番茄社区app

The use of intensity-modulated radiation therapy (IMRT) and the addition of gemcitabine to cisplatin increased the complete pathologic response (CPR) in women with locally advanced squamous cell carcinoma of the vulva not amenable to surgery, researchers found.

Although gemcitabine has not been used in that setting, its chemical and biologic properties, short infusion, and same-day administration make it an attractive agent to combine with cisplatin for the treatment of this group of women, Neil S. Horowitz, MD, of Brigham and Women's Hospital/Dana-Farber Cancer Institute in Boston, and colleagues explained.

Using 3-dimensional computed tomography images in conjunction with computerized dose calculations, IMRT allows for more precise, higher radiation doses that conform to tumor shapes while minimizing the dose to surrounding normal critical structures, which lessens toxicity. with a small number of vulvar carcinoma patients showed promising results, with a low incidence of severe toxicity.

Now, as Horowitz and co-authors reported in the single-arm, multicenter, phase II study in the , the team assessed the efficacy and toxicity of gemcitabine and cisplatin with IMRT, which replaced standard anteroposterior-posteroanterior (AP-PA) radiation, in patients with locally advanced vulvar cancer.

(None of the authors were available for an interview, and the answers here are from the text of the report.)

What does this study add to the literature?

The current study adding gemcitabine to cisplatin and using IMRT rather than standard AP-PA radiation, resulted in a significant improvement in CPR rate and excellent durable local control compared with previous Gynecologic Oncology Group studies. It is unclear whether the improvement in CPR was the result of the addition of gemcitabine, the increased radiation dose afforded by IMRT, or if both were mutually important to the outcomes.

A total of 52 of 57 enrolled patients were evaluable. Their median age was 58, and 94% were white. Forty patients (77%) had stage II or III disease, and all had squamous histology. They received a median of six chemotherapy cycles. Seven patients came off trial because of toxicity or patient withdrawal.

Of the 52 patients available for pathologic assessment, 38 (73%) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS rate was 74% and the 24-month OS rate was 70%.

A total of 80% of patients completed therapy as prescribed, despite 85% experiencing a grade 3 or higher toxicity and 65% requiring at least one dose modification. The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event, which was unlikely to be related to treatment.

What is the importance of maintaining a tolerable regimen despite dose intensification?

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.

While this clearly is an advantage over AP-PA delivery, this conformal planning raises concerns about under-dosing target lesions, resulting in worse local control. This trial dismissed these concerns as excellent local control and pathologic response were seen.

It appears that increasing radiation doses to at least 6,400 cGy is important for CPR, while intensifying chemotherapy or using a nonplatinum agent (cisplatin/gemcitabine or capecitabine) may increase toxicity while being less critical for response.

What advances have been made in targeted therapies and immunotherapies?

At the study's inception, the prevailing thought was to increase radiation and chemotherapy intensity to improve local response rates and to provide better long-term outcomes. 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.

for both HPV-positive (phosphatidylinositol 3-kinase/mammalian target of rapamycin) and HPV-negative (P53, TERTp, CDKN2A, CCND1, and epidermal growth factor receptor) squamous cell carcinomas of the vulva have also been elucidated. In addition, showed durable responses for women with recurrent squamous cell carcinoma of the vulva treated with pembrolizumab, regardless of PD-L1 status.

Whether adding immunotherapy or target agents to upfront chemoradiation regimens could improve CPR and survival beyond that shown in this study remains to be seen. Currently, an ongoing single-arm phase II clinical trial of pembrolizumab combined with cisplatin-sensitized radiation therapy for women with unresectable, locally advanced, or metastatic vulvar cancer will hopefully provide clarity.

What is your main message for practicing oncologists?

IMRT is appropriate for use in women for locally advanced vulvar carcinoma. A randomized trial would be needed to confirm benefits for the addition of gemcitabine, but this could be considered in patients of good performance status.

Read the study here.