Does debulking of enlarged positive lymph nodes improve survival in different gynaecological cancers?

Accepted Manuscript Does debulking of enlarged positive lymph nodes improve survival in different gynaecological cancers? Prof. Dr. S.P. Somashekhar, MS, MCh(Onco), FRCS.Edinburgh, Chairman & HOD Surgical Oncology, Consultant Surgical & Gynec. Onco & Robotic Surgeon PII:

S1521-6934(15)00078-4

DOI:

10.1016/j.bpobgyn.2015.04.010

Reference:

YBEOG 1501

To appear in:

Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 16 April 2015 Revised Date:

20 April 2015

Accepted Date: 28 April 2015

Please cite this article as: Somashekhar SP, Does debulking of enlarged positive lymph nodes improve survival in different gynaecological cancers?, Best Practice & Research Clinical Obstetrics & Gynaecology (2015), doi: 10.1016/j.bpobgyn.2015.04.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Does debulking of enlarged positive lymph nodes improve survival in different

Author: Dr. Somashekhar.S.P

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gynaecological cancers?

MS, MCh, FRCS.Ed

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Author affiliations (including city and country)

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Prof.Dr.Somashekhar.S.P MS,MCh(Onco),FRCS.Edinburgh Chairman & HOD Surgical Oncology, Consultant Surgical & Gynec. Onco & Robotic Surgeon Manipal Comprehensive Cancer Center, Manipal hospital , Bangalore-560017 , India: [email protected] Corresponding Author: Dr.Somashekhar.S.P

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Address: Chairman & HOD Surgical Oncology, Consultant Surgical & Gynec. Onco & ROBOTIC SURGEON, Manipal Comprehensive Cancer Center, Manipal hospital , Bangalore-560017 , India: [email protected]

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Email add: [email protected] Contact #: 0091 9845712012

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The word count abstract + article + references + table is as follows: Abstract: 205 words Article (including practice point and research agenda): 4654 References: 1820 Table: 750

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ABSTRACT Lymph node positive gynaecological cancers remain a pharmacotherapeutic challenge and

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patients with lymph node positive gynaecological cancers had poor survival. The purpose of this review is to determine if a survival advantage exists from surgical debulking of enlarged positive lymph nodes in different types of gynaecological cancers. Information from studies published on

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survival benefits from debulking lymph nodes in gynaecological cancers were searched. Pertaining to theraperutic lymphadenectomy, survival benefit can be analyzed by two ways,

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direct survival benefit following therapeutic lymphadenectomy of bulky positive metastatic lymph nodes and indirect survival benefit, which results after a sequale of systematic lymphadenectomy, proper, accurate staging of disease and stage migration and tailormade adjuvant treatment. The direct hypothesis of therapeutic lymphadenectomy and survival benefit has been prospected in cervical cancers and vulval cancers and in post chemotherapy residual

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paraarotic nodal mass in germ cell ovarian cancer. The indirect survival benefit in high risk endometrial cancers and advanced epitherlial ovarian cancers with therapeutic paraarotic

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lymphadenectomy needs to be tested in randomized controlled trials. More randomized controlled trials to test this research question are required. Further, indirect benefit due to

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tailormade adjuvant treatment, secondary to accurate staging achieved as a sequale of systematic lymphadenectomy needs to be analyzed in future trials.

Key-words: Cervical cancer, debulking, epithelial cancer, endometrial cancer, germ cell cancer, gynaecological cancer, lymph node, uterine sarcoma, vulvar cancer

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A. GYNAECOLOGICAL CANCERS

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Node positive gynaecological cancers remain a pharmacotherapeutic challenge and patients with lymph node positive gynaecological cancers have been reported to have poor survival. Lymphatic spread has been reported as a common feature of all stages of gynaecological cancers

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as per the International Federation of Gynaecology and Obstetrics (FIGO) staging system [1]. Palpation is a traditional method to detect lymph node metastasis, however it is not considered

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accurate to detect lymph nodes metastastatic deposit <2 mm in diameter with in a lymphnode [2]. Hence, newer modalities such as positron emission tomography (PET) or sentinel lymph node mapping in combination with laparoscopic assessment are used to identify patients with lymph node metastasis; however the sensitivity of newer modalities in identifying patients with positive lymph nodes is low - 55% for magnetic resonance imaging (MRI) and computed tomography

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(CT), and 75% for PET [3].

