelvic radiotherapy. With complete surgical staging, Mohan et al. suggested a therapeutic benefit, lower complication and similar cure rates than those with a “comparable series” of incomplete surgical staging and pelvic radiotherapy, and implied essentially no role for pelvic radiotherapy in the subgroup of stage I patients studied. Only surgical stage I patients were evaluated. All patients had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node sampling, and peritoneal cytologic sampling. A median of 33 lymph nodes were retrieved. One hundred ninety-two patients were identified, from which 33 patients were excluded: 14 because of incomplete staging and 19 because of incomplete follow-up. The majority of patients had low-risk prognostic factors: 94% had either histologic grades 1 or 2 and 83% had either stage IA or IB disease. All patients had adjuvant radiation with either a low-dose-rate or high-dose-rate vaginal brachytherapy, although 7% of patients received pelvic radiotherapy to 45 Gy because of extension to the uterine serosa or clear cell histology. The 15-year overall survival and disease-free survivals were 98% and 96%, respectively. Despite these excellent cure rates, significant morbidity was observed in 13% of patients (nonactuarial reporting). The authors imply that “skeletonizing the external iliac vessels” improves outcome by removing occult tumor emboli
that are not documented pathologically [1]. This mechanism of improving outcome has also been suggested by Kilgore et al [2]. Did the 7% of patients who received pelvic radiotherapy have outer 1/3 myometrial invasion and/or high grade tumors? Is it possible that the addition of pelvic radiotherapy resulted in similar outcomes for the high-risk patients and the low-risk patients? This conversion of high- to low-risk patients with pelvic radiotherapy has been verified by others [3]. The authors erroneously compare their results to Kucera et al. and claim to achieve superior results because of complete surgical staging. The report by Kucera et al. is a prospective study that tailored radiation to the extent of uterine disease [3]. The majority of patients that received pelvic radiotherapy had stage IC disease, while the remaining patients received vaginal cuff brachytherapy. They were able to demonstrate that high-risk stage I patients treated with adjuvant pelvic radiotherapy can have outcomes similar to those of low-risk patients. The low-risk population had 5-year overall survival rates ranging from 91 to 100%, with much lower complication rates than those reported by Mohan et al. The primary issue is whether grade 1 or 2, stage IA/IB patients even need an assessment of the pelvic lymph nodes (they certainly do not need pelvic radiotherapy). Patients with stage IA or IB (4]. In the current study, 83% of patients had either stage IA or IB disease. The 13% significant morbidity rate seems unnecessary for these patients. Why are the authors advocating such an aggressive surgical approach (median number of nodes removed 33) when other surgeons have reported that limited surgical assessment will provide the same information with lower morbidity rates [3, 5]? Even in the Kilgore et al. study, the median number of lymph nodes removed was 11 [2]. Chuang et al. from M. D. Anderson suggested that a selective lymphadenectomy in which nine sites were assessed accurately predicted the lymph node status [6].
468
LETTERS TO THE EDITOR
The results of GOG 99, a randomized study comparing adjuvant pelvic radiotherapy to no adjuvant therapy for patients with stage I or II endometrial cancer with any myometrial invasion, were recently presented [7]. Despite the fact that the majority of patients studied had low-risk disease, the relapsefree survival was significantly improved (96 vs 88% at 2 years) following pelvic radiotherapy. Approximately half the failures in the observation arm occurred in the vaginal cuff with very few in the pelvis suggesting that vaginal brachytherapy may have been an adequate treatment for many of these patients. Unfortunately, 8% (nonactuarial) of patients suffered significant bowel complications with thorough surgical staging and pelvic radiotherapy. At the University of Wisconsin, the 4-year disease-free survival, vaginal control, and significant complication rates were 96, 100, and 0% in a similar group of 200 patients (grade 1/2, stage IB) who had minimal assessment of the pelvic lymph nodes followed by two high-dose-rate brachytherapy insertions. Eltabbakh et al. reported a 97% 30-year disease-free survival with 2% significant radiation complications utilizing an approach in which there was no assessment of the pelvic or para-aortic lymph nodes [5]. These latter two data sets achieve a wider therapeutic window for managing low-risk endometrial cancer than the approach taken by Mohan et al. Our conclusion from the Mohan et al. report is that excellent survival rates were observed because the majority of patients had early stage disease and were appropriately treated with adjuvant vaginal cuff brachytherapy. Complete surgical staging only contributed to high morbidity rates that could have been avoided through limited surgical staging, or no pathologic assessment of the lymph nodes at all. This study does not support the emerging practice that surgical staging eliminates the need for pelvic radiotherapy for high-risk stage I endometrial patients. REFERENCES
