Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients.

Abstract

6069 Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and < 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were < 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939.

Treatment de-escalation for HPV-driven oropharyngeal cancer: Where do we stand?

“…This trial, which alters both radiation dose and chemotherapy, does not include a standard of care treatment arm, but would be expected to have decreased toxicity and equivalent locoregional control and progression-free-survival at 3 years compared to standard therapy. Very preliminary outcomes were presented at ASCO 2017 meeting and the 2-years PFS for patients receiving 56 Gy and standard dose were respectively 87.5% and 83% [28] . Toxicity and quality of life data were not presented.…”

“…However several important limitations must be highlighted. The trial focused on a very favorable risk cohort of HPV-driven OPSCC and radiation alone could have been sufficient in some of these patients (T1-2 N0-1 and potentially T3N2a-b) [28] . The follow-up period is very short (median 14, 3 months) especially for the toxicity assessment, which is the final goal of any de-escalation strategy.…”

Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions

“…The prognostic value of HPV and p16 positivity has been demonstrated in the ICT (paclitaxel/carboplatin or TPF) setting, where patients with HPV-positive disease had a higher ORR and more than double the 5-year survival rates versus patients with HPV-negative disease [ 66 , 67 ]. In the phase II Eastern Cooperative Oncology Group 1308 study, Marur et al [ 68 ] suggested that ICT with cisplatin/paclitaxel/cetuximab may allow patients with HPV-positive oropharyngeal carcinoma and an otherwise favorable prognosis to undergo reduced-dose intensity-modulated radiation therapy (IMRT) without reducing efficacy. This chemoradiotherapy de-escalation plan led to a significant decrease in radiotherapy-associated toxicities, such as difficulty swallowing or impaired nutrition, compared with patients who received regular-dose IMRT (40% versus 89% difficulty swallowing and 10% versus 44% impaired nutrition in the reduced-dose versus regular-dose IMRT arms, respectively) [ 69 ].…”

“…This chemoradiotherapy de-escalation plan led to a significant decrease in radiotherapy-associated toxicities, such as difficulty swallowing or impaired nutrition, compared with patients who received regular-dose IMRT (40% versus 89% difficulty swallowing and 10% versus 44% impaired nutrition in the reduced-dose versus regular-dose IMRT arms, respectively) [ 69 ]. Although the data concerning the utility of ICT in patients with HPV-associated LA SCCHN are still incomplete, these early investigations suggest a role for ICT in treatment deintensification in patients with favorable prognoses [ 68 ].…”

Has the time come for de-escalation in the management of oropharyngeal carcinoma?

“…Very preliminary outcomes based on 23 patients enrolled and 20 randomised were presented at the ASCO meeting in 2017, and the 2-year PFS were 87.5% for those patients receiving standard doses and 83.3% (ref. 35 ) for those patients receiving dose deescalation. Toxicity and quality of life data were not included.…”