Patients are usually treated with radiation dose of 50-60-Gy, however this radiation dose is

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insufficient to sterilize the bulky lymph nodes (>2 cm) and doses beyond this should be avoided due to risk of severe or fatal toxicities in neighbouring organs such as small bowel. Further,

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addition of chemotherapy to radiation therapy has been shown to decrease local failure by 3350% [4,5]. Pelvic and paraaortic lymph node dissection have become an important part of the surgical treatment of gynaecological cancers as the presence of positive lymph nodes is a signal of advanced, high risk disease. In case of high-risk endometrial cancers, 67% of women with positive pelvic lymph nodes are reported to have tumor in the paraaortic area also. Mariani et al. reported that lymphadenectomy only up to the inferior mesenteric artery could miss 38-46% of women with positive paraaortic lymph nodes [6]. (Figure No.1)

Previous literature has 3

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supported a positive role of debulking of lymph nodes in terms of survival benefits in different types of gynaecological cancers (Table 1). However, for all types of gynaecological cancers, the

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presence of enlarged bulky lymph nodes poses a serious challenge [7]. Systematic lymphadenectomy leads to proper and accurate stage mapping of disease and helps to tailor appropriate adjuvant treatment selection, which has an influence on overall outcome and

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survival. This lays the hypothesis for therapeutic value of lymphadenectomy of positive bulky metastatic lymph nodes, more so in cervical cancers, high-risk endometrial cancers and vulval

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cancers.

The objective of this article is to evaluate whether patients with different types of gynaecological cancers undergoing debulking of enlarged positive lymph nodes would benefit from this approach.

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Status in endometrial cancer

One of the most important prognostic factors for endometrial carcinoma (particularly pelvic and

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paraaortic lymph node metastases) is the presence of extra-uterine disease. There is considerable controversy in the literature as to the value of lymphadenectomy, partly due to the

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heterogeneity and retrospective nature of many clinical trials. Clinical practice is therefore not uniform and the data should be evaluated in this context. As per FIGO, the status of both pelvic and paraaortic lymph nodes should be assessed intraoperatively in all patients as in some cases paraaortic lymph nodes may be positive in the case of negative pelvic nodes [8]. Lymph node dissection is considered as an important aspect of the management of endometrial cancer [7]. Researchers have recommended that complete pelvic and paraaortic node 4

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dissection should be performed compared to selective nodal sampling as the latter may miss positive nodes. Chan et al. in a retrospective analysis of 12333 patients with endometrial cancer

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reported that patients with high risk disease (stage IB, grade 3 or greater) who underwent extensive lymph node sampling had an increased 5-year survival as compared with those who had fewer lymph nodes removed (75.3% with one node removed versus 86.8% with ≥ 20 nodes

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removed). In patients with stage IIIC-IV, significant benefits in 5-year survival were obtained from extensive nodal resection (72% for 20 nodes versus 53% for 2-5 nodes resection) [9].

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Several studies have evaluated the safety and survival outcomes of pelvic and paraaortic lymphadenectomy in patients with endometrial cancer. Havrylesky et al. in a retrospective analysis evaluated 5-year disease free survival (DFS) rate in patients with (stage IIIC endometrial cancer with pelvic and/or aortic lymph node metastases) after they underwent resection of grossly positive lymph nodes to those with microscopically positive lymph node.

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The 5-year disease specific survival rate was 63% in patients with microscopic metastatic disease compared to 50% in patients with complete resection grossly positive lymph node and 43% in

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patients with residual macroscopic disease [10]. In a retrospective cohort study of 671 women with high risk endometrial carcinoma, the 8-year survival rate was reported to be higher in the

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combined pelvic and paraaortic lymph node dissection group versus only pelvic lymph node dissection group (84 versus 69%) [11]. A 10.6% increase in 5-year overall survival (OS) was reported for pelvic and paraaortic lymphadenectomy compared to pelvic lymphadenectomy alone in patients with endometrial cancer at intermediate to high risk of recurrence (previous FIGO staging IA grade 3, IB and IC any grade, stage II-IV disease) [12]. Resection of the bulky lymph nodes is reported to be beneficial if the patients had clear cell histology, myometrial invasion (>50%) and large tumor (>2 cm in diameter). Otsuka et al. 5

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retrospectively evaluated the therapeutic benefit of retroperitoneal lymphadenectomy and chemotherapy in 106 patients with endometrioid adenocarcinoma. The 5-year survival rate of 23

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patients with lymph node metastasis was worse than that of patients without lymph node metastasis (60 versus 96%) [13]. Abu-Rustum et al. reported that lymph node dissection is essential for accurate surgical staging and the removal of regional lymph nodes (10 or more) was

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associated with improved OS in lower-stage, older patients with endometrial carcinoma who received no adjuvant therapy [8]. Mariani et al. reported that patients with paraaortic node

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metastases (myometrial invasion >50%, positive pelvic lymph nodes, or adnexal involvement) undergoing paraaortic lymphadenectomy had an improved 5-year progression free survival (PFS) (76 versus 36%) and OS (77 versus 42%) compared to patients without paraaortic lymph node dissection [14]. Chan et al. evaluated the database from the National Cancer Institute of women with disease stages I-IV endometrioid endometrial cancer and the 5-year disease specific survival

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rates were 96%, 90%, 74%, and 53% for women who underwent lymphadenectomy compared to 97%, 82%, 63%, and 27% for women not undergoing lymphadenectomy, respectively [15]. In a

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study of 649 patients with stage I or II endometrial adenocarcinoma, 5-year survival rate (extrapolated from survival curves) was higher for patients undergoing multiple site pelvic

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lymph node dissection compared to patients who did not undergo lymph node dissection (95% versus 75%) [16].

