- Email: [email protected]
Lymphadenectomy in endometrial cancer
Correspondence
with lymph-node metastases have involved para-aortic nodes.4 Fourth, the ASTEC trial was too small to detect an overall survival difference because the expected proportion of isolated pelvic lymph-node recurrences is as low as 2–3% in early endometrial carcinoma. In conclusion, we believe that there is still an indication to do a comprehensive lymphadenectomy to select patients at high risk of pelvic side wall recurrence. The selection of patients for a lymphadenectomy should be based on myometrial invasion, grade, and diameter of the tumour.5 We declare that we have no conflict of interest.
*Frédéric Amant, Patrick Neven, Ignace Vergote [email protected] Division of Gynaecological Oncology, Department of Obstetrics & Gynaecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 1
2
3
4
5
The writing committee on behalf of the ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125–36. Cragun JM, Havrilesky LJ, Calingaert B, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 2005; 23: 3668–75. Chan JK, Cheung MK, Huh WK, et al. Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients. Cancer 2006; 107: 1823–30. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008; 109: 11–18. Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet 2005; 366: 491–505.
The ASTEC study group asserts that there is “no evidence of a benefit for systematic lymphadenectomy” in patients with endometrial cancer. This statement is subject to several pitfalls in trial design and execution. The negative results are therefore expected and not surprising. First, inclusion of patients with stage IA–IB, grade 1–2 disease (44·7% of all cases) led to a low rate (9%) of nodal metastases and to “surgical overtreatment” of 91% of patients. 1
1170
We wonder whether the stratification into risk subgroups (only briefly mentioned in the Results section) has sufficient statistical power for detecting a therapeutic value in highrisk patients. Second, since 67% of endometrial cancer patients with positive nodes have para-aortic involvement, a surgical procedure aimed at removing metastatic nodal disease with therapeutic intent must include bilateral systematic dissection of paraaortic nodes.2 However, para-aortic lymphadenectomy was not included in this trial. As a consequence, paraaortic residual disease was left in more than half of patients with lymphatic malignant dissemination. Third, one of the theoretical benefits of surgical staging is the use of nodal information to modulate postoperative treatment,3 but the design of this trial does not allow testing of this hypothesis. Given the above observations, the conclusions of the ASTEC study should be that pelvic node dissection has no therapeutic effect in most patients with endometrial carcinoma. The real question is which subgroup of high-risk patients might possibly benefit from systematic surgical staging to guide postoperative treatment.3 The question remains open. We declare that we have no conflict of interest.
Stefano Uccella, Karl C Podratz, Giovanni D Aletti, *Andrea Mariani [email protected] Division of Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA 1
2
3
The writing committee on behalf of the ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125–36. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008; 109: 11–18. Mariani A, Dowdy SC, Keeney GL, Long HJ, Lesnick TG, Podratz KC. High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy. Gynecol Oncol 2004; 95: 120–26.
Authors’ reply We should emphasise that there are now two independent randomised controlled trials of lymphadenectomy in early endometrial cancer (with a total of 1922 women), both of which have confirmed no clinical benefit for lymphadenectomy.1,2 In fact, in both randomised trials there is a suggestion of worse survival in the lymphadenectomy group: the hazard ratio for overall survival in ASTEC (1·16, 95% CI 0·87–1·54)1 and Panici and colleagues (1·20, 0·70–2·07),2 and the pooled hazard ratio combining data from both trials (1·17, 0·91–1·50), favour the standard surgery group. M J E Mourits and colleagues ask about the use of laparoscopic surgery, which was evolving over the course of the trial. It was allowed under strict conditions and included as a stratification factor to avoid an imbalance (and bias) between the two groups. Bias from substandard surgery in the lymphadenectomy group is extremely unlikely since surgical procedures (hysterectomy and bilateral salpingo-oophorectomy) and lymph-node counts in the lymphadenectomy group were similar, if not better, in women who had laparoscopic procedures. Aoun Hakmi asks whether allowing node sampling in the standard group affected the results. The intention was to mirror clinical practice and allow surgeons to remove suspicious nodes that they were unhappy to leave in situ; 5% of patients in the standard surgery group had any nodes removed compared with 92% in the lymphadenectomy group. Turning to the “reliability” of the randomisation procedure, by chance there were slightly more higher-risk women in the lymphadenectomy group, which is why we did adjusted analyses to take account of these differences. With respect to small imbalances in external-beam radiation therapy within subgroups, it is neither methodologically appropriate to adjust for post-randomisation treatments, www.thelancet.com Vol 373 April 4, 2009
with lymph-node metastases have involved para-aortic nodes.4 Fourth, the ASTEC trial was too small to detect an overall survival difference because the expected proportion of isolated pelvic lymph-node recurrences is as low as 2–3% in early endometrial carcinoma. In conclusion, we believe that there is still an indication to do a comprehensive lymphadenectomy to select patients at high risk of pelvic side wall recurrence. The selection of patients for a lymphadenectomy should be based on myometrial invasion, grade, and diameter of the tumour.5 We declare that we have no conflict of interest.
