Chi_Principles and Practice of Gynecologic Oncology 8e

24 SECTION 2 ■ Vulvar Cancer

of IMRT, and dose escalation to 64 Gy (NCT01595061). This trial recently closed to accrual, with results pending. Definitive Radiotherapy Historical data evaluating the use of RT alone for vulvar cancer were generally disappointing, with a significant number of recur rences and considerable toxicity. However, integration of more modern, advanced techniques such as IMRT has resulted in more favorable results from preoperative RT (51,52). As such, some have reexplored the role of definitive RT using higher cumulative doses. Stecklein et al published a series of 33 patients with grossly enlarged inguinal nodes treated with dose-escalated definitive RT or chemora diation (65) at MD Anderson Cancer Center. Patients received 40 to 50 Gy to the pelvis, vulva, and groins with either three-dimensional (3D) RT or IMRT, followed by a boost to gross disease to at least 60 Gy. The 3-year actuarial vulvar, groin, and distant recurrence rates were 24.2%, 17.7%, and 30.3%, whereas the 3-year OS was 51%, consistent with other dose-escalated series. Only three major late events were deemed potentially related to irradiation, consisting of iliac artery thrombosis, femoral neck fracture, and grade 3 lymphedema. In a series of 49 women treated with dose-escalated ( ≥ 55 Gy) IMRT-based chemoradiation from 2012 to 2018 at the University of Pittsburgh Medical Center, the median vulva dose was 66 Gy for patients undergoing definitive treatment and 59.4 Gy for those un dergoing preoperative therapy (66). The median dose to involved nodes was 60.6 Gy. Almost all (94%) patients received concurrent chemotherapy, consisting of weekly cisplatin for a median of five cycles, and 55% ( n = 27) were grossly node-positive by imaging. The cCR and pCR were 76% and 70%, respectively, which was nota bly higher compared to both GOG 101 and GOG 205. Only 9 of the 27 patients who presented with imaging-positive LNs underwent groin assessment at the time of surgery, selected based on the pres ence of visible residual nodal disease on posttreatment CT, and for these patients the nodal pCR rate was 67%. Of the 27 node-positive patients, the crude isolated inguinal nodal recurrence rate was 3.7% ( n = 1). Two-year disease-free survival for definitive and preoper ative patients was 81% and 55%, respectively. Grade 3 or higher acute and late toxicities occurred in 29% and 6%, respectively. A recent Dutch multicenter phase II study showed the feasibil ity of capecitabine-based CRT to 64.8 Gy for locally advanced vul var cancer, with a local cCR rate of 62% at 12 weeks after treatment. At 2 years, 42% had persistent local cCR and 58% had regional con trol (67). As mentioned previously, the ongoing GOG 279 trial is examining treatment intensification with RT dose escalated to 64 Gy with concurrent gemcitabine and cisplatin, and has recently closed to accrual. In an effort to reach higher doses when treating definitively, a few studies have assessed the role of interstitial brachytherapy, either alone or after external beam radiotherapy (EBRT) (68,69). When de livering a high dose via EBRT (mean dose, 50.4 Gy) followed by an interstitial brachytherapy boost (mean dose, 28.7 Gy), Tewari et al (69) illustrated no local failures among patients with primary advanced vulvar SCC. Hoffman et al (68) similarly evaluated patients treated with interstitial brachytherapy with or without EBRT, demonstrating disease control in 7 of 10 patients receiving 70 to 90 Gy, albeit with high rates of necrosis. The considerable hot spot at the skin achieved with brachytherapy may account for this high rate of soft tissue ne crosis. Brachytherapy boost should therefore be used cautiously and possibly selectively for patients with significant vaginal extension. In summary, given the encouraging early results, dose-escalated definitive IMRT-based chemoradiation may be an acceptable alter native to extensive surgery for locally advanced vulvar cancer, with salvage surgery reserved for persistent or recurrent disease. Radiation Therapy Technique Patients should undergo CT or PET-CT simulation using vacuum-bag immobilization in the supine position, with lower ex tremities abducted in the “frog leg” position in order to reduce the