A study in 284 patients (FIGO stage IA, IB, IC, IIA, IIB, IIIA, IIIC and IV) with paraaortic lymph node metastasis in endometrial carcinoma undergoing systematic pelvic and paraaortic lymphadenectomy reported the 5- and 10-year OS rates in patients with negative paraaortic lymph nodes as 96% and 93% versus 72% and 62% in patients with positive paraaortic lymph node; suggesting that surgery with systematic pelvic and paraaortic lymphadenectomy to 6

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improve long-term survival in patients with paraaortic metastasis [17]. Todo et al. reported that the 5-year OS was better for patients with endometrial cancer who underwent comprehensive

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pelvic and paraaortic lymphadenectomy in the presence of positive nodes in comparison with pelvic lymphadenectomy alone in the presence of positive pelvic nodes (89.3 versus 46.5%) [18]. However, a recent European randomized clinical trial (ASTEC trial) performed at 85

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institutions in 4 countries, in which 1408 women with endometrial carcinoma failed to demonstrate a 5-year survival advantage with pelvic lymph node dissection versus no pelvic

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node dissection (90 versus 80%) [19]. There are criques and shortcomings of the ASTEC trial: first, the number of resected lymph nodes were insufficient in many patients (35% of patients in the lymphadenectomy group had 9 or fewer lymph nodes removed); second, the trial was too small to detect an OS difference because the expected proportion of isolated pelvic lymph node recurrences is as low as 2-3% in early endometrial carcinoma [20]. Further, in a phase 3

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randomized trial for patients with early-stage endometrial carcinoma, Panici et al. compared the standard surgery of total hysterectomy with bilateral salpingo-oophorectomy with or without

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lymph node dissection and reported that there was no significant difference in the 5-year DFS and OS in the lymph node dissection group compared to patient with no lymph node dissection

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(81 versus 81.7% and 85.9 versus 90%) [21].

Status in cervical cancer

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Cervical cancer spreads via the lymphatics, with metastases first occurring in the pelvic lymph nodes followed by spreading to the paraaortic nodes [22]. As per earlier reports, assessment of

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regional lymph nodes is the primary goal in women with early stage cervical cancer. Laparotomy or laparoscopy or robotic assisted surgery through a transperitoneal or extraperitoneal approach is the most used evaluation procedure in cervical cancer. Both extraperitoneal and transperitoneal

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approach by laparotomy in paraaortic advanced cervical cancer have similar sensitivity in

detecting nodal spread [23,24]. The most important prognostic factors for survival in cervical

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cancer are the status of lymph nodes [1]. In some Institutions, lymph node debulking is performed in patients with stage IB/IIB cervical cancer, tumor size of >2 cm and <8 cm, stage IIIB with unilateral disease only, enlarged lymph nodes (macroscopically) confined to pelvis (>2 cm and <5 cm), and normal size common iliac and paraaortic nodes [7]. High quality

unresolved.

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randomised data on the role of lymphadenectomy in advanced stage cervical disease remains

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Several trials have identified that the bulky pelvic and/or paraaortic nodes (>2 cm) are resistant to radiotherapy and/or chemotherapy and pose a serious challenge [4,5]. Hence, surgical

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debulking of enlarged lymph node would be effective in chemo-radiation resistant lymph nodes. There are four basic approaches for debulking retroperitoneal nodes in cervical cancer patients extraperitoneal laparotomy, transperitoneal laparotomy, extraperitoneal laparoscopy and transperitoneal laparoscopy or robotic assisted surgery [7]. Several retrospective studies reported potential survival benefits of pelvic and/or paraaortic lymph nodes debulking over no debulking in women with bulky metastases disease. In 1989, Downey et al. evaluated the impact of pelvic node resection in 156 cervical cancer patients divided in 4 groups by pelvic node status. The 58

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year recurrence free survival in macroscopic nodal metastases group was 51% versus 57% in microscopic metastases versus 0% in unresectable nodal metastases. Patients undergoing pelvic

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node resection showed improvement in recurrence, recommending surgical removal of pelvic nodal metastases before radiation therapy [25]. In a retrospective study 159 women with advanced cervical cancer received definitive radiation therapy following extraperitoneal surgical

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staging (thus included pelvic lymph node dissection and periaortic lymph node sampling). 5-year relapse free rate in women without pelvic node metastases was higher compared to unresectable

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pelvic node metastases (86 versus 0%) [26]. In a retrospective analysis by Hacker et al. 34 patients with advanced cervical cancer had resection of bulky positive lymph nodes prior to radiation therapy. 5-year survival was 80% for patients with disease involving pelvic and common iliac lymph nodes, and 48% for those with positive paraaortic nodes, and the survival for patients with completely resected bulky pelvic and common iliac nodes was comparable to

