Lymph-node-positive gynaecological cancers remain a pharmacotherapeutic challenge, and patients with lymph-node-positive gynaecological cancers have poor survival. The purpose of this review is to determine whether a survival advantage arises from surgical debulking of enlarged positive lymph nodes in different types of gynaecological cancers. Information from studies published on the survival benefits from debulking lymph nodes in gynaecological cancers was investigated. Pertaining to therapeutic lymphadenectomy, survival benefit can be analysed in two ways, direct survival benefit following therapeutic lymphadenectomy of bulky positive metastatic lymph nodes and indirect survival benefit, which results after a sequela of systematic lymphadenectomy, proper, accurate staging of disease and stage migration and tailor-made 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 paraarotic nodal mass in germ cell ovarian cancer. The indirect survival benefit of therapeutic paraarotic lymphadenectomy in high-risk endometrial cancers and advanced epithelial ovarian cancers needs to be tested in randomized controlled trials. More randomized controlled trials are required to investigate this research question. Further, indirect benefit due to tailor-made adjuvant treatment, secondary to accurate staging achieved as a sequela of systematic lymphadenectomy, needs to be analysed in future trials.
Gynaecological cancers
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 to be a common feature of all stages of gynaecological cancers as per the International Federation of Gynaecology and Obstetrics (FIGO) staging system . Palpation is a traditional method of detecting lymph node metastasis; however, it is not considered accurate for the detection of lymph node metastatic deposits <2 mm in diameter within a lymph node . 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 (CT), and 75% for PET .
Patients are usually treated with a radiation dose of 50–60 Gy; however, this radiation dose is insufficient to sterilize bulky lymph nodes (>2 cm) and doses beyond this should be avoided due to the risk of severe or fatal toxicities in neighbouring organs such as small bowel. Further, addition of chemotherapy to radiation therapy has been shown to decrease local failure by 33–50% . Pelvic and paraaortic lymph node dissection has 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 the case of high-risk endometrial cancers, 67% of women with positive pelvic lymph nodes are reported to have tumour in the paraaortic area as well. Mariani et al. reported that lymphadenectomy only up to the inferior mesenteric artery could miss 38–46% of women with positive paraaortic lymph nodes ( Fig. 1 ). Previous studies have 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 presence of enlarged bulky lymph nodes poses a serious challenge . Systematic lymphadenectomy leads to proper and accurate stage mapping of disease and helps to tailor appropriate adjuvant treatment selection, which has an influence on the overall outcome and survival. This sets the hypothesis for the therapeutic value of lymphadenectomy of positive bulky metastatic lymph nodes, more so in cervical cancers, high-risk endometrial cancers and vulval cancers.
| Type of cancer and number of patients | Treatment | Outcomes | Reference |
|---|---|---|---|
| Advanced squamous vulvar cancer ( n = 57) | Inguinofemoral lymphadenectomy | 3-year and 5-year OS: 60.5% and 48.6% | |
| Advanced ovarian cancer ( n = 101, controls and n = 50, cases) | Systematic lymphadenectomy versus no lymphadenectomy | 2-year PFS rates: 36% versus 25%; OS rates: 69% versus 88% | |
| Endometrial cancer | Comprehensive pelvic and paraaortic lymphadenectomy versus pelvic lymphadenectomy alone | 5-year survival: 89% versus 46.5% | |
| Endometrial carcinoma ( n = 671) | Pelvic and paraaortic lymph node dissection versus pelvic lymph node dissection | 8-year survival rates: 84% versus 69% | |
| SEER registry of ovarian cancer data from 17 registries ( n = 49,783) | Lymphadenectomy | 5-year cause specific survival rates: 37%, 62% and 71% for no lymph nodes, one to nine nodes and 10 or more nodes resected | |
| Paraaortic lymph node metastasis in endometrial carcinoma ( n = 284) | Negative versus positive paraaortic lymphadenectomy | 5- and 10-year OS rates: 96% and 93% versus 72% and 62% | |
| Ovarian cancer ( n = 1924) | Systematic lymphadenectomy versus no lymphadenectomy | Median survival time and 5-year OS: 103 versus 84 months, and 67.4% versus 59.2% | |
| ASTEC trial in endometrial carcinoma ( n = 1408) | Pelvic lymph node dissection versus no pelvic node dissection | Failed to demonstrate a 5-year survival advantage: 90% versus 80% | |
| Early-stage endometrial carcinoma | Lymph node dissection versus no dissection | 5-year survival: 85.9% versus 90% | |
