De-escalation of chemoradiotherapy after induction chemotherapy yields excellent oncologic outcomes in patients with high-risk oropharyngeal cancer associated with the human papillomavirus (HPV). Results of the nonrandomized phase II Quarterback trial suggest that this subset of patients may be treated effectively while sparing the numerous toxicities associated with standard-dose radiotherapy. Marshall R. Posner, MD, Professor of Medicine, Hematology and Medical Oncology, and Otolaryngology at the Icahn School of Medicine at Mount Sinai, New York, and Director of the Head and Neck Medical Oncology Program, reported on this study at the 2023 ASCO Annual Meeting.¹

The Quarterback trial evaluated the use of reduced-dose chemoradiotherapy with 5,600 cGy and weekly carboplatin in patients who responded to induction chemotherapy. Outcomes exceeded the noninferiority boundary for 3-year locoregional recurrence, progression-free survival, and overall survival that were based on outcomes seen in HPV-positive subjects in the landmark RTOG 1029 chemoradiotherapy study,² Dr. Posner reported. “This approach is now our institutional standard of care for nonsmoking, HPV-positive patients with advanced disease,” he said.

Randomized, potentially practice-changing phase III trials that leverage multidisciplinary treatments—to reduce radiotherapy and establish de-escalation strategies as standard of care—are warranted and long overdue.

— Marshall R. Posner, MD

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Risks of Overtreatment

As Dr. Posner pointed out, HPV-associated oropharyngeal cancer is highly curable, but current standard-of-care chemoradiotherapy results in overtreatment across all stages of the disease and leads to long-term significant morbidity. In an interview with The ASCO Post, Dr. Posner emphasized his concerns about unnecessary toxicity and how that was the impetus for designing this de-escalation trial.

“We are curing these patients, but they have severe radiation-induced acute toxicity. Between 5 and 15 years later, they have scarring and fibrosis leading to esophageal strictures; may need stomach tubes; and are developing osteoradionecrosis, aspiration pneumonia, and strokes from their carotid arteries. We are seeing these terrible late consequences of the toxicities associated with chemoradiation,” he explained.

According to Dr. Posner, many radiation oncologists are often not called in to see the consequences of treatment years down the road. “During active treatment, there is often also confusion about toxicities, he continued. “Many radiation oncologists consider all grade 3 and 4 toxicities the same, but they are not. Grade 3 neutropenia is a piece of cake for the medical oncologist. It is short-lived and rarely symptomatic. On the other hand, grade 3 acute radiation-induced oral mucositis is long-lasting and can mean the patient is not eating and is at risk for aspiration. It can be—and often is—life-threatening.”

Quarterback Details

To try to reduce or eliminate these toxic effects of radiotherapy, clinicians involved in the Quarterback trial used induction chemotherapy with modified docetaxel, cisplatin, and fluorouracil (TPF) and reduced-dose chemoradiotherapy involving 5,600 cGy and weekly carboplatin in advanced, high-risk, HPV-associated tumors. They hypothesized that this approach would be noninferior to standard therapy (by historical controls) in terms of locoregional recurrence and progression-free survival at 3 years (based on the results of the RTOG 1029 trial)² as well as significantly less toxic.

Although the investigators initially planned to randomly assign half the patients to standard-dose chemotherapy, generally all patients wanted the experimental approach. Thus, in the phase II study, all later patients were treated with de-escalation, Dr. Posner explained.

Patients had HPV-positive oropharyngeal tumors and documented high-risk features, such as radiographic extracapsular extension; T4 primaries; contralateral lymph nodes; or a high-risk, non-HPV16 genotype. All patients reported a smoking history of ≤ 20 pack years. Responders to three cycles of TPF induction chemotherapy were then treated with reduced-dose chemoradiotherapy; nonresponders followed the standard treatment algorithm and were monitored off study.

The study enrolled 64 patients, 8 of whom were randomly assigned to receive standard-dose chemoradiotherapy, 5 had an inadequate response to induction chemotherapy, and 6 were eliminated from the study for other reasons. Ultimately, 45 patients were treated with reduced-dose chemoradiotherapy. The primary endpoints were locoregional tumor control and progression-free survival at 3 years.

De-escalation Therapy Noninferior

Minimum follow-up was 18 months, and the median follow-up was 69 months (range, 18–126 months). Here are the key outcomes, as of this analysis (June 2023), for the 45 patients who received reduced-dose chemoradiotherapy:

• Locoregional recurrence–free survival: 87%
• Distant metastasis–free survival: 96%
• Progression-free survival: 78%
• Disease-specific survival: 93%
• Overall survival: 87%.

At the 3-year timepoint, for the comparison with RTOG 1029, the Kaplan-Meier 3-year locoregional control rate was 88% (vs 85%), progression-free survival rate was 86% (vs 80%), and overall survival rate was 93% (vs 90%), thus meeting the noninferiority threshold for locoregional tumor control and progression-free survival.

“Compared with other phase II and phase III de-escalation trials, this approach is reasonable, effective, and feasible, addressing the needs of patients with high-risk features,” Dr. Posner concluded.

“I believe the oncology community has failed in its job by not allowing robust, well-designed phase III trials that result in a comparison of reduced-dose radiation to standard treatment for these patients,” he added. “Randomized, potentially practice-changing phase III trials that leverage multidisciplinary treatments—to reduce radiotherapy and establish de-escalation strategies as standard of care—are warranted and long overdue.”

Dr. Posner and his team next plan to evaluate an even more de-escalated approach, using 4,600 cGy, possibly eliminating fluorouracil and perhaps adding immunotherapy to induction. 

DISCLOSURE: Dr. Posner reported no conflicts of interest.

REFERENCES

1. Posner MR, Botzler J, Takahashi M, et al: The Quarterback trials: Phase 2 series of sequential studies of induction chemotherapy followed by reduced dose chemoradiation for human papillomavirus positive oropharynx cancer. 2023 ASCO Annual Meeting. Abstract 6020. Presented June 5, 2023.

2. Ang KK, Harris J, Wheeler R, et al: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24-35, 2010.