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The article by Mahdi et al. in this issue illustrates the never-ending debate on the role and impact of lymphadenectomy in the treatment of gynaecologic malignancies. It is a retrospective study evaluating the role of lymphadenectomy in uterine serous cancer. In common with other gynaecological cancers where lymphadenectomy might be indicated, there is a lack of robust evidence from randomised controlled trials to support its use. In the last 40 years, the American Board of Medical Specialties, the Royal College of Obstetricians and Gynaecologists (RCOG) and other national bodies have approved certification in gynaecologic oncology training, without standardising surgical competencies, defining the adequacy of lymphadenectomy or, more importantly, setting goals for determining the prognostic or therapeutic impact of this procedure in the treatment of any gynecologic malignancy.

In early cervical cancer, radical surgery has been widely accepted as the optimum treatment, with no standardisation of how radical the procedure should be. There has been a rather uncritical universal acceptance of the role of lymphadenectomy, with both diagnostic and therapeutic intent, except for the most superficial disease, despite the lack of standardised techniques or prospective randomised trials demonstrating benefit. Similarly, there is only anecdotal evidence for the role of adjuvant treatment in early stage-I squamous cell carcinoma of the cervix with only a single positive node, leading to conflicting recommendations for practice.

In advanced ovarian cancer, Burghardt and colleagues, in a single-institution study reported in 1986, demonstrated a high rate of involved nodes, and a survival benefit of systematic aortic and pelvic lymphadenectomy in women with advanced-stage ovarian cancer.[1] Spirtos et al. demonstrated in a cohort study that removing bulky nodes improved outcomes, but there was no advantage in resecting clinically negative nodes.[2] This was later confirmed in 2005 by Hacker et al. in a randomised controlled trial.[3] As in many gynaecological surgical studies, there was no standardisation of technique, and there is always the risk of selection bias in non-randomised studies.[1-3] However, these studies all demonstrated that as many as 70% of women with advanced-stage ovarian cancer have disease present in the retroperitoneal lymph nodes, with two-thirds of those involved lymph nodes being present in the aortic region, suggesting that studies evaluating the effect of maximum debulking surgery should consider evaluating the specific therapeutic benefit of extensive lymphadenectomy, as opposed to more conservative surgery (with fewer immediate side effects). Perhaps even more importantly, there remains the question of whether the disease in women with positive lymph nodes is biologically more aggressive than disease that does not metastasise to the lymph nodes. There is scant literature directly addressing this issue, but the work of Kimball et al. suggests that nodal metastases are biologically less aggressive, with the DNA of the cancer cells in the retroperitoneal nodes often being characterised as diploid, as opposed to aneuploid (cancer cells in both the primary tumour and the intraperitoneal metastases are usually aneuploid). Instead of the retroperitoneal disease indicating a more aggressive process, perhaps it is the more benign nature of these metastases that leads to their relative resistance to chemotherapy.[4] This may explain why historical second-look data demonstrate that as many as one-half of women with negative intraperitoneal findings have persistent disease present in the retroperitoneal nodes.[5] In no published report has there been documented (by photography) surgical control of either the extent of the lymph node dissection or the resulting cytoreductive effect.

In a previous BJOG commentary in 2010, on current practice and potential future trials in early-stage ovarian cancer, Naik and colleagues argued that the evidence base for the diagnostic and therapeutic role of lymphadenectomy suffers from the non-standardisation of surgical technique and a lack of randomised controlled trials.[6] The commentary focused on a study by Rouzier and colleagues based on data from the SEER database covering a 17-year period, and demonstrated a survival advantage for women who had had thorough surgical staging including lymphadenectomy, suggesting that either alone or in combination with tailored adjuvant chemotherapy, women who had undergone lymphadenectomy performed better.[7]

The evidence regarding endometrial cancers is even more problematic to interpret. Only early Gynecologic Oncology Group (GOG) feasibility trials have required photo-documentation to demonstrate the adequacy of the lymphadenectomy when performed using minimally invasive surgical techniques, in contrast to later less rigorous GOG studies, when approximately 25–30% appeared to have less than four lymph nodes resected.[8-10] The GOG surgical manual calls for the removal of all lymph node-bearing tissue (skeletonisation) of the aorta and vena cava, as well as the pelvic vasculature from the inferior mesenteric artery superiorly to the external iliac artery at the level crossed by the circumflex iliac vein distally.[11] These findings led to GOG adopting a minimum of ten lymph nodes being present in the resected specimen in order for a lymphadenectomy to be considered adequate (four from each side of the pelvis and one from each of the right and left aortic regions).

The extent of the lymph node dissection is unknown in the Mahdi article, and this is also the case in the great majority of publications dating as far back as GOG 33 [which determined the extent of disease by surgical staging, and which served as a basis for the 1989 change in the International Federation of Gynecology and Obstetrics (FIGO) staging criteria].[12] As in the Mahdi paper, the histological examination technique for processing lymphadenectomy specimens has never been standardised, resulting in marked variations in nodal counts across published studies. For example, one laboratory may only count and examine palpable lymph nodes, whereas others may use solvent to help separate the fat from lymph nodes, resulting in more lymph nodes being counted and examined. Until photographic documentation is required and a standard to evaluate the specimens histologically is agreed upon, realistically it will be impossible to discuss the impact of lymphadenectomy on any patient with gynecological cancer. Furthermore, some studies will assess for micro-metastases in otherwise lymph node ‘negative’ cases, whereas others will not.

