Special Feature
Systematic Lymphadenectomy in Ovarian Cancer Surgery: Now We Know!
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston Texas, is Associate Editor for OB/Gyn Clinical Alert
The well-known mantra of primary ovarian cancer management is surgery. The procedure has modified little in the last 30 years as the goal in advanced cases has been cytoreduction and, in seemingly early cases, it has been accurate staging. Although, heretofore unstudied in a randomized fashion, surgery has decisive merit, reflected in better long-term survival for those patients with metastases rendered disease-free, and in increased precision of therapy through the avoidance of over- or under-treatment in limited-stage patients.1,2 In the latter scenario, systematic evaluation of all sites of spread is critical to accurate representation of the disease process. It is now well described that as many as 30% of patients with limited-stage disease will be upstaged on the basis of systematic biopsies, and under-sampling leads to higher misclassification—an event usually associated with early recurrence.
One target area of continued interest has been the retroperitoneum. Clinicopathologic studies have reported that approximately 10-15% of grossly non-metastatic ovarian cancer patients and 40-70% of metastatic patients will have retroperitoneal metastases, particularly in the paraortic regions. Their presence has been associated with poor clinical outcome. Thus, in 1988, FIGO amended the staging classification of ovarian cancer to include a subclassification for retroperitoneal metastases. In addition, many investigators and clinicians have described the retroperitoneum as a safe-haven of disease being less sensitive to systemic chemotherapy. What has been debated for more than 2 decades is whether systematic lymphadenectomy should accompany a debulking effort, particularly for those in whom complete or near complete intraperitoneal resection is feasible. Proponents, supported by retrospective clinical data, state that retroperitoneal resection will allow truly complete cytoreduction and removal of treatment sanctuary sites leading to improved survival. Further, they contend that basing a decision for resection on intraoperative nodal morphology is hazardous and unreliable, potentially overlooking more than half of the metastatic cases, even those greater than 1 cm!3,4 Opponents counter, stating that the procedure has attendant morbidity, adds unnecessary time and cost to the already long operation, and adds little value in a patient with grossly apparent metastatic intraperitoneal disease. Further, they take issue with the contention that the nodal reservoirs are chemoresistant, citing many trials of patients with metastatic retroperitoneal disease that respond to chemotherapy and noting, retroperitoneal-only recurrence is a rare phenomenon in this diseaese.5
Settling the score and highlighting the scientific prowess of dedicated investigators comes the recently published randomized clinical trial from Benedetti-Panici and colleagues evaluating the performance of systematic lymphadenectomy in otherwise, optimally cytoreduced stage III and IV ovarian cancer.6 Even if the subject of this debate holds little interest to the reader, one must congratulate these clinicians on completing an extremely difficult, randomized, proof-of-principle study among surgeons regarding—surgery! If nothing else, it is proof that the often used "crutch" debate position, ". . . this [insert unique clinical situation] could really only be solved by a randomized clinical trial—which can’t be done . . ." can indeed be overcome. In the study, 452 patients were enrolled from 13 centers located in 5 countries. Less than 6% were excluded after randomization and the cohorts were well balanced for known prognostic factors such as stage, grade, histology and tumor residual. Although eligible if defined by malignant pleural effusion, no stage IV patients were enrolled. Patients were allocated to retroperitoneal lymphadenectomy or simple biopsy intraoperatively after optimal intraperitoneal cytoreduction had been achieved. Optimal debulking was defined as less than or equal to 1 cm residual. The minimum requirements for systematic lymphadenectomy in this trial were impressive. Complete en bloc excision of all node-bearing tissue from the pelvic, common iliac, and paraortic regions was required. No less than 25 pelvic and 15 paraortic nodes were considered an appropriate dissection in the experimental cohort. Those patients randomized to simple biopsy were to have inspection of the retroperitoneum with excision of any grossly evident metastasic nodes. In all, just 8% of those randomized to no lymphadenectomy had too many nodes resected and just 13% of lymphadenectomy patients had too few (less than 25 pelvic or 15 paraortic nodes) resected. All, however, were included in the intent-to-treat analysis. Following surgery, all patients received platinum-based chemotherapy, however, the specific regimen was not proscribed.
As anticipated, performance of the extended operation did increase operative time, blood loss, and transfusion, but hospital stay, while long in both cohorts, was equivalent. There were also more perioperative complications observed in the lymphadenectomy cohort, consisting of, predominately, lymphocysts and lymphedema. Little other complication data are described including their impact on quality of life. In terms of the primary end point and overall survival, no difference was observed (56.3 mos vs 62.1 mos; HR, 0.97; P = 0.77) between the 2 cohorts. Recurrence was observed in 69% of the control arm and 63% of the experimental arm. Time to recurrence, measured as progression-free survival, was statistically improved in the lymphadenectomy cohort. In this regard, there was a 24% reduction in the risk of progression for those patients undergoing systematic lymphadenectomy relative to biopsy alone (P = 0.02). The difference amounted to 5-7 months, depending on the statistical methodology used to describe this difference. Interestingly, the pattern of recurrence between the two groups was no different, with isolated retroperitoneal recurrence seen in just 2% of both cohorts. The finding of metastatic retroperitoneal disease overall was an adverse prognostic factor in this optimal cytoreduced population. However, whether lymphadenectomy offered any benefit among these patients was not directly analyzed and is still unknown. Multivariate analysis teased out only residual tumor as the independent prognostic variable to overall survival.
The trial is commendable on many levels already alluded to above and should serve as a reference point in addressing this issue for patients undergoing optimal cytoreduction. The results of this trial and the patterns of recurrence suggest that the retroperitoneum is probably not a major sanctuary for tumor growth and that intraoperative inspection may be sufficient for evaluation of metastatic disease. The appearance of a progression-free survival endpoint not reflected in a benefit to overall survival is unusual in primary therapy trials but not unheard of.7 Such observations always evoke consideration of a detection bias, in which the observation under study (in this case, progression-free survival) is not equally probable between the two arms. In other words, could the performance of lymphadenectomy affect how recurrence is determined through imaging, biochemical marker evaluation or both? Another possibility is that modern chemotherapy given after recurrence could have made up any small change demonstrated in intermediate endpoints. While likely to be lost in the randomization process, such effects should be considered. For instance, nearly 85% of randomized patients came from one area. Practice patterns in this one site could have profound effects on the trial post-randomization. Nonetheless, the trial’s conclusions are in line with their pre-trial expectations and reflect good data in a difficult to study arena.
References
- Bristow RE, et al. J Clin Oncol. 2002;20:1248-1259.
- Le T, et al. Gynecol Oncol. 2002;85:351-355.
- Eisenkop SM, Spirtos NM. Gynecol Oncol. 2001;82:143-149.
- Morice P, et al. Eur J Gynaecol Oncol. 2004;25:169-174.
- Isonishi S, et al. Gynecol Oncol. 2004;93:647-652.
- Panici PB, et al. J Natl Cancer Inst. 2005;97:560-566.
- Muggia FM, et al. J Clin Oncol. 2000;18:106-115.
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