| Stages I, II, III, IV endometrioid endometrial cancer | Lymphadenectomy versus no lymphadenectomy | 5-year disease specific survival: 96%, 90%, 74% and 53% versus 97%, 82%, 63% and 27% | |
| Stage III–IV epithelial ovarian cancer ( n = 13918) | Extensive lymph node dissection: zero, one, two to five, six to 10, 11–20, and >20 nodes | 5-year disease specific survival rates: 26.1%, 35.2%, 42.6%, 48.4%, 47.5% and 47.8% | |
| Epithelial ovarian cancer and recurrent bulky lymph node disease ( n = 48) | Systematic lymphadenectomy | 5-year OS and disease-free interval: 87% and 31% | |
| Stage IB/IIA cervical cancer | Lymph node dissection in patients without pelvic node metastases versus one pelvic lymph node metastasis versus two to three pelvic lymph node metastasis versus ≥4 pelvic lymph metastasis versus paraaortic metastasis | 5-year DFS: >90% versus 81% versus 41% versus 23% versus 30–35% | |
| 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) | |
| Epithelial ovarian cancer macroscopically confined to the pelvis ( n = 268) | Systematic lymphadenectomy versus lymph node sampling | 5-year PFS: 71.3% versus 78.3% and 5-year OS: 81.3% versus 84.2 | |
| Endometrioid endometrial high-risk cancer (stage IB, grade 3 or greater) ( n = 12,333) | Extensive lymph node sampling versus fewer lymph nodes removed | 5-year survival: 75.3% with one node removed versus 86.8% with ≥20 nodes removed | |
| Optimally debulked stage IIIBC–IV epithelial ovarian cancer ( n = 427) | Systematic lymph node dissection versus resection of bulky nodes | 7-month improvement in PFS with no OS compared to resection of bulky nodes only: 29.4 versus 22.4 months | |
| 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% versus 50% versus 43% | |
| Node-positive endometrial cancer | Paraaortic lymphadenectomy versus no lymphadenectomy | 5-year PFS: 76% versus 36% and OS: 77% versus 42% | |
| 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% | |
| Advanced-stage cervical cancer ( n = 266) | Extraperitoneal pelvic and paraaortic lymphadenectomy in microscopic and macroscopic metastatic nodes | 10-year DFS rates: 35% and 46% | |
| Advanced ovarian cancer ( n = 488) | Systematic pelvic and paraaortic lymphadenectomy in negative nodes versus node metastases | 5-year survival: 46% versus 25% | |
| Cervical carcinoma ( n = 34) | Resection of bulky positive lymph nodes | 5-year survival: 80% for pelvic and common iliac lymph nodes, and 48% for positive paraaortic nodes | |
| All-stage epithelial ovarian cancer with recurrent bulky nodes ( n = 180) | Systematic pelvic lymphadenectomy | 5-year survival (stage III) with no, one or >1 positive nodes: 69, 58 and 28% | |
| Cervical carcinoma ( n = 156) | 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% | |
| Advanced cervical cancer ( n = 159) | Pelvic lymph node dissection | 5-year relapse-free rate: 86% without pelvic node metastases versus 0% in unresectable pelvic node metastases |
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.
Status in endometrial cancer
One of the most important prognostic factors for endometrial carcinoma (particularly pelvic and paraaortic lymph node metastases) is the presence of extrauterine disease. There is considerable controversy in the literature as to the value of lymphadenectomy, partly due to the heterogeneity and retrospective nature of many clinical trials. Clinical practice is therefore not uniform, and the data should be evaluated in this context.
According to 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 .
Lymph node dissection is considered an important aspect of the management of endometrial cancer . Researchers have recommended that complete pelvic and paraaortic node dissection be performed rather than selective nodal sampling as the latter may miss positive nodes. In a retrospective analysis of 12,333 patients with endometrial cancer, Chan et al. 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 vs. 86.8% with ≥20 nodes removed). In patients with stage IIIC–IV, significant benefits in the 5-year survival were obtained from extensive nodal resection (72% for 20 nodes vs. 53% for resection of two to five nodes) .
Several studies have evaluated the safety and survival outcomes of pelvic and paraaortic lymphadenectomy in patients with endometrial cancer. In a retrospective analysis, Havrylesky et al. evaluated the 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. The 5-year disease-specific survival rate was 63% in patients with microscopic metastatic disease compared with 50% in patients with complete resection of grossly positive lymph node and 43% in patients with residual macroscopic disease . 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 combined pelvic and paraaortic lymph node dissection group versus the group that underwent pelvic lymph node dissection alone (84% vs. 69%) . A 10.6% increase in the 5-year overall survival (OS) was reported for pelvic and paraaortic lymphadenectomy compared with 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) .