tomy for stage I endometrial adenocarcinoma. Gynecol Oncol 70:165– 171, 1998 2. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F, Conner W: Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 56:29 –33, 1995 3. Kucera H, Vavra N, Weghaupt K: Benefit of external irradiation in pathologic stage I endometrial carcinoma: A prospective clinical trial of 605 patients who received postoperative vaginal irradiation and additional pelvic irradiation in the presence of unfavorable prognostic factors. Gynecol Oncol 38: 99 –104, 1990 4. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB: Surgical pathologic spread patterns of endometrial cancer: A Gynecologic Oncology Group Study. Cancer 60:2035–2041, 1987 5. Eltabbakh GH, Piver MS, Hempling RE, Shin KH: Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: Report of a prospective trial. IJROBP 38:373– 80, 1997 6. Chuang L, Burke TW, Tornos C, Marion BD, Mitchell MF, TortoleroLuna G, Levenback C, Morris M, Gershenson DM: Staging laparotomy for endometrial carcinoma: Assessment of retroperitoneal lymph nodes. Gynecol Oncol 58:189 –193, 1995 7. Roberts JA, BrunettoVL, Keyes HM, Zaino R, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG: A Phase III randomized study of surgery vs. surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG 99) (abstract 35). Proc Soc Gynecol Oncol 70: 1998
Daniel Petereit, M.D.* Kathryn M. Greven† *Deparment of Radiation Oncology, University of Wisconsin Medical School Madison, Wisconsin 53706 †Department of Radiation Oncology Wake Forest University Baptist School of Medicine Winston-Salem, North Carolina 27157-1030
1. Mohan DS, Samuels MA, Selim MA, Shalodi AD, Ellis RJ, Samuels JR, Yun HJ: Long-term outcomes of therapeutic pelvic lymphadenec-
Article ID gyno.1999.5451
Reply To the Editor: We appreciate the comments of Dr. Petereit and Dr. Greven [1]. As demonstrated in our paper [2], we agree with your assertion that patients with pathologic stage IA or IB, grade 1 or 2 disease do not need pelvic radiotherapy (RT); however, we disagree with your assessment of the potential value of total pelvic lymph node dissection (TPLND).
most common complication in our series was leg edema in 5.7% (9/159), which was transient in most patients. We also classified pelvic lymphocele as a significant morbidity. Only 4 (3%) patients experienced serious morbidity (3 deep venous thromboses and 1 bowel obstruction), which is comparable to rates in other series using more conservative surgical approaches [3].
Treatment Morbidity
Converting “High-Risk” Patients to “Low-Risk” Using External-Beam Radiation
Drs. Petereit and Greven suggest that TPLND results in an elevated morbidity rate. On the contrary, our significant complication rate of 13% results from inclusion of relatively minor complications in order to err on the side of conservatism. The
Drs. Petereit and Greven note that 11/159 (7%) patients in our series received external-beam pelvic irradiation. Seven of these patients had stage IC and 2 patients had grade 3 disease. They postulate, based on the Kucera et al. study [4], that this selective
LETTERS TO THE EDITOR Pearlman A, Maiman MA, Bell JG: A Phase III randomized study of surgery vs surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG No. 99) Abstract. In: 29th Annual meeting of the Society of Gynecologic Oncologists, Proc Soc Gynecol Oncol, 1998, p. 70 12. Podratz KC, Mariani A, Webb MJ: Staging and therapeutic value of lymphadenectomy in endometrial cancer [editorial]. Gynecol Oncol 70: 163–164, 1998 13. Grigsby PW, Perez CA, Kuten A, Simpson JR, Garcia DM, Camel HM, Kao MS, Galakatos AE: Clinical stage I endometrial cancer: results of adjuvant irradiation and patterns of failure. Int J Radiat Oncol Biol Phys 21:379 –385, 1991 14. Greven KM, Lanciano RM, Herbert SH, Hogan PE: Analysis of complications in patients with endometrial carcinoma receiving adjuvant irradiation. Int J Radiat Oncol Biol Phys 21:919 –923, 1991
15. Petereit D, Greven KM: Surgical staging in endometrial cancer: Is excellent survival due to thorough staging or a patient selection? [letter]. Gynecol Oncol 73:467– 468, 1999
Dasaarahally S. Mohan, M.D. 1 Michael A. Samuels, M.D. Department of Radiation Oncology University Hospitals of Cleveland/CWRU Cleveland, Ohio 44106 Article ID gyno.1999.5450 1
Current address: Department of Radiation Oncology/T28, The Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail: [email protected].
