A Phase 2 Dose and Volume De-escalation Trial for High- and Low-Risk HPV+ Oropharynx Cancer: Efficacy, Toxicity, and Dosimetric Analyses

Abstract

In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or >10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50 Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45 Gy (CRT45). 3) All other ( = poor response) pts received regular-dose chemoradiotherapy to 75 Gy (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. RT50 was delivered in 2 Gy/fx once daily. CRT arms consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5 Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Sixty-two pts were enrolled. Twenty-eight pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. A total of 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Mean dose to all OARs was significantly reduced as shown in the table below. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, P = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, P = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, P<.001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, P = .066) post-treatment. Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50 Gy RT or 45 Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Benefits in OAR sparing translated to significantly improved toxicity and functional outcomes.Abstract 290; Table 1OAR ─ Mean Dose (Gy)RT50CRT45CRT75ANOVA P-valueIpsilateral Parotid29.927.341.7<.001Contralateral Parotid14.715.624.3.001Ipsilateral Submandibular51.446.077.1<.001Contralateral Submandibular40.937.961.6<.001Pharyngeal Constrictor45.038.062.4<.001Larynx40.534.754.2<.001Oral Cavity26.424.543.9<.001 Open table in a new tab