Complete Responses With Reduced-Dose Radiation in HPV-Linked Oropharynx Cancers


For patients with HPV-related oropharyngeal squamous cell carcinoma, induction chemotherapy plus reduced-dose radiation and weekly cetuximab brought improvements for swallowing and nutritional status along with complete clinical responses.

Barbara Burtness, MD

Barbara Burtness, MD

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.

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