Surgical Staging in Endometrial Cancer: Is Excellent Survival Due to Thorough Staging or Patient Selection? To the Editor: A recent report from Mohan et al. suggested a therapeutic benefit for patients with Stage I endometrial cancer undergoing a therapeutic lymphadenectomy [1]. A supporting editorial by Podratz et al. also appeared in the same issue. As stated by the authors, the purpose of the study was to determine “whether the survival and morbidity of patients treated with therapeutic lymphadenectomy are equal to or better than with these alternative treatments, ”i.e., limited surgical assessment followed by pelvic radiotherapy. With complete surgical staging, Mohan et al. suggested a therapeutic benefit, lower complication and similar cure rates than those with a “comparable series” of incomplete surgical staging and pelvic radiotherapy, and implied essentially no role for pelvic radiotherapy in the subgroup of stage I patients studied. Only surgical stage I patients were evaluated. All patients had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node sampling, and peritoneal cytologic sampling. A median of 33 lymph nodes were retrieved. One hundred ninety-two patients were identified, from which 33 patients were excluded: 14 because of incomplete staging and 19 because of incomplete follow-up. The majority of patients had low-risk prognostic factors: 94% had either histologic grades 1 or 2 and 83% had either stage IA or IB disease. All patients had adjuvant radiation with either a low-dose-rate or high-dose-rate vaginal brachytherapy, although 7% of patients received pelvic radiotherapy to 45 Gy because of extension to the uterine serosa or clear cell histology. The 15-year overall survival and disease-free survivals were 98% and 96%, respectively. Despite these excellent cure rates, significant morbidity was observed in 13% of patients (nonactuarial reporting). The authors imply that “skeletonizing the external iliac vessels” improves outcome by removing occult tumor emboli
that are not documented pathologically [1]. This mechanism of improving outcome has also been suggested by Kilgore et al [2]. Did the 7% of patients who received pelvic radiotherapy have outer 1/3 myometrial invasion and/or high grade tumors? Is it possible that the addition of pelvic radiotherapy resulted in similar outcomes for the high-risk patients and the low-risk patients? This conversion of high- to low-risk patients with pelvic radiotherapy has been verified by others [3]. The authors erroneously compare their results to Kucera et al. and claim to achieve superior results because of complete surgical staging. The report by Kucera et al. is a prospective study that tailored radiation to the extent of uterine disease [3]. The majority of patients that received pelvic radiotherapy had stage IC disease, while the remaining patients received vaginal cuff brachytherapy. They were able to demonstrate that high-risk stage I patients treated with adjuvant pelvic radiotherapy can have outcomes similar to those of low-risk patients. The low-risk population had 5-year overall survival rates ranging from 91 to 100%, with much lower complication rates than those reported by Mohan et al. The primary issue is whether grade 1 or 2, stage IA/IB patients even need an assessment of the pelvic lymph nodes (they certainly do not need pelvic radiotherapy). Patients with stage IA or IB (4]. In the current study, 83% of patients had either stage IA or IB disease. The 13% significant morbidity rate seems unnecessary for these patients. Why are the authors advocating such an aggressive surgical approach (median number of nodes removed 33) when other surgeons have reported that limited surgical assessment will provide the same information with lower morbidity rates [3, 5]? Even in the Kilgore et al. study, the median number of lymph nodes removed was 11 [2]. Chuang et al. from M. D. Anderson suggested that a selective lymphadenectomy in which nine sites were assessed accurately predicted the lymph node status [6].
