The results of a phase II clinical trial suggest that patients with head and neck cancers associated with the human papillomavirus (HPV) may receive significantly lower doses of radiation safely and effectively after response to induction chemotherapy.¹ These findings from the OPTIMA study, presented at the 2018 Multidisciplinary Head and Neck Cancer Symposium, showed a 2-year progression-free survival of 91% for patients receiving de-escalated treatment after induction chemotherapy. According to the investigators, the majority of patients (82%), including those with advanced nodal disease, received de-escalated treatment with limited-field radiotherapy. However, an expert cautioned that phase III data are needed before changes in clinical practice ensue.

“With this de-escalation approach, we observed excellent pathologic complete response and survival outcomes, with no failures in omitted elective coverage,” said Tanguy Seiwert, MD, lead author of the study and Assistant Professor of Medicine at the University of Chicago Medicine. “We also saw clear improvements in both acute and chronic toxicity in patients receiving lower-dose radiotherapy.”

For an approach that gives 35% less radiation, these outcomes are quite good. De-escalation translated directly and rather impressively to decreases in acute toxicity.

— Tanguy Seiwert, MD

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As Dr. Seiwert reported, de-escalation of treatment for HPV-positive head and neck cancers, which generally have a favorable prognosis, is an emerging standard of care at large cancer centers. Although approaches involving response-adapted volume reductions in radiotherapy have been shown to be feasible and effective in reducing long-term side effects,² challenges remain.

“Despite the overall good prognosis, some HPV-positive tumors behave very aggressively and are unlikely to be de-escalation candidates, but there are no biomarkers for that,” Dr. Seiwert explained. “The other problem is that the predominant pattern of failure is distant failure. By treating patients with radiation—giving something locally—you’re not going to get to that distant problem.”

To decrease the risk of distant failure, de-escalation approaches at the University of Chicago are centered around induction chemotherapy. At the same time, said Dr. Seiwert, researchers are trying to identify adverse tumor biology and dynamic biomarkers to stratify by response.

OPTIMA Trial Details

For this prospective, phase II, single-center trial, investigators at the University of Chicago classified patients as at low and high risk based on the American Joint Committee on Cancer staging system. Low-risk patients (45%) had a primary tumor rated T3 or lower, lymph node involvement rated N2B or lower, and less than 10 pack-years of smoking history. High-risk patients (55%) had a T4 rating or N2C or greater nodal involvement or more than 10 pack-years of smoking history. The median patient age was 57 years (range, 31–85 years), and most patients (85%) were male.

All patients in the trial received three cycles of induction chemotherapy consisting of carboplatin and nanoparticle albumin-bound (nab)-paclitaxel (Abraxane). Low-risk patients who had a dramatic response by Response Evaluation Criteria in Solid Tumors (more than 50% reduction in tumor volume) received radiation therapy alone to 50 Gy. Low-risk patients who had an intermediate response (30%–50% reduction in volume) received low-dose chemoradiation to 45 Gy. Patients who did not respond favorably to induction chemotherapy received standard-dose chemoradiation to 75 Gy.

High-risk patients who had more than 50% reduction in tumor volume after induction chemotherapy received low-dose chemoradiation to 45 Gy, whereas high-risk patients with less than 50% reduction in tumor volume after induction therapy received standard-dose chemoradiation to 75 Gy.

When delivered without concomitant chemotherapy, radiotherapy was delivered over 5 weeks in 2-Gy fractions daily. In the chemoradiation arms, treatment consisted of paclitaxel, fluorouracil, and hydroxyurea systemic therapy with 1.5-Gy radiation twice daily every other week. Median follow-up for the study was 22.3 months (range, 9–39 months).

Toxicity

Of the 60 patients who received induction chemotherapy, 50 (82%) were subsequently de-escalated. The response rate from induction therapy was 88.5%; Dr. Seiwert said it is important to note that 72% of patients had deep responses with near-complete clinical response. At 2 years after treatment, progression-free survival was 91% in low-risk patients and 94% in high-risk patients. In addition, 2-year overall survival rates were 100% for low-risk patients and 97% for high-risk patients. According to Dr. Seiwert, these outcomes were matched by excellent locoregional and distant control, with no difference between the treatment arms.

“For an approach that gives 35% less radiation, these outcomes are quite good,” reported Dr. Seiwert. “De-escalation translated directly and rather impressively to decreases in acute toxicity.”

Compared with standard chemoradiation treatment, side effects from de-escalated therapy were significantly improved. Although 63.6% of patients treated with standard chemoradiation experienced grade 3 or higher mucositis, this rate dropped to 46.7% of patients in the low-dose chemoradiation arm; when low-dose radiotherapy was administered as a single agent, the incidence of mucositis was 15%. The rates of dermatitis were even more impressive, Dr. Seiwert added. No patients in the low-dose radiotherapy arm experienced grade 3 or higher dermatitis, as compared with 45.5% in the standard-dose chemoradiation arm.

Finally, de-escalation also led to improvements in functional outcomes, as measured by long-term dependency on a feeding tube. Although 18.2% of patients receiving standard-dose chemoradiation were dependent on a feeding tube after 6 months, no patients receiving single-agent radiotherapy required percutaneous endoscopic gastronomy.

Dr. Seiwert and colleagues at the University of Chicago are currently enrolling patients in the OPTIMA II trial, which will add the checkpoint inhibitor nivolumab (Opdivo) to the chemotherapy regimen and test for volume and dose de-escalation of radiotherapy.

Cautious Optimism

Sue S. Yom, MD, PhD, MAS

The discussant of the abstract, Sue S. Yom, MD, PhD, MAS, of the University of California, San Francisco, underscored the difficulties of assessing the precise contributions of radiation dose, radiation volume, and induction chemotherapy to disease control and survival in a disease for which patients have a very low overall rate of metastasis and high quality of life, even following intensive treatments.

“All de-intensification approaches remain strictly experimental, in my opinion, given their newness and the lack of any definitive or phase III data in this space,” said Dr. Yom. “The risk of impaired decision-making is an ethical and public health consequence of this environment.” ■

DISCLOSURE: Dr. Seiwert has received research funding from BMS, Jounce, and Merck. Dr. Yom has received research funding from Genentech, Merck, and Bristol-Myers Squibb.

REFERENCES

1. Seiwert T, Melotek JM, Foster CC, et al: OPTIMA—A phase II trial of induction chemotherapy response-stratified RT dose and volume de-escalation for HPV+ oropharynx cancer: Efficacy, toxicity, and HPV subtype analysis. 2018 Multidisciplinary Head and Neck Cancer Symposium. Abstract 5. Presented February 15, 2018.

2. Marur S, Li S, Cmelak AJ, et al: E1308: Phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx. ECOG-ACRIN Cancer Research Group. J Clin Oncol 35:490-497, 2017.