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the patients with micrometastases, suggesting removal of positive lymph node [27]. In another study, 35% and 46% 10-year DFS was reported in patients with microscopic and macroscopic

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metastatic nodes respectively, after they underwent extraperitoneal pelvic and paraaortic lymphadenectomy before radiotherapy [28]. Morice et al. evaluated the potential therapeutic

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value of systematic pelvic and paraaortic lymphadenectomy in 421 patients with stage IB and II cervical carcinoma. 3-year survival was 94% for patients with negative nodes compared to 64% for patients with positive pelvic nodes and 35% for patients with positive paraaortic nodes; adding the therapeutic value of complete removal of bulky positive nodes [1]. In 2005, Marnitz et al. demonstrated better survival for patients with laparoscopic debulking of pelvic and paraaortic lymph nodes with primary chemo-radiation in 456 all stage consecutive patients with histologically confirmed primary cervical cancer. The study reported that removal of more than 5 9

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pelvic and/or more than 5 positive paraaortic lymph nodes was associated with significant improvement of OS [29]. In a single institution review of 467 patients with early-stage cervical

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cancer, the author did not find any association between the number of nodes removed and survival of node negative patients; but there was an improved survival in node positive patients who underwent lymphadenectomy [30]. In another study of stage IB/IIA cervical cancer patients,

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5-year DFS was >90% without pelvic node metastases, 81% in patients with 1 pelvic lymph node metastasis, 41% in patients with 2-3 pelvic lymph node metastasis, 23% in patients with ≥4

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pelvic lymph metastasis, or 30-35% in patients with paraaortic metastasis, demonstrating decreased 5-year DFS with pelvic lymph node involvement [31]. In 2010, Jimenez and Covens reported that 5-year survival rates ranged from 46-90% and 50-80% after debulking of macroscopic and microscopic pelvic lymph nodes in patients with stage IB-IVB cervical cancer [7]. Shah et al. examined the surveillance, epidemiology, and end results (SEER) database of

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5522 women with early-stage (IA2-IIA) cervical cancer who underwent radical hysterectomy with lymphadenectomy (893 had <10 nodes, 2030 had 11-20, 1487 had 21-30 nodes, and 1112

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had >30 nodes removed). A more extensive lymphadenectomy had no effect on survival of women with positive lymph nodes but improved survival was observed in women with negative

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lymph node. Patients with 21-30 nodes removed were 24% less likely to die and patients with >30 nodes removed were 37% less likely to die from their tumors compared to node negative patients with >10 nodes removed [32]. In a study conducted by Cheung et al. enlarged suspicious pelvic nodes in 110 early stage (1B to stage IIA) and 97 advanced stage (1B2 or above) cervical cancer patients were debulked which led to reduction in pelvic recurrence but did offer any survival benefit [33]. Status in vulvar cancer 10

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Status of the groin lymph nodes is the most important prognostic factor in vulvar cancer patients. In vulvar cancer patients, surgical removal of involved inguinofemoral lymph nodes followed by

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radiotherapy has a relevant therapeutic value, as survival is markedly decreased when these lymph nodes are not dissected [34]. Debulking of the macroscopically involved nodes (with unilateral or bilateral inguinofemoral lymphadenectomy) helps the radiotherapy to treat any

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remaining microscopic disease; thereby potentially decreasing morbidity without compromising survival [35].

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There are limited studies on debulking of positive enlarged lymph nodes in vulvar cancer. In previous literature involving 588 patients with vulvar carcinoma, 5-year relative survival rates was reported as 98%, 87%, 75%, and 29% for the risk group categories of minimal (negative groin nodes and lesion diameter ≤2 cm), low (1 positive groin node and lesion diameter ≤2 cm or negative groin nodes and fewer than 2 lesions ≤8 cm diameter), intermediate (negative groin

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nodes and lesion diameter >8 cm, 1 positive groin node and lesion diameter >2 cm, or 2 unilaterally positive groin nodes and lesion diameter ≤8 cm), and high (3 or more positive groin

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nodes or 2 bilaterally positive groin nodes) [36]. Hyde et al. in a retrospective study compared the groin recurrence rate and survival of 40 patients with clinically involved groin nodes and

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squamous cell vulvar carcinoma treated by full inguinofemoral lymphadenectomy or by a nodal debulking followed by radiotherapy. In univariate analysis, the study reported that removal of only bulky nodes followed by groin and pelvic radiotherapy offers better overall and DFS than performing full inguinofemoral lymphadenectomy in patients with vulvar cancer. However, in a multivariate analysis, other variables like extracapsular growth were independent predictors for survival [37]. In 2010, a study also showed a significant improvement in DFS after removal of lymph node (>10) in patients with stage III node-negative vulvar carcinoma [38]. Fambrini et al. 11

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evaluated the role of modified triple-incision total radical vulvectomy and inguinofemoral lymphadenectomy in 57 patients with locally advanced squamous vulvar cancer. The OS for the

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entire cohort was 65.4%, with 3-year and 5-year OS of 60.5% and 48.6%, respectively [39]. However, more studies on debulking of lymph nodes are required to support survival benefit in

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patients with vulvar cancer.