*Frédéric Amant, Patrick Neven, Ignace Vergote [email protected] Division of Gynaecological Oncology, Department of Obstetrics & Gynaecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 1
2
3
4
5
The writing committee on behalf of the ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125–36. Cragun JM, Havrilesky LJ, Calingaert B, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 2005; 23: 3668–75. Chan JK, Cheung MK, Huh WK, et al. Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients. Cancer 2006; 107: 1823–30. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008; 109: 11–18. Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet 2005; 366: 491–505.
The ASTEC study group asserts that there is “no evidence of a benefit for systematic lymphadenectomy” in patients with endometrial cancer. This statement is subject to several pitfalls in trial design and execution. The negative results are therefore expected and not surprising. First, inclusion of patients with stage IA–IB, grade 1–2 disease (44·7% of all cases) led to a low rate (9%) of nodal metastases and to “surgical overtreatment” of 91% of patients. 1
1170
We wonder whether the stratification into risk subgroups (only briefly mentioned in the Results section) has sufficient statistical power for detecting a therapeutic value in highrisk patients. Second, since 67% of endometrial cancer patients with positive nodes have para-aortic involvement, a surgical procedure aimed at removing metastatic nodal disease with therapeutic intent must include bilateral systematic dissection of paraaortic nodes.2 However, para-aortic lymphadenectomy was not included in this trial. As a consequence, paraaortic residual disease was left in more than half of patients with lymphatic malignant dissemination. Third, one of the theoretical benefits of surgical staging is the use of nodal information to modulate postoperative treatment,3 but the design of this trial does not allow testing of this hypothesis. Given the above observations, the conclusions of the ASTEC study should be that pelvic node dissection has no therapeutic effect in most patients with endometrial carcinoma. The real question is which subgroup of high-risk patients might possibly benefit from systematic surgical staging to guide postoperative treatment.3 The question remains open. We declare that we have no conflict of interest.
Stefano Uccella, Karl C Podratz, Giovanni D Aletti, *Andrea Mariani [email protected] Division of Gynecologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA 1
2
3
The writing committee on behalf of the ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125–36. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008; 109: 11–18. Mariani A, Dowdy SC, Keeney GL, Long HJ, Lesnick TG, Podratz KC. High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy. Gynecol Oncol 2004; 95: 120–26.
Authors’ reply We should emphasise that there are now two independent randomised controlled trials of lymphadenectomy in early endometrial cancer (with a total of 1922 women), both of which have confirmed no clinical benefit for lymphadenectomy.1,2 In fact, in both randomised trials there is a suggestion of worse survival in the lymphadenectomy group: the hazard ratio for overall survival in ASTEC (1·16, 95% CI 0·87–1·54)1 and Panici and colleagues (1·20, 0·70–2·07),2 and the pooled hazard ratio combining data from both trials (1·17, 0·91–1·50), favour the standard surgery group. M J E Mourits and colleagues ask about the use of laparoscopic surgery, which was evolving over the course of the trial. It was allowed under strict conditions and included as a stratification factor to avoid an imbalance (and bias) between the two groups. Bias from substandard surgery in the lymphadenectomy group is extremely unlikely since surgical procedures (hysterectomy and bilateral salpingo-oophorectomy) and lymph-node counts in the lymphadenectomy group were similar, if not better, in women who had laparoscopic procedures. Aoun Hakmi asks whether allowing node sampling in the standard group affected the results. The intention was to mirror clinical practice and allow surgeons to remove suspicious nodes that they were unhappy to leave in situ; 5% of patients in the standard surgery group had any nodes removed compared with 92% in the lymphadenectomy group. Turning to the “reliability” of the randomisation procedure, by chance there were slightly more higher-risk women in the lymphadenectomy group, which is why we did adjusted analyses to take account of these differences. With respect to small imbalances in external-beam radiation therapy within subgroups, it is neither methodologically appropriate to adjust for post-randomisation treatments, www.thelancet.com Vol 373 April 4, 2009