Reduced-Dose Radiation Effective in HPV-Associated Oropharynx Cancers

Barbara Burtness, MD

Induction chemotherapy (IC) followed by reduced-dose radiation and weekly cetuximab demonstrated improved swallowing and nutritional status as well as an excellent complete clinical response (cCR) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), according to the results of a phase II study published in the Journal of Clinical Oncology.

Fifty-six patients (70%) achieved a primary-site cCR to IC, and 51 patients continued to cetuximab with 54 Gy of intensity-modulated radiation therapy (IMRT). After a median follow-up of 35.4 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 94%, respectively, for patients with P = .011) or had impaired nutrition (10% vs 44%; P = .025).

“We found there are some patients who have very high cure rates with reduced doses of radiation,” Barbara Burtness, MD, professor of Medicine (Medical Oncology), Yale Cancer Center, disease research team leader for the Head and Neck Cancers Program at Smilow Cancer Hospital, and the chair of the ECOG-ACRIN head and neck committee, said in a statement. “Radiation dose reduction resulted in significantly improved swallowing and nutritional status,” added Burtness.

This phase II single-arm study enrolled patients at 16 ECOG-ACRIN sites between March 2010 and October 2011. In order to be eligible for the trial, patients had to have newly diagnosed resectable, stage III/IV OPSCC positive for p16 immunohistochemistry (IHC) and/or HPV16 in situ hybridization as determined by a central laboratory.

On day 1, eligible patients were administered IC with cisplatin at 75 mg/m². On days 1, 8, and 15, patients received paclitaxel at 90 mg/m². Patients received cetuximab at 400 mg/m² on day of cycle 1, followed by cetuximab at 250 mg/m² weekly. These cycles were repeated every 21 days for 3 total cycles.

Within 2 weeks of completing IC, clinical response at the primary and involved nodal sites was determined by a complete head and neck examination, with mandatory fiberoptic nasopharyngolaryngoscopy, as well as CT or MRI.

Primary-site cCR was defined as a complete disappearance of the primary lesion on manual and endoscopic inspection. Nodal cCR was defined as complete resolution of palpable adenopathy.

The radiation dose to the oropharynx was determined by the primary site clinical response, and the nodal clinical response determined the radiation dose to involved nodes.

Patients with primary-site cCR to IC received 54 Gy in 27 fractions (IMRT) to the primary site. Those with less than cCR, on the other hand, were scheduled to receive 69.3 Gy in 33 fractions.

Involved nodes with cCR to IC received 54 Gy in 27 fractions to nodes, while those with less than cCR received 69.3 Gy in 33 fractions. A 1-cm margin was required around the involved nodes to minimize the dose administered to the oropharynx.

The uninvolved cervical nodes received 51.3 Gy in 27 fractions (1.9 Gy per fraction) to the clavicles bilaterally.

Both of these patient cohorts received weekly cetuximab to the end of radiation therapy.

Eight weeks after completion of chemoradiation, treatment response was evaluated by the radiographic method used at baseline. Patients were evaluated every 6 months for 2 years.

Late effects of treatment of lower versus standard-dose IMRT on patient-reported outcomes were measured at baseline, 12, and 24 months posttreatment using the Vanderbilt Head and Neck Symptom Survey version 2 (VHNSSv2).

This study was designed to estimate the 2-year PFS rate for patients with HPV-associated OPSCC who achieved a primary-site cCR following IC and reduced-dose radiation treatment. Secondary endpoints in the trial included safety and toxicity of the treatment, 2-year OS, and clinical and radiologic responses at the primary and nodal sites after IC and after overall treatment.

Overall, 90 patients were enrolled in the study, though 9 patients were ineligible due to out-of-window baseline scans, no measurable disease, cardiac history, and individual withdrawal from the treatment. The median age was 57 years (range, 35-73), and the majority of patients had stage T1-3 (89% of 80 eligible patients), N0-N2b (69% of eligible patients) OPSCC. Moreover, the majority were not current smokers (84%). Ninety-six percent of patients were positive for p16.

Seventy-seven of 80 eligible patients (96.2%) received all 3 cycles of IC. Three eligible patients received only 1 cycle due to a grade 4 cetuximab infusion reaction, grade 3 infection, and an unrelated surgical procedure, respectively. Cisplatin dose was reduced for 14 patients who experienced grade 3 or 4 hematologic toxicity, neuropathy, or tinnitus. Carboplatin was substituted in 2 patients who had grade 3 neuropathy. Eighteen patients received a modified dose of cetuximab during IC due to grade 3 or 4 acneiform rash, mucositis, or hypomagnesemia.

A primary-site cCR was identified in 56 out of 77 patients who completed IC (70%; 95% CI, 59%-80%). Partial response (PR) was observed in 7 patients, and stable disease (SD) was observed in 11 patients.