Status in uterine sarcoma

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Debulking (pelvic and paraaortic lymph node dissection) can help treatments like radiation or chemotherapy work better for some types of cancer, however its role in treating uterine sarcoma is not clear [40]. In early stage leiomyosarcoma of uterine, routine pelvic and paraaortic lymphadenectomy is not indicated, as the incidence of lymph node metastases is approximately 3% [41,42]; however in advanced stage lymph node involvement is common and debulking of

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enlarged positive lymph node is recommended as a part of optimal cytoreduction [43]. In 2015, Mahdi et al. evaluated the SEER database, estimated the survival impact of

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lymphadenectomy in 955 of 1385 patients diagnosed with uterine clear cell cancer. Patients who underwent lymphadenectomy were 39% less likely to die than patient who did not have the

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procedure. Compared to patients with 0 nodes removed, patients with more extensive lymphadenectomy (1 to 10 and >10 nodes removed) were 32% and 47% less likely to die from the disease [44]. However, there is lack of data demonstrating the benefits of debulking of enlarged positive nodes in patients with uerine sarcoma, which may be due to lower chances of lymph node metastases (<3%), necessating the requirement of more randomized control trials. Status in ovary cancer

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Ovarian germ cell tumors can spread directly to the adjacent pelvic organs and through the lymph system to the pelvic, aortic, chest (mediastinal), groin and neck lymph nodes. There is

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benefit in resecting residual paraaortic nodal mass post chemotherapy in ovarian germ cell tumors. (Figure 2, 3, 4) Primary cytoreductive surgery (removal of complete tumor at the time of initial surgery, with resection of bulky nodes only) has been an integral part of the treatment

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of advanced ovarian cancer [45]. However, whether systematic removal of retroperitoneal lymph nodes should be part of complete cytoreductive surgery is still unclear [46].

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Retroperitoneal lymph node involvement is reported in 50-75% of patients with advanced stage disease [47,48]. Systematic lymphadectenomy has been reported to increase OS in patients with all stage epithelial ovarian cancer with recurrent bulky nodes. In a retrospective analysis of 1924 ovarian cancer patients, du Bois et al. observed that in patients with no residual tumor after cytoreductive surgery, systematic lymph node dissection significantly improved the median

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survival time and 5-year OS compared to patients without lymphadenectomy (103 versus 84 months, and 67.4 versus 59.2% patients, respectively). In addition, systematic lymph node

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dissection might offer an additional survival benefit for patients with advanced ovarian cancer in whom complete intraperitoneal debulking can be achieved. For patients with small residual

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disease and clinically suspect lymph nodes, lymphadenectomy resulted in a 16% gain in 5-year OS [49]. Panici et al. in a prospective randomized trial on 427 patients with optimally debulked (residual tumor <1) stage IIIBC-IV epithelial ovarian cancer evaluated the impact of lymphadenectomy on PFS and OS. The patients were randomized to systematic pelvic and paraaortic lymphadenectomy or resection of bulky nodes (lymph nodes were considered bulky if they were 1 cm in diameter) only. After a median follow-up of 68.4 months, patients with systematic lymph node dissection had a 7-month improvement in PFS with no OS compared to 13

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resection of bulky nodes only (29.4 vs 22.4 months) [46]. Burghardt et al. compared complete pelvic lymphadenectomy or pelvic and paraaortic lymphadenectomy in 180 ovarian cancer

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patients with stage I-IV. The incidence of positive lymph nodes was 24% in stage I, 50% in stage II, 74% in stage III, and 73% in stage IV. The study reported the 5-year survival rate of patients with stage III disease with no, 1, or more than 1 positive nodes as 69, 58, and 28%, respectively

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[50]. In a case control study of 105 patients with Stage IIIC-IV of epithelial ovarian cancer evaluated the potential benefit on survival with and without systematic pelvic and paraaortic

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lymphadenectomy during primary or secondary cytoreductive surgery. The study reported that pelvic and paraaortic lymphadenectomy significantly improved the survival, advising aggressive surgical cytoreduction with systematic pelvic and paraaortic lymphadenectomy [51]. In another study, 77 patients with advanced epithelial ovarian cancer (Stages IIIa-IVa) either underwent (56/77) or not underwent (21/77) aortic and pelvic lymphadenectomy. Survival analysis revealed

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that 50% patients with negative lymph nodes, 46% patients with microscopically positive lymph nodes, 43 patients with macroscopically positive but surgically removed lymph nodes, and only

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10% patients with residual disease (at least 1 cm) were alive without evidence of disease after a median follow-up of 30 months; concluding that removal of bulky nodes improves patients

