Women with cervical cancer metastasized to para-aortic lymph nodes have historically had a poor prognosis, with 3-year overall survival rates of 25% to 40%.1-3 This has been attributed to the presence of occult systemic disease at the time of presentation and a high rate of distant recurrences following therapy.
The practice of pretreatment para-aortic lymph node dissection among patients with locally advanced cervical cancer, as in the study reported by Gouy et al, remains a controversial practice. The potential benefit is supportable by three assumptions: (1) that pretreatment imaging assessment of lymph node involvement is limited, (2) that treatment will be modified based on the findings of the lymph node dissection, and (3) that these modifications will result in improved survival.
Imaging of Para-aortic Lymph Nodes
Imaging for para-aortic lymph nodes with either standard computed tomography (CT) or magnetic resonance imaging (MRI) is indeed limited, with sensitivities of 55.5% and 57.5%, respectively.4 Positron-emission tomography (PET) or PET-CT does appear to have increased sensitivity.
A review of patients who underwent PET followed by histologic evaluation of the para-aortic lymph nodes found an overall sensitivity of 78%, but the false-negative rate for detecting para-aortic lymph node metastases was 12%. This increased to 22% for patients with PET uptake in the pelvis.4 Gouy and colleagues report a false-negative rate for PET-CT that is consistent with the published literature at 12% (29/237 patients), with slightly less than half of these being micrometastases ≤ 5 mm (13/29) and the rest > 5 mm.5
Even though the sensitivity of PET appears superior to CT and MRI, detection of para-aortic lymph nodes remains problematic. It should be noted that the work by Gouy and colleagues provides useful estimates for false-negative rates for PET-CT in both pelvic PET-CT–positive and PET-CT–negative populations, which is, in and of itself, an important contribution to the literature.
Treatment Modification
That knowledge of positive para-aortic lymph nodes changes management is clear—especially when microscopically positive para-aortic lymph nodes are found and subsequently treated. In the Gouy et al study, 12% of the population received extended-field radiation therapy following identification of involved lymph nodes. Perhaps more important, 208 patients were not at risk for overtreatment with extended-field radiation therapy based on definitive knowledge of their para-aortic lymph nodes.5
This is again consistent with the literature, which indicates that in a para-aortic lymph node PET-negative population, approximately 78% of patients with locally advanced cervical cancer would have been overtreated with extended-field radiation therapy were it not for histologic confirmation of negative para-aortic lymph nodes.4
Survival Benefit
That the removal of positive para-aortic lymph nodes in and of itself improves survival is yet unproven. The benefit of lymph node dissection has been demonstrated in retrospective series that report improved survival for patients after debulking of grossly involved nodes.6-11
The Gouy et al study found that for patients identified as having para-aortic lymph node metastases ≤ 5 mm and who were subsequently treated with extended-field radiation therapy, survival was no different than for those with negative para-aortic lymph nodes. Whether this is due to identification and treatment of the micrometastases vs the actual removal is difficult to discern from the data, but in a patient population in which treatment decisions based on PET alone would have resulted in pelvic irradiation alone, these 13 patients would have been undertreated and at risk for at least para-aortic lymph node failure if not distant failure.
Unfortunately, for patients with para-aortic lymph nodes > 5 mm, survival remained poor, with only 17% event-free at 3 years vs 69% and 74% for patients with para-aortic lymph nodes ≤ 5 mm and negative para-aortic lymph nodes, respectively.5
Moving Forward
Studies in locally advanced cervical cancer have primarily focused on the addition of either cytotoxic12-15 or biologic16,17 agents to concurrent cisplatin and radiation. These efforts have not demonstrated large gains in outcome and have added toxicity, prompting different strategies for improving outcomes in patients with high-risk locally advanced cervical cancer.
Gynecologic Oncology Group (GOG) 9926 (NCT01295502) is an ongoing phase I trial for patients with positive para-aortic lymph nodes receiving extended-field radiation therapy and concurrent cisplatin followed by adjuvant paclitaxel and carboplatin. GOG 9929 (NCT01711515) follows extended-field radiation therapy and concurrent cisplatin with ipilimumab (Yervoy). With the recent National Cancer Institute press release reporting improved overall survival for patients with advanced/recurrent cervical cancer treated with bevacizumab (Avastin) on GOG 240, further exploration of bevacizumab as an adjuvant therapy to follow chemoradiation therapy may be a consideration in this high-risk group of patients, as well.18,19
Patients with PET-positive para-aortic lymph nodes would qualify for our most aggressive therapies without undergoing a pretreatment lymph node dissection, since the sensitivity of a positive PET approximates 73%, making histologic confirmation unnecessary. Patients who have no uptake in the pelvic lymph nodes on PET have a false-negative rate for positive para-aortic lymph nodes of 9%, so the possible risks of the pretreatment lymph node dissection (delay to start of chemoradiotherapy) may outweigh any benefits.
The group of patients with PET-positive uptake in the pelvic nodes and negative uptake in the para-aortic lymph nodes has a false-negative rate of 24% according to the Gouy et al study, which is consistent with estimates from the literature.5 This is the group of patients for whom pretreatment lymph node dissection makes the most sense, especially if, as Gouy et al report, approximately half of these patients have metastases ≤ 5 mm and can be shifted into para-aortic lymph node–negative survival curves with identification and appropriate treatment.
Potential Complications
While pretreatment lymph node dissection does appear to improve survival for patients with PET-negative para-aortic lymph node metastases ≤ 5 mm, this group represents approximately 5% of the para-aortic lymph node PET-negative locally advanced cervical cancer population and is a small subset of the entire locally advanced cervical cancer population. The potential complications of pretreatment lymph node dissection cannot be overstated.
Gouy et al report a median time of 14 days between PET and lymph node dissection and 35 days between PET and start of chemoradiotherapy. Only two patients in their series experienced additional delay due to postoperative morbidity, but the literature reports rates of complications between 1% and 19% following lymph node dissection, varying according to the surgical approach used.4 This raises the possibility of additional delays prior to the initiation of curative therapy with widespread adoption of this practice. Given the reality that most patients are not cared for at centralized treatment centers, the likelihood of complications and delays may be higher than that predicted by Gouy and colleagues, and the improvement for this minority of patients will be difficult to justify given the risk to those with little expected benefit from the procedure.
Toward Standardization of Imaging
Efforts are underway to validate better pretreatment imaging assessment of lymph nodes via two large trials evaluating PET and MRI using ultrasmall iron oxide particles (GOG0233/ACRIN 6671 and ACRIN 6682). In addition, as mentioned in the Gouy et al article, two randomized phase III trials of the effect of pretreatment lymph node dissection on survival in locally advanced cervical cancer are ongoing. The results of these studies are anxiously awaited and will inform standardization of imaging vs lymph node dissection in this population. ■
Dr. Moore is Mai Eager Anderson Chair of Cancer Clinical Trials, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City.
Disclosure: Dr. Moore reported no potential conflicts of interest.
References
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