Three patients were deemed to be unevaluable at the primary site, one of whom underwent extensive primary-site tumor biopsy, and 2 of whom underwent tonsillectomy following baseline tumor measurements.

Nodal cCR was found in 46 of the 77 patients (58%; 95% CI, 46%-68%), and 4 patients had no follow-up assessment of the cervical lymph nodes.

All 77 patients who completed IC treatment proceeded on to IMRT with cetuximab.

Of the 56 patients with a primary-site cCR, 51 went on to receive 54 Gy of radiation per protocol, and 5 received 69.3 Gy, which was considered a deviation from protocol.

Of the 51 patients who were set to proceed with 54 Gy of radiation, 49 received that dose, 1 discontinued at 52 Gy because of grade 3 fatigue, and 1 stopped at 40 Gy due to grade 3 mucositis and acneiform rash.

Ten of the 18 patients with less than cCR at the primary site after IC proceeded to 69.3 Gy of radiation per protocol, and 8 (2 with PR, 6 with SD) patients went on to receive 54 Gy of radiation, which was considered a protocol deviation.

Thus, a total of 62 out of 80 eligible patients (77.5%) proceeded to 54 Gy of radiation and weekly cetuximab (51 with cCR at the primary site, 8 with less than primary-site cCR, and 3 unevaluable patients).

The median IMRT duration was 6 weeks for the patients receiving 54 Gy of radiation, and 7 weeks for those receiving 69.3 Gy of radiation.

Cetuximab dose modifications were mandated during IMRT for 22 of 77 patients (28%) for grade 3 rash, thromboembolism, mucositis, radiation dermatitis, and sepsis.

During IC treatment, the most common grade 3 or 4 adverse events included acneiform rash (28%), lymphopenia (6%), and neutropenia (12%).

For patients who received 54 Gy of radiation and concurrent cetuximab, the most frequent grade 3 adverse events were mucositis (30%), dysphagia (15%), acneiform rash (12%), radiation dermatitis (7%), and lymphopenia (12%).

For those who were treated with 69.3 Gy of radiation and cetuximab, they experienced more frequent grade 3 mucositis (47%), dysphagia (29%), acneiform rash (24%), radiation dermatitis (12%), thromboembolism (6%), and lymphopenia (29%).

Overall, the incidence of grade 4 toxicity was less than 5% in both radiation cohorts.

PFS and OS were analyzed among the 69 surviving, eligible patients after a median follow-up of 35.4 months (range, 3.9-41.6 months). At the time of this analysis, 11 of 80 evaluable patients had died, including 8 resulting from disease progression, 1 on-treatment sudden death without apparent cause after 56 Gy of IMRT and cetuximab, 1 death that occurred 4 months after study termination while on non-protocol treatment, and 1 death that occurred 2 months post-treatment as a result of accidental drowning.

The 2-year PFS estimate for patients with a primary-site cCR treated to 54 Gy of radiation (n = 51) was 80% (95% CI, 65%-89%). The 2-year OS for these 51 patients was 94% (95% CI, 82%-98%).

For all 80 evaluable patients, the 2-year PFS was 78% (95% CI, 67%-86%) and the OS was 91% (95% CI, 82%-96%).

Of all the patients treated with ≤54 Gy of radiation, the 2-year PFS was significantly higher among patients with ≤10 pack-years compared with those with >10 pack-years of smoking history (92% vs 57%; P = .0014). A statistically significant difference in 2-year OS was observed between these patients as well (93% vs 86%; P = .040).

Additionally, a subset analysis combining tumor and nodal status with smoking history showed a statistically significant difference in the 2-year PFS estimate for the patients with a ≤10 pack-year smoking history, < T4, 10 pack-year smoking history (n = 35) of 96% versus 71% (P = .010). The corresponding 2-year OS was 96% versus 91% (P = .13).

Among the 51 patients with primary-site cCR to IC who were treated with ≤54 Gy of radiation, 9 experienced treatment failure, including 4 with primary-site failure only, 2 with nodal failure only, 2 with nodal plus primary site failure, and 1 with distal failure only.

Four patients (3 with >10 pack-year smoking and 1 never-smoker) developed secondary primary cancers—specifically, adenosquamous carcinoma of the lung, gastroesophageal adenocarcinoma, larynx cancer, and nonmelanoma skin cancer.

Thus, the authors concluded that for patients with favorable-risk, HPV-associated OPSCC who respond to treatment with IC, reduced-dose IMRT with concurrent cetuximab is worthy of further research.

“While traditional chemoradiation has demonstrated good tumor control and survival rates for patients, too often they encounter unpleasant outcomes that can include difficulty swallowing solid foods, impaired nutrition, aspiration and feeding tube dependence,” said Burtness. “Younger patients may have to deal with these side effects for decades after cancer treatment. We want to help improve our patients’ quality of life.”

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 [published online December 27, 2016]. J Clin Oncol. doi: 10.1200/JCO.2016.68.3300.