Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer

Abstract

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

Keywords: chemotherapy; deintensification; human papillomavirus; oral and oropharyngeal neoplasms; radiation oncology.

Figure 1.

Radiation dosimetry with standard versus reduced PORT doses. Figure 1a illustrates radiation dosimetry with SOC 60Gy (pink 6000 line) PORT to the neck. Figure 1b illustrates radiation dosimetry with reduced-dose 50Gy PORT to the neck (magenta 5000 line). IMRT can limit medium/high dose scatter to central swallowing structures like the esophagus (pink). There is no notable difference in medium/high dose spillover of 45Gy (blue 4500 line) or 40Gy (teal 4000 line) between 60Gy and 50Gy dose prescriptions.

Figure 1.

Radiation dosimetry with standard versus reduced PORT doses. Figure 1a illustrates radiation dosimetry with SOC 60Gy (pink 6000 line) PORT to the neck. Figure 1b illustrates radiation dosimetry with reduced-dose 50Gy PORT to the neck (magenta 5000 line). IMRT can limit medium/high dose scatter to central swallowing structures like the esophagus (pink). There is no notable difference in medium/high dose spillover of 45Gy (blue 4500 line) or 40Gy (teal 4000 line) between 60Gy and 50Gy dose prescriptions.

Figure 2.

Radiation dosimetry with nodal irradiation to 56Gy (magenta 5600 line) with inclusion of level IB LNs (left) versus omission (right). There is a drastic difference in anterior oral cavity dose spillover with level IB omission.

Figure 3.

Tumor control probability (TCP) dose-response curves with definitive chemoradiation in HPV+ OPC. (A) Bubble plot of LRC rates from modern chemoradiation trials (colored circles) shows no relationship between radiation dose and LRC (rho= 0.009, p= 0.978). Superimposed seminal T2 and T3 tonsil cancer TCP curves with radiation (black lines) modeled at the turn of the century (predating concurrent chemotherapy use) show shallow LRC improvements when increasing radiation doses from 55–75Gy. (B) Bubble plot of PFS rates from modern chemoradiation trials show no relationship between radiation dose and PFS (rho= −0.357, p= 0.254).

Figure 3.

Tumor control probability (TCP) dose-response curves with definitive chemoradiation in HPV+ OPC. (A) Bubble plot of LRC rates from modern chemoradiation trials (colored circles) shows no relationship between radiation dose and LRC (rho= 0.009, p= 0.978). Superimposed seminal T2 and T3 tonsil cancer TCP curves with radiation (black lines) modeled at the turn of the century (predating concurrent chemotherapy use) show shallow LRC improvements when increasing radiation doses from 55–75Gy. (B) Bubble plot of PFS rates from modern chemoradiation trials show no relationship between radiation dose and PFS (rho= −0.357, p= 0.254).