Compared with historic results from the GOG studies, the addition of gemcitabine to cisplatin once per week given concurrently with intensity-modulated radiation therapy (IMRT) significantly improved pathological complete response (pCR) rate and resulted in excellent durable local control in women with locally advanced unresectable vulvar squamous cell carcinoma included in the NRG Oncology/GOG Study 279. Although toxicities were tolerable, it is unclear if the improved outcome resulted from adding gemcitabine or radiation intensification with IMRT.
This study was conducted over an approximately 8-year time frame. Confirmation of these results would require a randomised trial, but design of such a trial would require intentional thought to ensure that a diverse population is enrolled and consider the emergence of new therapies, specifically immunotherapy according to Dr. Neil S. Horowitz of the Brigham and Women's Hospital/Dana-Farber Cancer Institute in Boston, MA, US and colleagues, who published the findings on 4 April 2024 in the JCO.
Since the initiation of GOG 101 and GOG 205, significant advances have been made in radiation techniques, more specifically, the IMRT use. Using 3-dimensional computed tomography images, in conjunction with computerised dose calculations, IMRT allows for more precise, higher radiation doses to be conformed to tumour shapes while minimising the dose to surrounding normal critical structures, lessening toxicity and had previously been evaluated in patients with vulvar carcinoma.
Cisplatin plus fluorouracil or mitomycin C, and capecitabine have all been evaluated as radiation sensitizers for vulvar carcinoma with acceptable toxicity. Although gemcitabine has not been used to treat vulvar carcinoma to date, its chemical and biologic properties, short infusion and same-day administration, made it an attractive agent to combine with cisplatin for the treatment of women with locally advanced vulvar carcinoma.
GOG 9912 previously defined the maximum tolerated dose of gemcitabine and cisplatin in combination with anteroposterior-posteroanterior radiation as 50 and 40 mg/m2 once per week. Although different doses were used, improved pCR rates were reported with this regimen in women with locally advanced cervical cancer.
The primary objective of the GOG Study 279 study was to determine the efficacy of adding gemcitabine to cisplatin and using IMRT rather than anteroposterior-posteroanterior radiation measured by the pCR in women with locally advanced vulvar squamous cell carcinoma. Secondary objectives included rate of complete clinical response (CCR), progression-free survival (PFS), and assessment of toxicities.
In patients enrolled in this single-arm phase II study, pretreatment inguinalfemoral nodal assessment was performed; 64 Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy plans were quality-reviewed pretreatment. Cisplatin 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. A total, 57 patients were enrolled of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White; 40 (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received; 85% of radiation therapy plans were quality reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal.
Of 52 patients available for pathologic assessment, 38 (73%; 90% confidence interval [CI] 61 to 83) achieved pCR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI 62.2 to 82.7) and the 24-month overall survival was 70% (90% CI 57 to 79). The most common grade 3 or 4 adverse events were haematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment
Before the current study, the use of IMRT for treating vulvar carcinoma was not considered standard. Despite intensification of radiation and chemotherapy, toxicities in the current study were acceptable regardless of participants’ age. The ability to maintain a tolerable regimen despite dose intensification was likely the result of IMRT, which allowed conformal radiation delivery, thus sparing normal tissue and thereby reducing treatment-related toxicity.
The authors commented that HPV status of the tumors in this study was not collected. It therefore remains unclear whether both HPV and non-HPV vulvar squamous cell carcinoma treated with cisplatin/gemcitabine and IMRT would have equivalent outcomes to those reported in this study.
During the study, advances were made in targeted therapies and immunotherapies both in terms of primary treatments or as a radiation sensitizer in a variety of cancers. Potential targets for both HPV-positive (PI3K/mTOR) and HPV-negative (P53, TERTp, CDKN2A, CCND1, and EGFR) vulvar squamous cell carcinoma have also been elucidated. In KEYNOTE 258, durable responses were achieved for women with recurrent vulvar squamous cell carcinoma treated with pembrolizumab, regardless of PD-L1 status.
Whether adding immunotherapy or targeted agents to upfront chemoradiation regimens could improve pCR and survival beyond that shown in this study remains to be seen. Currently, an ongoing single-arm phase II study of pembrolizumab combined with cisplatin-sensitized radiation therapy for women with unresectable, locally advanced, or metastatic vulvar carcinoma will hopefully provide clarity.
The study was previously presented at the 54th Annual Society of Gynecologic Oncology Annual Meeting (Tampa, FL, US; 25-28 March 2022).
The study was supported by the US National Cancer Institute grants to NRG Oncology.
Reference
Horowitz NS, Deng W, Peterson I, et al. Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279. JCO; Published online 4 April 2024. DOI: https://doi.org/10.1200/JCO.23.02235