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survival, but added no advantage in resecting clinically negative nodes [52]. Maggoni et al. in 268 patients with early stage ovarian cancer investigated the role of systematic aortic and pelvic lymphadenectomy compared with lymph node sampling in the management of early stage ovarian cancer. 5-year PFS was 71.3 and 78.3%, and 5-year OS was 81.3 and 84.2% respectively; however the trial lacked the power to exclude clinically important effects of systematic aortic and pelvic lymphadenectomy on PFS and OS [53]. In a prospective observational study the role of systematic lymphadenectomy was evaluated in 29 epithelial 14

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ovarian cancer patients with recurrent bulky lymph node disease. The median number of resected aortic and pelvic nodes was 15 (range: 2-32) and 17 (range: 8-47), respectively. 5-year OS and

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disease free interval was 87% and 31%, respectively [54]. The SEER registry evaluated the cancer data from 17 registries comprising 49783 patients with epithelial ovarian tumors undergoing lymphadenectomy. 5-year cause specific survival rates were 37%, 62% and 71% for

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the groups in which no, 1-9, and 10 or more nodes were removed, respectively. When more nodes were resected, the cause specific survival was found to significantly increase even if

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patients are undergoing debulking surgery or a pelvic exenteration; suggesting beneficial effect of lymphadenectomy in epithelial ovarian tumors regardless of the stage of disease [55]. Chan et al. further evaluated the SEER database and reported that in 13918 women with stage III-IV epithelial ovarian cancer, a more extensive lymph node dissection (0, 1, 2-5, 6-10, 11-20, and >20 nodes) was associated with an improved 5-year disease specific survival rates of 26.1, 35.2,

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42.6, 48.4, 47.5, and 47.8%, respectively. Of the stage IIIC patients with nodal metastasis, the extent of nodal resection (1, 2-5, 6-10, 11-20, and >20 nodes) was related with improved survival

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of 36.9, 45.0, 47.8, 48.7, and 51.1%, respectively [56]. A similar study in 6686 patients with stage I ovarian cancer reported the 5-year survival significantly better in the group of patients

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with lymphadenectomy compared to patients who did not undergo lymphadenectomy (92.6 versus 87%) [57].

In a retrospective analysis of 219 patients with stage IIIC/IV epithelial ovarian cancer who had undergone primary surgery (residual disease >1 cm), complete pelvic and paraaortic lymphadenectomy was found to be superior to lymph node sampling and no lymph node assessment (5-year OS, 50% versus 33% versus 29%) [58]. In another retrospective study of 488 patients with untreated advanced ovarian cancer reported that systematic pelvic and paraaortic 15

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lymphadenectomy improved survival in patients with negative nodes (5-year survival, 46%) than those who had node metastases (5-year survival, 25%) [59]. In 2010, Kim et al. analyzed 9

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studies (2 randomized controlled trials and 7 observational studies) for the evaluation of the role of systematic lymphadenectomy or unsystematic lymphadenectomy in 21919 patients with epithelial ovarian cancer (5014 receiving systematic and 16905 receiving unsystematic

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lymphadenectomy). The results suggested systematic lymphadenectomy to increase OS in patients with all-stage disease who underwent optimal debulking surgery [60]. A retrospective

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study further evaluated the role of systematic lymphadenectomy in optimally debulked patients with advanced ovarian cancer (n = 101, controls and n = 50, cases) and reported the 2-year PFS rates as 36 versus 25% and the OS rates as 69 versus 88% for those who did and did not undergo lymphadenectomy [61]. Similarly, Mikami et al. reported that patients with FIGO stage III-IV ovarian cancer with small residual tumor (<1 cm) who underwent complete pelvic and paraaortic

B. SUMMARY

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node dissection showed better OS [62].

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There are several hypotheses regarding the success of treatments in gynaecological cancers: 1) patients undergoing intraperitoneal debulking (leaving residual tumors >1 cm) would not benefit

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from lymphadenectomy; 2) patients with bulky nodes but complete intraperitoneal debulking could benefit from removal of enlarged metastatic nodes; 3) lymphadenectomy in patients without clinically suspect lymph nodes and small residual disease intraperitoneally might not change the residual disease status but may reduce tumor burden [63]. Pertaining to therapeutic lymphadenectomy, survival benefit can be analyzed by 2 ways: 1) direct survival benefit following therapeutic lymphadenectomy of bulky positive metastatic lymph nodes; and 2) indirect survival benefit which is defined as survival benefit after a sequel of systematic 16

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lymphadenectomy, proper, accurate staging of disease and stage migration and tailormade adjuvant treatment. The direct hypothesis of therapeutic lymphadenectomy and survival benefit

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has been prospected in cervical cancers and vulval cancers and in post chemotherapy residual paraarotic nodal mass in germ cell ovarian cancers. The indirect survival benefit in high-risk endometrial cancers and advanced epithelial ovarian cancers with therapeutic paraarotic

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lymphadenctomy needs to be tested in randomized controlled trials.

