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Adding concurrent chemotherapy (CT) to cetuximab (Erbitux) plus radiotherapy (CT-cetux-RT) improved progression-free survival (PFS) and locoregional control but not overall survival compared with cetuximab plus RT (cetux-RT) in patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), researchers found.

The international phase III GORTEC 2007-01 randomized trial showed that at 3 years, the PFS in 204 patients randomized to additional CT consisting of carboplatin (Paraplatin) and fluorouracil (Adrucil; FU) was 52.3%. The median PFS time in the CT-cetux-RT treatment arm was 37.9 months. By comparison, PFS in the 202 patients randomized to have cetux-RT was 40.5%, with a median PFS time of 22.4 months.

The adjusted hazard ratio [HR] in favor of CT-cetux-RT was 0.73; P=0.015, said Jean Bourhis, MD, PhD, of the Centre Hospitalier Universitaire Vaudois, in Lausanne, Switzerland, and colleagues.

Similarly, locoregional control was better in the CT-cetux-RT arm compared with the cetux-RT arm (21.6% versus 38.8%, respectively, HR 0.54; P<0.001). These benefits were observed regardless of p16 status for oropharynx carcinomas, the study authors reported online in the

The study also revealed no significant differences in the rates of overall survival (HR 0.80; P=0.11) or distant metastases (HR 1.19; P=0.50) between the two groups. However, there was a higher incidence of grade 3 or 4 mucositis in the CT-cetux-RT arm than in the cetux-RT arm (73% versus 61%, respectively; P=0.014). More patients receiving concurrent chemotherapy had to be hospitalized because of toxicity (42% versus 22%, respectively; P<0.001), the researchers noted.

"To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in locally advanced squamous cell carcinomas of the head and neck," the study authors wrote.

"Considering the current [standard of care] in LA-SCCHN, this trial answers an important scientific question, but it could have a limited clinical impact, essentially for patients not eligible for high-dose cisplatin (impaired renal or hearing functions) and for whom carboplatin plus FU combined with cetux-RT can still be used."

Although SCCHN is closely associated with tobacco and alcohol use, a growing proportion of squamous cell carcinomas (SCCs) of the oropharynx are associated with human papillomavirus (), the researchers pointed out. HPV-positive SCCHNs have a higher than HPV-negative tumors.

Asked for her perspective, Nicole Schmidt, MD, of Johns Hopkins University in Baltimore, who was not involved with the study, told MedPage Today: "Recent data suggest that chemotherapy regimens should not be de-escalated in patients with HPV-negative, carcinogen-related head and neck cancers. This study is in support of that idea, since the majority of patients had HPV-negative tumors."

As did Bourhis et al, she also noted that the Radiation Therapy Oncology Group (RTOG) 0522 demonstrated no benefit with the addition of cetuximab to cisplatin (Platinol) chemoradiation. Since the current study did not include a comparison to platinum-based chemoradiation without cetuximab, it isn't clear whether this regimen is as effective as standard cisplatin chemoradiation.

"Currently, patients with intermediate-risk disease are often treated with radiation plus cetuximab when they cannot tolerate cisplatin due to renal disease or pre-existing hearing loss," Schmidt continued. "This study suggests that adding carboplatin plus FU, which is less toxic to the inner ear and kidney, may be a nice alternative for these patients."

The study's findings don't come as a surprise, she added, since numerous clinical and preclinical studies have suggested that cytotoxic platinum-based chemotherapy is more effective when given concurrently with radiation than with cetuximab. In addition, the retrospective trial by showed that use of cetuximab plus radiation was more effective than radiation alone.

Study Details

The Bourhis et al study, conducted from January 2008 to March 2014, randomized 406 patients from 31 centers to one of two treatment arms: CT-cetux-RT or cetux-RT. Patients had to be no older than 70, and to have a Karnofsky performance score of 80 to 100.

More than 60% of patients had an oropharyngeal carcinoma, 79% were p16-negative, and the majority had T2-3 tumors (70% in the CT-cetux-RT and 69% in the cetux-RT arms). The rate of N0 disease was 34% in both arms.

A total of 39% of patients in the CT-cetux-RT arm were treated with intensity-modulated RT, with 88% receiving 35 fractions during a mean overall treatment time of 51.8 days. In the cetux-RT arm, 42% were treated with the same recommended RT, and 90% received 35 fractions during a mean overall treatment time of 52 days. The remaining patients in each arm received three-dimensional conformal RT.

A total of 85% of patients in the cetux-RT arm and 73% of patients in the CT-cetux-RT arm were able to receive at least seven injections of cetuximab. A loading dose of 400 mg/m² at day 7 was followed by a weekly dose of 250 mg/m² during RT in both treatment arms.

RT was prescribed at 70 Gy, 2 Gy per fraction, 5 days a week. Concurrent CT consisted of three cycles of carboplatin 70 mg/m²/d on days 1 to 4 and FU 600 mg/m²/d on days 1 to 4 with continuous infusions.

The median follow-up was 4.4 years for patients in the CT-cetux-RT arm, and 4.6 years for those in the cetux-RT arm.

After excluding early deaths due to progression, six patients (3%) died in the CT-cetux-RT arm, either during treatment or in the 30-day period after treatment. In the cetux-RT arm, there were two (1%) early deaths (P=0.28).

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