presence of skin folds, which may contribute to excess skin toxicity by an auto bolus effect. Radiopaque wire should be placed to iden tify the visible gross disease and any relevant postoperative scars. If there is vaginal involvement, full and empty bladder scans should be obtained for use in creation of an internal target volume (ITV) to account for organ motion. Consensus guidelines for radiation target delineation and treat ment for vulvar cancer have been published (70). For adjuvant RT, the primary tumor clinical target volume (CTV) should include the entire surgical bed. Nodal CTV should include the inguinal nodal region and entire nodal dissection bed including areas of ex tranodal extension, and include one echelon of LN drainage above and below the involved nodes. In case of unilateral groin involve ment, the contralateral groin is typically included prophylactically as well. Although the GROINSS-VII protocol allowed ipsilateral nodal treatment if the other side was negative by SLNB, recurrence patterns according to receipt of ipsilateral versus bilateral groin RT were not reported (14). Of note, when delineating the inguinal nodal compartment, it is important to use anatomic landmarks as opposed to using fixed expansions around the vessels (71). Elec tive nodal CTV also includes external iliac, internal iliac, and distal common iliac LNs. Dose should be 45 to 50.4 Gy to the pelvic and inguinal nodal regions and to the primary tumor surgical bed in the case of widely negative margins. In cases of close or positive margin, higher doses of 54 to 60 Gy should be used to the area of margin concern or extracapsular extension (40,41). For preoperative or definitive radiation, the gross tumor vol ume (GTV) should be delineated based on both clinical examina tion and imaging findings including MRI for the primary tumor and PET-CT for involved LNs. The CTV should include the entire vulva, as well as the GTV with a 1-cm margin. Additional areas may need to be included depending on involvement of adjacent structures including vagina, anus, anal canal, rectum, periurethral region, urethra, bladder, and clitoris. A brachytherapy boost to the primary tumor may be required in case of significant vaginal exten sion, periurethral disease, or thick perineal disease. In preoperative cases, RT dosing typically consists of 45 Gy in 25 fractions to the primary tumor and elective nodes, 50 to 50.4 Gy in 25 to 28 fractions to the involved inguinal nodal region, 55 to 58.8 Gy in 25 to 28 fractions to grossly involved nodes, and a sequential boost to the primary vulvar tumor to 56 to 60 Gy. For bulky involved nodes greater than 2 cm, an additional sequential nodal boost of 4 to 6 Gy should be considered, with plan for surgi cal removal of any residual LNs that persist after chemoradiation. In addition, final dose may be adjusted based on disease location, treatment tolerance and response, and likelihood of resectability. If the disease is assessed by the surgeon as unlikely to be resectable with acceptable functional outcome, then definitive chemoradia tion to a total dose of 66 Gy should be considered. A 0.5- to 1.0-cm-thick customized bolus for the vulva should be used daily during treatment and also may be required on the groin in case of superficial involved node, skin involvement, or extracap sular extension. Separate plans should be generated with and with out bolus so that once the patient develops a brisk skin reaction, one can switch to the no-bolus plan. In addition, during treatment planning, a 1- to 2-cm-thick virtual bolus is created for IMRT plan optimization, which serves to extend the isodose line beyond the skin to create flash (72). On the first few days of treatment, in vivo surface dosimetry should be checked using a device such as a ther moluminescent dosimeter in order to confirm the delivered dose. A mid-treatment replan may be needed in case of significant swell ing or response to treatment. Intensity-Modulated Radiotherapy In modern practice, IMRT has largely replaced conventional 2D and 3D external beam approaches in the treatment of vulvar can cer ( Figure 2.6-1 ) and has been incorporated in recent clinical tri als (ie, GOG 279). It is an attractive approach to RT in the pelvis and groin because of its ability to escalate radiation dose while

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