Neil Horowitz, MD, Dana-Farber Cancer Institute, Boston, MA, discusses the NRG/GOG-279 study, a phase 2 trial investigating the efficacy of cisplatin and gemcitabine concurrent with intensity-modulated radiation therapy (IMRT) for locally advanced squamous cell carcinoma of the vulva, at topic he presented at the 2023 Society of Gynecological Oncology’s Annual Meeting on Women’s Cancer in Tampa, FL.

Transcript

Hi, my name is Neil Horowitz. I'm a juvenile oncologist at Brigham and Women's Hospital in Dana-Farber in Boston. I'm currently at the SGO Annual Meeting on Women’s Cancer in Tampa, FL, and I've been asked to talk to you about my presentation on NRG/GOG-279, which was a phase 2 trial looking at the management of women with unresectable, locally advanced vulvar cancers and using a combination of gemcitabine, cisplatin, and IMRT radiation.

As many of you know, vulvar cancer is a rare malignancy. There are approximately 6,400 cases every year in the United States. Most of these are managed with simple surgeries, but there are some that are locally advanced and are unresectable. Although you can use staging criteria to sort that out, it's sometimes when you see it, you know what you have, and so it's an unresectable disease and advanced. Historically, those were managed with exenterative procedures, which led a lot of disfigurement and morbidity.

More recently, the management of those women has been with chemotherapy and radiation. Back in the late 1990s, GOG-101 used a combination of cisplatin plus fluorouracil (5FU) in a split-course of AP/PA radiation to treat those women. And those results showed about 32% had a complete pathologic response, and only 4% needed an exenterative procedure. That protocol was modified in GOG-205, which dropped the 5FU, increased the radiation dose by 20% and got rid of the planned treatment break and had even better results with about 50% complete pathologic response rate and no women needing exenterative procedures.

NRG/GOG-279, which is the presentation from this meeting, was looking at that same patient population of women with unresectable locally advanced vulvar cancers and treating them with additional chemotherapy and using IMRT. Before treatment began, women who had resectable lymph nodes had either sentient lymph node biopsy or full lymphadenectomy. All women got weekly gemcitabine at 50 mg/m², cisplatin at 40 mg/m² and 64 Gray (Gy) of IMRT to the vulva. The dosing of the lymph nodes depended on the nodal status. Those who had no nodal metastases got either no radiation or 45 Gy to the nodes. If they had a positive lymph node, they got 50 Gy delivered with a boost of 60 Gy, for 3 or more positive lymph nodes or extra-nodal spread. And if they had unresectable lymph nodes, they got 64 Gy to both the vulva and the groins. Women in the trial at 6- or 8-weeks post-treatment had a clinical and radiographic assessment response. And for those that had complete clinical response, they had a fine needle aspiration. And for those that had residual disease, they then went on to have section or continued chemoradiation.

The trial enrolled patients between 2012 and 2020, there were 57 patients that were enrolled and 52 were treated and eligible. The median age was 58, 94% were Caucasian. All had squamous cell carcinomas with a median tumor size of about 5 cm, and the stage distribution was what you would expect for patients who had unresectable disease. Most women were treated per protocol and as prescribed. There were 7 patients that came off early because of either toxicity or patient preference. There was 1 patient who died while they were on trial. The median number of cycles of chemo were 6 and the radiation compliance was very high with 75%, meaning the study hit requirements. Interestingly, there were 9 patients, or 17%, that did not undergo a post-treatment biopsy, and we couldn't comment on their pathologic response because of that.

If you look at the toxicities on the trial, there were about 25 participants who experienced a grade 3 toxicity as their highest reported adverse event. Approximately 18 out of the 52 patients had a grade 4 toxicity, and there was the 1 grade 5 toxicity. That grade 5 event was a sudden death not otherwise specified and happened during the fourth cycle of chemotherapy and attribution to the study treatment was unlikely.

At a medium follow-up of 51 months, the complete pathologic response rate was 30 out of 52, so response rate of 73% and 12-month progression free survival of about 74%. Compare that to GOG-205, where the complete pathologic response rate was 50%, so 23% improvement, which was deemed statistically significant in the pre-study determination and power calculations. Compared to GOG-101, it was a 40% improvement.

Based on these results, it's a little bit unclear exactly why there was such an improved complete pathological response rate. Was it the addition of gemcitabine or was it the use of IMRT, which is different than the prior 2 studies? The use of IMRT allowed for about 13% increase in radiation dose compared to the older trials. It is unclear which of those 2 changes impacted the complete pathologic response rate. We didn't know the HPV-status of these tumors so whether the results of the study can be applied to both HPV- and non-HPV-related tumors is unclear and remains to be seen. I think importantly, with the 70% of our patients not getting the post-treatment biopsy, which was really the main endpoint of the study, which was the pathological response rate, we can't really comment on whether they had a complete pathological response or not.

If you assume that all 9 of those patients had a complete clinical response and that perhaps is why they didn't have a biopsy or a resection, then the pathological response rate could be as high as 47 out of 52 or 90% rather than the 73% that was reported. It remains to be seen.

In the conclusion of the study, the addition of gemcitabine to weekly cisplatin and the use of IMRT rather than AP/PA radiation improved the complete pathologic response rate for women with locally advanced vulvar cancers. Whether this will change the standard of care remains to be seen. Again, this study has lots of strengths just being a large study for a rare malignancy and performed at multiple different sites. But there's still some lots of questions that remain to be answered.

What was the rationale for studying IMRT?

If you look at the rationale behind the study design and the use of gemcitabine was chosen because at the time that the trial was designed, there really wasn't a lot of data about using immunotherapies or other target agents in conjunction with cisplatin. They just didn't exist. And gemcitabine was a known radiation sensitizer. It had been studied in conjunction with cisplatin previously in a phase 1 study with Dr. Rose, and then in a phase 3 study in cervical cancer patients, both of which showed an improvement over single agent cisplatin by adding the gemcitabine.

IMRT is a mechanism of radiation where you can create very specific and detailed designed radiation treatment fields, which is very different than the AP/PA radiation, which is not that sophisticated. By doing the very detailed treatment mapping and planning, the radiation oncologist can give much higher doses of radiation that's very precise and tailored so that you'd minimize the amount of toxicity that you can get. By doing that, again, we were able to increase the dose of radiation by about 13% compared to GOG-205. If you look at the toxicities that you might prescribe to radiation, like radiation dermatitis or moist desquamation, there really was no difference in the rate of grade 3 or grade 4 dermatitis in our study versus what they saw in the GOG-205. We're able to get a higher dose of radiation with less skin toxicity despite the higher doses.

Source:

Horowitz, N. “A Phase II Trial Evaluating Cisplatin and Gemcitabine Concurrent with Intensity-Modulated Radiation Therapy (IMRT) for the Treatment of Locally Advanced Squamous Cell Carcinoma of the Vulva: NRG Oncology Trial #279” Presented at SGO Annual Meeting on Women's Cancer; March 25-28, 2023; Tampa, FL

Moore DH, Thomas GM, Montana GS, Saxer A, Gallup DG, Olt G. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys. 1998;42(1):79-85. doi:10.1016/s0360-3016(98)00193-x

Moore DH, Ali S, Koh WJ, et al. A phase II trial of radiation therapy and weekly Cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: A gynecologic oncology group study. Gynecol Oncol. 2012;124:529–533