Chi_Principles and Practice of Gynecologic Oncology 8e

Chapter 2.6 ■ Therapy for Vulvar Cancer: Radiation, Systemic Therapy, and Treatment of Persistent and Recurrent Disease 23

extension, or inadequate LN dissection ( ≥ 20% positive LNs). The role of adjuvant RT in patients with a single positive LN without extranodal extension remains controversial, but retrospective data suggest these patients should be strongly considered to receive ra diation based on suboptimal outcomes. Adjuvant Radiotherapy in the Setting of Sentinel Lymph Node Biopsy As discussed elsewhere in the text, SLNB should be offered as stan dard of care for women with early-stage clinically node-negative tumors of size 4 cm or more and DOI greater than 1 mm. The application of sentinel node biopsy for this population enables avoidance of the morbidity of inguinal dissection, in addition to potential identification of unexpected LN drainage patterns be cause of pathologic ultrastaging otherwise missed by standard dis section, and has been validated by the prospective GROINSS-VI and GOG 173 studies (13,58). The GROINSS-VII study was designed to determine whether adjuvant RT could be a safe alternative to completion inguinofem oral dissection in patients with a positive SLNB (14). In this study, patients with negative SLNs were observed, whereas patients with positive SLN(s) received adjuvant RT with or without chemotherapy. Interim analysis demonstrated a high rate of inguinal recurrences in patients with macrometastases, defined as LN greater than 2 mm (2% for LN ≤ 2 mm vs 20% for LN > 2 mm). Based on these findings, the trial protocol was modified to mandate completion dissection followed by possible adjuvant RT for patients with macrometastases. Final GROINS-VII results were recently published. Overall, 21% of patients had positive SLN, of which 50% had macrometastases and 50% had micrometastases or ITCs. Among the 162 patients with macrometastases, 31% received only RT to the groins (of which 14% also had concurrent chemotherapy), and 65% underwent comple tion inguinofemoral LN dissection (of which 56% also received ad juvant RT). In patients with macrometastases, 2-year isolated groin recurrence rate was 22% following RT alone versus 6.9% following inguinofemoral dissection. These results suggest suboptimal effi cacy of RT for macrometastases, but significant concerns have been raised regarding inadequate contouring and target volume delinea tion described in the original protocol, which could lead to potential geographical miss, prompting subsequent protocol modification of RT contouring details (59). Of note, no groin recurrences were ob served in seven patients who received adjuvant chemoradiation, and there was a trend toward better disease control in patients who re ceived chemoradiation ( P = .091), suggesting that the use of concur rent chemotherapy warrants further investigation in this population. On the other hand, GROINSS-VII results confirmed the safety of adjuvant RT with omission of completion lymphadenectomy in patients with micrometastases ( ≤ 2 mm). Among 160 patients with micrometastases/ITCs, 79% underwent adjuvant RT, with a 2-year ipsilateral isolated groin recurrence rate of 1.6%. Among the subset of patients with only ITCs, the groin recurrence rate was 0%. Preoperative Radiotherapy In patients who present with more advanced primary tumors, RT may be delivered preoperatively. Advocates of this approach have listed several theoretical advantages for patients with locally ad vanced vulvar carcinomas: 2. Tumor regression during radiation may allow the surgeon to obtain adequate tumor-free surgical margins without sacrific ing important pelvic structures such as the urethra, anus, and the clitoris. 3. RT alone may be sufficient to sterilize microscopic regional disease when the inguinal nodes are not radiographically de termined to be involved and may mobilize fixed and matted nodes, facilitating subsequent surgical excision.

Although the published experiences with preoperative single- modality RT are small, several investigators have reported excellent responses and high local control rates after treatment of advanced tumors with relatively modest doses of radiation followed by local resection (60,61). These early reports provided evidence that radia tion could significantly debulk advanced local disease and allow for more conservative, viscera-sparing surgery, while preserving good local control. Data have since emerged supporting the therapeutic benefit of concurrent chemotherapy with radiation, typically followed by limited surgical resection, in managing locally advanced disease (11,62,63). Typical regimens have included combinations of ra diation coadministered with 5-FU, and cisplatin or mitomycin C. However, randomized trials of the role of concurrent chemother apy have not been done and are unlikely to be feasible given the small number of patients with this disease. The most compelling data in support of concurrent chemoradia tion in the management of locally advanced disease come from two large prospective phase II trials performed by the GOG. In the first study (GOG protocol 101), 71 evaluable patients with locally ad vanced T3 or T4 disease who were deemed not resectable by standard radical vulvectomy underwent preoperative CRT (62). Chemotherapy consisted of two cycles of 5-FU and cisplatin. Radiation was delivered to a dose of 47.6 Gy, using a planned split-course regimen, with part of the radiation given twice daily during the 5-FU infusion. Patients underwent planned resection of the residual vulvar tumor, or inci sional biopsy of the original tumor site in the case of complete clin ical response (cCR), 4 to 8 weeks after CRT. A cCR was noted in 33 of 71 patients (47%). Following vulvar excision or biopsy, 22 patients (31%) were found to have no residual tumor in the pathologic spec imen. In all, only 2 of 71 patients (3%) had unresectable disease af ter CRT, and in only 3 patients was it impossible to preserve urinary and/or gastrointestinal continuity following complete resection of the primary tumor. With a median follow-up interval of 50 months, 11 patients (16%) have developed locally recurrent disease in the vulva (62). These results are all the more notable considering the relatively low dose of radiation used in these typically bulky, advanced tumors. In GOG 101, there was also a separately reported cohort of 46 evaluable patients with N2 or N3 nodal disease who were deemed ini tially unresectable (64). Patients received 47.6 Gy of RT in split-course fashion, with two concurrent cycles of 5-FU and cisplatin, as de scribed earlier. Planned inguinofemoral LN dissection was performed 3 to 8 weeks later. In only two patients (5%) did nodal disease remain unresectable, and the pCR rate was 41%. At a median follow-up of 78 months, only 1 of 37 patients (3%) who completed the fully prescribed regimen of preoperative therapy and bilateral inguinofemoral node dissection relapsed in the groin. This study, although nonrandom ized, provided further evidence of the efficacy of combined CRT in the management of local regionally advanced vulvar cancer. Building on this experience, investigators sought to study weekly cisplatin (40 mg/m 2 ) coadministered with radiation (GOG proto col 205). Additionally, this study eliminated the break in RT and increased RT dose to 57.6 Gy. In this trial, 58 evaluable patients with untreated locally advanced T3 or T4 disease not amenable to standard radical vulvectomy underwent preoperative radiation with concurrent chemotherapy (11). Following preoperative therapy, 64% had a cCR and 50% had a pathologic complete response (pCR), a no table improvement compared with the regimen used in GOG 101. Following preoperative chemoradiation for locally advanced disease, it remains unclear whether surgery is necessary in those who achieve cCR. In GOG 101, approximately 70% of patients who achieved cCR were found to have no pathologic residual disease in the surgical specimen (62). In GOG 205, 34 of 37 patients (92%) underwent surgical biopsy only to assess treatment response (11). Of these 34 women, 29 (78%) had biopsies showing a pCR. Based on this 22% to 30% risk of discordant findings between CR and partial response (PR), at a minimum, an excisional biopsy of the primary site should be completed to confirm a CR to treatment. In an attempt to further improve on the pCR rate, the ongoing GOG 279 uses concurrent gemcitabine with cisplatin, integration

Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited. 1. Less radical resection of the vulva may be adequate to achieve local tumor control after preoperative treatment of the vulva with radiation.