A similar problem is encountered when predicting the incidence of lymph node metastases in relationship to grade and depth of invasion in women with endometrial cancer. Except in rare situations, these relationships (which form the basis of many decision-making algorithms) are established after surgery has been undertaken. The correlation between intraoperative and final pathology is sufficiently poor to preclude it from being used in routine clinical practice. In the GOG 210 study Molecular Staging of Endometrial Cancer, when tissue was bio-banked, over 40% of the stage-III patients had a grade-1 lesion, but in many US and European management algorithms women diagnosed with grade-1 cancers do not have lymphadenectomy at the time of surgery, resulting in these women not being adequately staged.

Few studies have evaluated surgical morbidity or quality-of-life outcomes associated with full surgical staging, as compared with women receiving radiation therapy based on uterine characteristics alone. The importance of this issue cannot be overstated, particularly in light of the results reported on behalf of the PORTEC study group over the years,[13] and most recently in an article by Creutzberg et al., demonstrating no overall survival benefit in women receiving radiation therapy compared with those receiving no adjuvant therapy.[14] Perhaps even more concerning was the potential for those receiving adjuvant radiation therapy to be at increased risk of developing secondary cancers. Moreover, the quality of life of women receiving radiation therapy was significantly and adversely affected compared with women receiving no further therapy.

Several current studies from Europe claiming no advantage in performing lymphadenectomy in women with endometrial cancer are flawed, as there was no reliable surgical quality control and therefore the lymphadenectomies performed lacked standardisation (as demonstrated by the wide range in the number of lymph nodes harvested).[15, 16] Additionally, the removal of grossly positive lymph nodes further dilutes the conclusions drawn in these studies. The study designs resulted in 30–40% of women with endometrial cancer receiving radiation therapy to the whole pelvis. This is particularly alarming given the extended reporting by the PORTEC group demonstrating no survival benefit and a poorer quality of life associated with postoperative radiation therapy in women with endometrial cancer, compared with those receiving no adjuvant therapy. Given the lack of long-term benefit to postoperative radiation therapy, every effort should be made to stage women with endometrial cancer as fully as possible, with the goal of treating only those women with extrauterine disease. Comprehensive staging would probably result in less than 15% of all women being treated with radiotherapy. A randomised study designed to address this issue needs to be performed, and only when a trial is designed to tailor adjuvant treatment on the basis of comprehensive staging can the role of lymphadenectomy be properly ascertained. The evidence from such an RCT might spare women with intermediate or high uterine risk factors, but node negative from radiotherapy, particularly as there is no evidence of its long-term benefits.

The current study, despite all of its weaknesses, once again brings to the forefront the need to undertake a prospective trial with women randomised to limited surgery or complete lymphadenectomy (including pelvic and paraaortic lymph nodes at least or to a minimum to the level of the inferior mesenteric artery), with women then treated with either a defined regimen of chemotherapy or brachytherapy, if disease is identified outside the uterus. It is essential that the surgery is standardised and documented photographically, and that the histologic preparation of specimens is also uniform. If overall survival, and not recurrence-free interval, is the end point of the study, then treating women without extrauterine disease is not supported by current evidence. The data from GOG 33 supports this management schema, even in women with papillary serous tumours, specifically when disease was limited to the uterus, this subgroup had very similar survival rates to those women with adenocarcinoma of the endometrium.[16, 17] Debating whether there is a therapeutic benefit associated with lymphadenectomy, or whether that benefit is only attributable to the identification of extrauterine disease, and subsequent adjuvant treatment, is academic. A study designed to evaluate the therapeutic effect of lymphadenectomy would require women with positive lymph nodes to forego treatment, and this study design would be unacceptable to most clinicians and women. A much more practical approach would be to determine whether treatment directed by surgical findings results in superior survival compared with either no treatment or treatment based on uterine risk factors alone. An economic analysis would be an essential component of such a trial.

Data from the SEER databases appear to show a survival benefit from comprehensive surgical staging in endometrial and early-stage ovarian cancer. Mahdi et al. in this edition and Rouzier et al.[7] suggest that until well-designed randomised controlled trials (RCTs) are conducted, the potential benefits of this surgical approach might be attributable to inherent flaws in the retrospective study approach, and are not true effects of the treatment. The article by Mahdi et al. has once again highlighted these flaws and hopefully will stimulate the profession to move forward and design a definitive RCT evaluating the role of lymphadenectomy in the management of uterine cancers.

References

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  2. Disclosure of interests
  3. References
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    Burghardt E, Pickel H, Lahousen M, Stettner H. Pelvic lymphadenectomy in operative treatment of ovarian cancer. Am J Obstet Gynecol 1986;155:3159.
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    Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst 2005;97:5605.
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    Creutzberg CL, Nout RA, Lybeert ML, et al. Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e6318.
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    Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomized trial. PORTEC Study Group. Post-Operative Radiation Therapy in Endometrial Cancer. Lancet 2000;355:140411.
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    Panici PB, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer InstI 2008;100:170716.
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    Morrow CP, Bundy BN, Kurman RJ, 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;40:5565.
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