468
LETTERS TO THE EDITOR
The results of GOG 99, a randomized study comparing adjuvant pelvic radiotherapy to no adjuvant therapy for patients with stage I or II endometrial cancer with any myometrial invasion, were recently presented [7]. Despite the fact that the majority of patients studied had low-risk disease, the relapsefree survival was significantly improved (96 vs 88% at 2 years) following pelvic radiotherapy. Approximately half the failures in the observation arm occurred in the vaginal cuff with very few in the pelvis suggesting that vaginal brachytherapy may have been an adequate treatment for many of these patients. Unfortunately, 8% (nonactuarial) of patients suffered significant bowel complications with thorough surgical staging and pelvic radiotherapy. At the University of Wisconsin, the 4-year disease-free survival, vaginal control, and significant complication rates were 96, 100, and 0% in a similar group of 200 patients (grade 1/2, stage IB) who had minimal assessment of the pelvic lymph nodes followed by two high-dose-rate brachytherapy insertions. Eltabbakh et al. reported a 97% 30-year disease-free survival with 2% significant radiation complications utilizing an approach in which there was no assessment of the pelvic or para-aortic lymph nodes [5]. These latter two data sets achieve a wider therapeutic window for managing low-risk endometrial cancer than the approach taken by Mohan et al. Our conclusion from the Mohan et al. report is that excellent survival rates were observed because the majority of patients had early stage disease and were appropriately treated with adjuvant vaginal cuff brachytherapy. Complete surgical staging only contributed to high morbidity rates that could have been avoided through limited surgical staging, or no pathologic assessment of the lymph nodes at all. This study does not support the emerging practice that surgical staging eliminates the need for pelvic radiotherapy for high-risk stage I endometrial patients. REFERENCES
tomy for stage I endometrial adenocarcinoma. Gynecol Oncol 70:165– 171, 1998 2. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F, Conner W: Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 56:29 –33, 1995 3. Kucera H, Vavra N, Weghaupt K: Benefit of external irradiation in pathologic stage I endometrial carcinoma: A prospective clinical trial of 605 patients who received postoperative vaginal irradiation and additional pelvic irradiation in the presence of unfavorable prognostic factors. Gynecol Oncol 38: 99 –104, 1990 4. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB: Surgical pathologic spread patterns of endometrial cancer: A Gynecologic Oncology Group Study. Cancer 60:2035–2041, 1987 5. Eltabbakh GH, Piver MS, Hempling RE, Shin KH: Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: Report of a prospective trial. IJROBP 38:373– 80, 1997 6. Chuang L, Burke TW, Tornos C, Marion BD, Mitchell MF, TortoleroLuna G, Levenback C, Morris M, Gershenson DM: Staging laparotomy for endometrial carcinoma: Assessment of retroperitoneal lymph nodes. Gynecol Oncol 58:189 –193, 1995 7. Roberts JA, BrunettoVL, Keyes HM, Zaino R, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG: A Phase III randomized study of surgery vs. surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG 99) (abstract 35). Proc Soc Gynecol Oncol 70: 1998
Daniel Petereit, M.D.* Kathryn M. Greven† *Deparment of Radiation Oncology, University of Wisconsin Medical School Madison, Wisconsin 53706 †Department of Radiation Oncology Wake Forest University Baptist School of Medicine Winston-Salem, North Carolina 27157-1030
1. Mohan DS, Samuels MA, Selim MA, Shalodi AD, Ellis RJ, Samuels JR, Yun HJ: Long-term outcomes of therapeutic pelvic lymphadenec-
Article ID gyno.1999.5451
Reply To the Editor: We appreciate the comments of Dr. Petereit and Dr. Greven [1]. As demonstrated in our paper [2], we agree with your assertion that patients with pathologic stage IA or IB, grade 1 or 2 disease do not need pelvic radiotherapy (RT); however, we disagree with your assessment of the potential value of total pelvic lymph node dissection (TPLND).
most common complication in our series was leg edema in 5.7% (9/159), which was transient in most patients. We also classified pelvic lymphocele as a significant morbidity. Only 4 (3%) patients experienced serious morbidity (3 deep venous thromboses and 1 bowel obstruction), which is comparable to rates in other series using more conservative surgical approaches [3].
Treatment Morbidity
Converting “High-Risk” Patients to “Low-Risk” Using External-Beam Radiation
Drs. Petereit and Greven suggest that TPLND results in an elevated morbidity rate. On the contrary, our significant complication rate of 13% results from inclusion of relatively minor complications in order to err on the side of conservatism. The
Drs. Petereit and Greven note that 11/159 (7%) patients in our series received external-beam pelvic irradiation. Seven of these patients had stage IC and 2 patients had grade 3 disease. They postulate, based on the Kucera et al. study [4], that this selective