Chi_Principles and Practice of Gynecologic Oncology 8e

22 SECTION 2 ■ Vulvar Cancer

irradiation compared with those undergoing LN dissection. Com bined across retrospective series, the incidence of groin recurrence following treatment of the undissected nodal region appears to be 0% to 12%. Improved pretreatment radiographic staging may fur ther contribute to lower inguinal recurrence rates. Adjuvant Regional Radiotherapy for Involved Lymph Nodes Although the role of prophylactic RT in the undissected but high-risk groin remains controversial, there is strong evidence that adjuvant RT after surgical assessment improves regional tumor control and survival in patients who have documented nodal metas tases following inguinal node dissection. This was established by the prospective GOG 37 trial (12,53), following which postoperative RT became standard for most patients with inguinal LN metastases. In GOG 37, 114 patients underwent radical vulvectomy and inguinal lymphadenectomy. Patients who had positive inguinal nodes were randomized intraoperatively to receive either pelvic node dissection on the side containing positive groin nodes or postoperative irradiation to the bilateral pelvic and inguinal nodes. This trial was closed before the projected accrual goal, based on interim analysis identifying a significant survival benefit with RT (68% vs 54%, P = .03). The difference in 2-year survival rates of patients treated with RT or pelvic dissection was most marked for patients presenting with clinically positive nodes (59% vs 31%, re spectively) and for those with two or more positive groin nodes (63% vs 37%, respectively). Extended follow-up showed a nonsig nificant 6-year OS benefit to the radiation arm (51% vs 41%) (12). Coupled with higher rates of inguinal failure for patients treated with surgery alone (24% vs 5%), these results emphasized the poor salvage rate seen in patients developing groin recurrences. Inter estingly, 8% of patients in both treatment arms had recurrences at the primary site, even though the vulva was not included in the RT field, raising the question of whether radiation to the vulva would have further increased the benefit of radiation. One challenge at present is whether RT should be applied to pa tients with a single node with an adequate dissection and without ulceration or extracapsular extension. On unplanned subset analysis in GOG 37, the survival benefit seen with radiation was maintained for those with N2/3 disease, two or more positive LNs, or inade quate nodal dissection (defined as node positivity ≥ 20% of dissected nodes). On the other hand, no significant difference in survival was seen for patients with one microscopically positive node; the au thors later commented that the number of patients in this subset was insufficient for reliable analysis. Retrospective data suggest that patients with even a single positive inguinal nodal metastasis benefit from adjuvant radiation, particularly if the groin dissection was less extensive or if nodal positive ratio is greater than 20% (12,54-56). Another indication that radiation may be useful in patients with a single positive inguinal LN comes from the GROINSS-V study (13). Patients with a single sentinel node metastasis larger than 2 mm had a lower disease-specific survival (69.5%) than patients with a single sentinel node metastasis 2 mm or less (94.4%, P = .001). Despite nodal dissection and adjuvant radiation, outcomes are poor in node-positive patients, even in the modern era. In GOG 37, the 6-year OS was only 51%, while retrospective data show sim ilarly suboptimal survival (12.54-56). Prospective GOG trials have demonstrated high rates of distant relapse among node-positive patients, particularly in those with multiple node involvement (11,12). Although there is growing application of concurrent che motherapy in the preoperative setting, the role of chemotherapy postoperatively has yet to be clearly addressed. Registry-based data using the National Cancer Database (NCDB) illustrated an OS ben efit with adjuvant chemotherapy for patients with node-positive vulvar cancer undergoing adjuvant RT (hazard ratio [HR], 0.62; P < .001) (57), although prospective data are lacking. In summary, based on GOG 37, current indications for adjuvant nodal RT following inguinofemoral LN dissection consist of: two or more positive inguinal LNs, fixated or ulcerated LN, extranodal

Of note, when adjuvant RT is delivered to the pelvic LNs for nodal indications, the vulvar primary site should be included in the treatment field as well. This is in contrast with historical prac tice, where attempts were made to avoid irradiation of the vulva in order to lessen treatment morbidity and because vulvar re currences were thought to be salvageable. For instance, GOG 37 used a central block to avoid the vulva. However, more recent data suggest lower salvage rates than previously thought. For instance, long-term follow-up of the GROINSS-V study showed a 10-year vulva recurrence of 40%, and 10-year disease-specific survival de creased from 90% to 69% for patients without versus with a local recurrence (13). In addition, a recent subset analysis of the AGO CARE-1 study showed that 30% of patients who developed isolated vulvar recurrence had a second recurrence (18). Subsequently, the AGO-CARE-1 study showed that adjuvant RT to the vulva reduces the risk of local recurrence in node-positive patients irrespective of local risk factors. This benefit was greatest in patients positive for HPV, suggesting HPV status may be predictive in addition to prognostic (43). Finally, overall treatment time greater than 15 weeks from the date of initial surgery to completion of RT has been shown to correlate with worse OS (44). The biggest predictor of mortality from vulvar cancer is inguinal nodal recurrence, as such recurrences are rarely salvageable (13). The two most important predictors of inguinal LN involvement are DOI (6), followed by clinical tumor size (45). In general, well-­ lateralized T1a lesions ( < 2 cm in size with ≤ 1 mm stromal inva sion) have a low probability of nodal involvement, and for these patients surgical nodal evaluation may be omitted. Traditionally, the standard of care for nodal management in early-stage vulvar cancer with DOI greater than 1 mm was in guinofemoral LN dissection. In this procedure, removal of both superficial and deep inguinal LNs was recommended given higher inguinal recurrence rates with limited superficial inguinal lymph adenectomy. Significant perioperative complications associated with inguinofemoral LN dissection include wound dehiscence, in fection, and long-term lymphedema. The GOG 88 study explored the question of whether groin ra diation could replace inguinofemoral dissection as a less morbid treatment for patients with clinically negative inguinal nodes (46). This study randomized patients with stage IB-III, node-negative vulvar cancer status post radical vulvectomy to either bilateral in guinal RT (50 Gy in 25 fractions) or bilateral inguinofemoral dis section followed by adjuvant RT to the pelvic and inguinal nodes in case of pathologically positive nodes. This study was closed after the entry of only 58 patients when there appeared to be a higher rate of groin recurrence in the RT arm (0% vs 18.5%). However, significant criticisms of this study include inadequate imaging assessment of the LNs and suboptimal RT technique re sulting in inadequate radiation dose delivered to the target. As this study was performed in the two-dimensional (2D) RT era, CT-based planning was not used, and target volumes were not de fined. Although the dose was prescribed to 3 cm depth in GOG 88, subsequent studies found that the median depth of inguinal nodes is greater than 5 cm (47). Review of GOG 88 treatment delivery revealed that all five patients who failed in the groin had inade quate tumor doses delivered ( < 47 Gy), and the mean depth of the inguinal vessels was 6.1 cm (48). Furthermore, 50 Gy is likely not an adequate dose for macroscopic nodal disease. By contrast, retrospective studies have shown that with careful RT planning using modern techniques such as IMRT delivering 40 to 50 Gy prophylactically to the inguinal-pelvic LNs, regional recurrences are rare (49-52). In a large single-institution retro spective analysis, Katz et al (49) reported no differences in the inguinal relapse rates for patients treated with prophylactic groin Adjuvant Regional Radiotherapy Prophylactic Regional Radiotherapy for Clinically Node-Negative Patients

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