Resection of the bulky lymph nodes is reported to be beneficial if the patients had clear cell histology, myometrial invasion (>50%) and large tumour (>2 cm in diameter). Otsuka et al. retrospectively evaluated the therapeutic benefit of retroperitoneal lymphadenectomy and chemotherapy in 106 patients with endometrioid adenocarcinoma. The 5-year survival rate of 23 patients with lymph node metastasis was worse than that of patients without lymph node metastasis (60% vs. 96%) . Abu-Rustum et al. reported that lymph node dissection is essential for accurate surgical staging, and the removal of regional lymph nodes (≥10) was associated with improved OS in lower-stage, older patients with endometrial carcinoma who received no adjuvant therapy . Mariani et al. reported that patients with paraaortic node metastases (myometrial invasion >50%, positive pelvic lymph nodes or adnexal involvement) undergoing paraaortic lymphadenectomy had an improved 5-year progression-free survival (PFS) (76% vs. 36%) and OS (77% vs. 42%) compared with patients without paraaortic lymph node dissection . Chan et al. evaluated the database from the National Cancer Institute of women with disease stages I–IV of endometrioid endometrial cancer, and the 5-year disease-specific survival rates were 96%, 90%, 74% and 53% for women who underwent lymphadenectomy compared with 97%, 82%, 63% and 27% for women not undergoing lymphadenectomy, respectively . In a study of 649 patients with stage I or II endometrial adenocarcinoma, the 5-year survival rate (extrapolated from survival curves) was higher for patients undergoing multiple-site pelvic lymph node dissection compared with patients who did not undergo lymph node dissection (95% vs. 75%) .
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 to be 96% and 93% vs. 72% and 62% in patients with positive paraaortic lymph node, suggesting that surgery with systematic pelvic and paraaortic lymphadenectomy improves long-term survival in patients with paraaortic metastasis . Todo et al. reported that the 5-year OS was better for patients with endometrial cancer who underwent comprehensive 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% vs. 46.5%) .
However, a recent European randomized clinical trial (A Study in the Treatment of Endometrial Cancer (ASTEC) trial) performed at 85 institutions in four countries, investigating 1408 women with endometrial carcinoma, failed to demonstrate a 5-year survival advantage with pelvic lymph node dissection versus no pelvic node dissection (90% vs. 80%) . There are critiques and shortcomings of the ASTEC trial: first, the number of resected lymph nodes was insufficient in many patients (35% of patients in the lymphadenectomy group had nine 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 . Further, in a phase 3 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 lymph node dissection, and they reported that there was no significant difference in the 5-year DFS and OS in the lymph node dissection group compared with patients with no lymph node dissection (81% vs. 81.7% and 85.9% vs. 90%) .
Status in cervical cancer
Cervical cancer spreads via the lymphatics, with metastases first occurring in the pelvic lymph nodes followed by spreading to the paraaortic nodes . As per earlier reports, assessment of regional lymph nodes is the primary goal in women with early-stage cervical cancer. Laparotomy or laparoscopy or robot-assisted surgery through a transperitoneal or extraperitoneal approach is the most used evaluation procedure in cervical cancer. Both the extraperitoneal and transperitoneal approaches by laparotomy in paraaortic advanced cervical cancer have similar sensitivity in detecting nodal spread . The most important prognostic factors for survival in cervical cancer are the status of lymph nodes . In some institutions, lymph node debulking is performed in patients with stage IB/IIB cervical cancer, tumour 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 . High-quality randomized data on the role of lymphadenectomy in advanced-stage cervical disease remain unresolved.
Several trials have identified that bulky pelvic and/or paraaortic nodes (>2 cm) are resistant to radiotherapy and/or chemotherapy, and they pose a serious challenge . Hence, surgical debulking of enlarged lymph nodes 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 robot-assisted surgery . Several retrospective studies reported the potential survival benefits of pelvic and/or paraaortic lymph nodes debulking over no debulking in women with bulky metastasis disease. In 1989, Downey et al. evaluated the impact of pelvic node resection in 156 cervical cancer patients divided into four groups by pelvic node status. The 5-year recurrence-free survival in the macroscopic nodal metastases group was 51% versus 57% in the microscopic metastases group versus 0% in the unresectable nodal metastases group. Patients undergoing pelvic node resection showed improvement in recurrence, recommending surgical removal of pelvic nodal metastases before radiation therapy . In a retrospective study, 159 women with advanced cervical cancer received definitive radiation therapy following extraperitoneal surgical staging (thus included pelvic lymph node dissection and periaortic lymph node sampling). The 5-year relapse-free rate in women without pelvic node metastases was higher compared with unresectable pelvic node metastases (86% vs. 0%) . In a retrospective analysis by Hacker et al., 34 patients with advanced cervical cancer underwent resection of bulky positive lymph nodes prior to radiation therapy. The 5-year survival was 80% for patients with disease involving the 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 the patients with micrometastases, suggesting removal of the positive lymph node . In another study, 10-year DFS of 35% and 46% was reported in patients with microscopic and macroscopic metastatic nodes, respectively, after they underwent extraperitoneal pelvic and paraaortic lymphadenectomy before radiotherapy . Morice et al. evaluated the potential therapeutic value of systematic pelvic and paraaortic lymphadenectomy in 421 patients with stage IB and II cervical carcinoma. The 3-year survival was 94% for patients with negative nodes compared with 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 . 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 five pelvic and/or more than five positive paraaortic lymph nodes was associated with significant improvement of OS . In a single institution review of 467 patients with early-stage cervical cancer, the author did not find any association between the number of nodes removed and survival of node-negative patients; however, there was an improved survival in node-positive patients who underwent lymphadenectomy . In another study of stage IB/IIA cervical cancer patients, the 5-year DFS was >90% without pelvic node metastases, 81% in patients with one pelvic lymph node metastasis, 41% in patients with two to three pelvic lymph node metastasis, 23% in patients with ≥4 pelvic lymph metastasis or 30–35% in patients with paraaortic metastasis, demonstrating decreased 5-year DFS with pelvic lymph node involvement . In 2010, Jimenez and Covens reported that the 5-year survival rates ranged from 46% to 90% and 50% to 80% after debulking of macroscopic and microscopic pelvic lymph nodes, respectively, in patients with stage IB–IVB cervical cancer . Shah et al. examined the Surveillance, Epidemiology, and End Results (SEER) database of 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 had >30 nodes removed). A more extensive lymphadenectomy had no effect on the survival of women with positive lymph nodes, but improved survival was observed in women with negative lymph nodes. 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 tumours compared with node-negative patients with >10 nodes removed .