Despite the prognostic involvement of lymph node metastasis, there is a great discussion

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about the role of pelvic and paraaortic lymph node dissection in management of different gynaecological cancers. du Bois et al. in a randomized phase III trial reported that more than 90% of patients with clinically suspected lymph nodes had histologically positive lymph nodes [49]. Hence, removal of positive bulky node along with cytoreductive surgery could offer survival benefits in patients with gynaecological malignancies. However, indirect benefit due to

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tailormade adjuvant treatment, secondary to accurate staging achieved as a sequale of systematic lymphadenecotmy needs to be analyzed in the future trials.

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Surgical debulking of enlarged nodes (to less than 2 cm) may improve the control of pelvic disease by chemo-radiation, and pelvic disease control may reduce the risk of distant metastatic

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spread by 60-75%. Hence patients for surgical debulking of lymph nodes should be selected among patients with a high probability of achieving local control, a low chance of developing distant metastases, and have lymph nodes of sufficient size is unlikely to be controlled with chemo-radiation [7].

In conclusion, although there is a convincing theoretical basis to examine this approach, however the magnitude of survival benefit is limited with respect to randomized controlled trials. More randomized controlled trials to test this research question are required that probably could 17

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shed more light on this important question. Further, indirect benefit due to tailormade adjuvant treatment, secondary to accurate staging achieved as a sequale of systematic lymphadenecotmy

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needs to be analyzed in the future trials.

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Practice points: Lymphatic spread has been reported as a common feature of all stages of gynaecological cancer Previous literature has supported a positive role of debulking of lymph nodes in terms of survival benefits Status of both pelvic and paraaortic lymph nodes should be assessed in all patients as in some cases paraaortic lymph nodes may be positive in the case of negative pelvic nodes Researchers have recommended systematic pelvic and paraaortic lymphadenectomy for the improvement in overall survival in endometrial cancer patients with lymph node metastases The most important prognostic factors for survival in cervical cancer are the status of lymph nodes Surgical debulking of enlarged lymph node would be effective in chemo-radiation resistant lymph nodes Several studies have reported potential survival benefits of pelvic and/or paraaortic lymph nodes debulking over no debulking in women with bulky metastases disease Surgical removal of involved inguinofemoral lymph nodes followed by radiotherapy has a relevant therapeutic value in vulvar cancer There are limited studies on debulking of positive enlarged lymph nodes in vulvar cancer In early stage uterine leiomyosarcoma, routine pelvic and paraaortic lymphadenectomy is not indicated, as the incidence of lymph node metastases is approximately 3% Retroperitoneal lymph node involvement is reported in 50-75% of patients with advanced stage ovary cancer Systematic lymphadectenomy has been reported to increase OS in patients with all stage epithelial ovarian cancer with recurrent bulky nodes

Research agenda: • The magnitude of survival benefit is limited with respect to randomized controlled trials, hence more randomized controlled trials to test the role of debulking of enlarged positive lymph node are required • Indirect benefit due to tailormade adjuvant treatment, secondary to accurate staging achieved as a sequale of systematic lymphadenecotmy needs to be analyzed in the future trials

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CONFLICT OF INTEREST & ROLE OF FUNDING SOURCE

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The authors declare that there are no conflicts of interest, nor there any sources of funding.

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Completed Systematic High Paraaortic lymphadenectomy

Figure 2:

CECT scan showing invaded IVC and Aorta

Figure 3:

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Residual Paraaortic nodal mass post chemotherapy in GCT

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Legends of Figures:

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Monobock therapeutically resected nodal mass with IVC and Aorta with Double grafting

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Monoblock Resected specimen

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Table 1: Status of debulking of lymph node in different gynaecological cancers Treatment

Outcomes

Advanced squamous vulvar cancer (n = 57)

Inguinofemoral lymphadenectomy

Advanced ovarian cancer (n = 101, controls and n = 50, cases)

Systematic lymphadenectomy versus no lymphadenectomy

Endometrial cancer

Comprehensive pelvic and paraaortic lymphadenectomy versus pelvic lymphadenectomy alone

Endometrial carcinoma (n = 671) SEER registry of ovarian cancer data from 17 registries (n = 49783)

3-year and 5-year OS: 60.5% and 48.6%

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2-year PFS rates: 36 versus 25%; OS [61] rates: 69 versus 88%

Pelvic and paraaortic lymph node dissection versus pelvic lymph node dissection

8-year survival rates: 84 versus 69%

[11]

Lymphadenectomy

5-year cause specific survival rates: 37, 62, and 71% for no lymph nodes, 1-9 nodes, and 10 or more nodes resected

[55]

5- and 10-year OS rates: 96% and 93% versus 72% and 62%

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ASTEC trial in endometrial carcinoma (n = 1408)