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 not offer any survival benefit .
Status in vulvar cancer
The status of the groin lymph nodes is the most important prognostic factor in vulvar cancer patients. In vulvar cancer patients, surgical removal of the involved inguinofemoral lymph nodes followed by radiotherapy has a relevant therapeutic value, as survival is markedly decreased when these lymph nodes are not dissected . Debulking of the macroscopically involved nodes (with unilateral or bilateral inguinofemoral lymphadenectomy) helps the radiotherapy to treat any remaining microscopic disease, thereby potentially decreasing morbidity without compromising survival .
There are limited studies on debulking of positive enlarged lymph nodes in vulvar cancer. In the previous literature involving 588 patients with vulvar carcinoma, the 5-year relative survival rates were reported to be 98%, 87%, 75% and 29% for the risk group categories of minimal (negative groin nodes and lesion diameter ≤2 cm), low (one positive groin node and lesion diameter ≤2 cm or negative groin nodes and fewer than two lesions ≤8 cm diameter), intermediate (negative groin nodes and lesion diameter >8 cm, one positive groin node and lesion diameter >2 cm or two unilaterally positive groin nodes and lesion diameter ≤8 cm) and high (three or more positive groin nodes or two bilaterally positive groin nodes) . In a retrospective study, Hyde et al. compared the groin recurrence rate and survival of 40 patients with clinically involved groin nodes and 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 survival and DFS than performing full inguinofemoral lymphadenectomy in patients with vulvar cancer. However, in a multivariate analysis, other variables such as extracapsular growth were independent predictors for survival . 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 . Fambrini et al. 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 entire cohort was 65.4%, with 3-year and 5-year OS of 60.5% and 48.6%, respectively . However, more studies on debulking of lymph nodes are required to support survival benefit in patients with vulvar cancer.
Status in uterine sarcoma
Debulking (pelvic and paraaortic lymph node dissection) can help treatments such as radiation or chemotherapy work better for some types of cancer; however, its role in treating uterine sarcoma is not clear . In early-stage leiomyosarcoma of uterine, routine pelvic and paraaortic lymphadenectomy is not indicated, as the incidence of lymph node metastases is approximately 3% ; however, in the advanced stage, lymph node involvement is common and debulking of enlarged positive lymph node is recommended as a part of optimal cytoreduction .
In 2015, Mahdi et al. evaluated the SEER database and estimated the survival impact of lymphadenectomy in 955 of 1385 patients diagnosed with uterine clear cell cancer. Patients who underwent lymphadenectomy were 39% less likely to die than patients who did not undergo the procedure. Compared with patients with zero nodes removed, patients with more extensive lymphadenectomy (one to 10 and >10 nodes removed) were 32% and 47% less likely to die from the disease . However, there is a lack of data demonstrating the benefits of debulking of enlarged positive nodes in patients with uterine sarcoma, which may be due to lower chances of lymph node metastases (<3%), necessitating more randomized control trials.
Status in ovary cancer
Ovarian germ cell tumours 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 benefit in resecting residual paraaortic nodal mass post chemotherapy in ovarian germ cell tumours ( Figs. 2–4 ). Primary cytoreductive surgery (removal of complete tumour at the time of initial surgery, with resection of bulky nodes only) has been an integral part of the treatment of advanced ovarian cancer . However, whether systematic removal of retroperitoneal lymph nodes should be part of complete cytoreductive surgery is still unclear .