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5-year survival: 89 versus 46.5%

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Paraaortic lymph node metastasis Negative versus positive paraaortic in endometrial carcinoma (n = 284) lymphadenectomy Ovarian cancer (n = 1924)

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Type of cancer and number of patients

Systematic lymphadenectomy versus no lymphadenectomy

Median survival time and 5-year OS: [49] 103 versus 84 months, and 67.4 versus 59.2%

Pelvic lymph node dissection versus no pelvic node dissection

Failed to demonstrate a 5-year survival advantage: 90 versus 80%

[19]

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Outcomes

Early-stage endometrial carcinoma

Lymph node dissection versus no dissection

Stages I, II, III, IV endometrioid endometrial cancer

Lymphadenectomy versus no lymphadenectomy

Stage III-IV epithelial ovarian cancer (n = 13918)

Extensive lymph node dissection: 0, 1, 2-5, 6-10, 11-20, and >20 nodes

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Treatment

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5-year survival: 85.9 versus 90%

[21]

5-year disease specific survival: 96%, 90%, 74%, and 53% versus 97%, 82%, 63%, and 27%

[15]

5-year disease specific survival rates: 26.1, 35.2, 42.6, 48.4, 47.5, and 47.8%

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Type of cancer and number of patients

5-year OS and disease-free interval: [54] 87% and 31%

Stage IB/IIA cervical cancer

Lymph node dissection in patients without pelvic node metastases versus 1 pelvic lymph node metastasis versus 2-3 pelvic lymph node metastasis versus ≥4 pelvic lymph metastasis versus paraaortic metastasis

5-year DFS : >90% versus 81% versus 41% versus 23% versus 3035%

[31]

Stage IIIC/IV epithelial ovarian cancer (n = 219)

Complete pelvic and paraaortic lymphadenectomy versus lymph node sampling versus no lymph node assessment

5-year OS: 50% versus 33% versus 29%; 5-year OS: 31.5% (positive nodal metastases) versus 54% (negative nodal metastases)

[58]

Systematic lymphadenectomy versus lymph node sampling

5-year PFS: 71.3 versus 78.3%and 5- [53] year OS: 81.3 versus 84.2

Epithelial ovarian cancer macroscopically confined to the pelvis (n = 268)

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Epithelial ovarian cancer and Systematic lymphadenectomy recurrent bulky lymph node disease (n = 48)

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Treatment

Outcomes

Endometrioid endometrial high risk cancer (stage IB, grade 3 or greater) (n = 12333)

Extensive lymph node sampling versus fewer lymph nodes removed

Optimally debulked stage IIIBCIV epithelial ovarian cancer (n = 427)

Systematic lymph node dissection versus resection of bulky nodes

Stage IIIC endometrial cancer with pelvic and/or aortic lymph node metastases

Microscopic metastatic disease versus grossly positive lymph node completely resected versus residual macroscopic disease

5-year disease specific survival: 63% [10] versus 50% versus 43%

Node positive endometrial cancer

Paraaortic lymphadenectomy versus no lymphadenectomy

5-year PFS: 76 versus 36% and OS: 77 versus 42%

[14]

Stage IB and II cervical carcinoma (n = 421)

Lymphadenectomy in negative nodes versus positive pelvic nodes versus positive paraaortic nodes

3-year survival: 94% versus 64% versus 35%

[1]

Advanced-stage cervical cancer (n = 266)

Extraperitoneal pelvic and paraaortic lymphadenectomy in microscopic and macroscopic metastatic nodes

10-year DFS rates: 35 and 46%

[28]

5-year survival: 46% versus 25%

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Type of cancer and number of patients

5-year survival: 75.3% with one node removed versus 86.8% with ≥ 20 nodes removed

[9]

7-month improvement in PFS with no OS compared to resection of bulky nodes only: 29.4 versus 22.4 months

[46]

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Advanced ovarian cancer (n = 488) Systematic pelvic and paraaortic lymphadenectomy in negative nodes versus node metastases

Reference

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Treatment

Outcomes

Cervical carcinoma (n = 34)

Resection of bulky positive lymph nodes

All stage epithelial ovarian cancer with recurrent bulky nodes (n = 180)

Systematic pelvic lymphadectenomy

Cervical carcinoma (n = 156)

Advanced cervical cancer (n = 159)

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Type of cancer and number of patients

Reference

5-year survival: 80% for pelvic and [27] common iliac lymph nodes, and 48% for positive paraaortic nodes [50]

Pelvic lymph nodes microscopic metastases versus pelvic lymph nodes macroscopic metastases resected versus pelvic lymph nodes unresectable metastases

5-year survival: 57% versus 51% versus 0%

[25]

Pelvic lymph node dissection

5-year relapse-free rate: 86% without pelvic node metastases versus 0% in unresectable pelvic node metastases

[26]

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5-year survival (stage III) with no, 1, or >1 positive nodes: 69, 58, and 28%

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