January 17, 2019
4 min read

Treatment de-intensification fails to reduce toxicity, maintain efficacy in HPV-positive oropharyngeal cancer

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Photo of Maura Gillison
Maura L. Gillison

Patients with advanced, HPV-positive oropharyngeal squamous cell carcinoma did not experience significant reductions in toxicity from treatment deintensification with cetuximab and had worse survival outcomes than those treated with the standard cisplatin regimen, according to findings from two studies published in The Lancet.

“HPV status is considered the most important prognostic indicator in head and neck oncology, reflected by the inclusion of p16 status in the eighth edition of the American Joint Committee on Cancer Staging System,” Johannes Christiaan Oosthuizen, MD, consultant otolaryngologist and head and neck surgeon at Ipswich Hospital and senior lecturer at University of Queensland in Australia, and Jaime Doody, MD, of the department of otolaryngology and communication at Boston Children’s Hospital and department of otolaryngology at Harvard Medical School, wrote in an editorial addressing both studies. “However, traditional therapeutic interventions are associated with substantial morbidity and have a great impact on quality of life. This impact is especially pertinent for patients with HPV-positive oropharyngeal squamous cell carcinoma because they are typically much younger and therefore have to live with the consequences of their treatment for far longer. These factors have led to the investigation of de-intensified therapies for patients with HPV-positive oropharyngeal squamous cell carcinoma.”


N oninferiority trial

In the randomized, multicenter noninferiority RTOG 1016 trial, Maura L. Gillison, MD, PhD, of the department of thoracic head and neck medical oncology, division of cancer medicine at The University of Texas MD Anderson Cancer Center, and colleagues sought to determine whether replacing cisplatin with cetuximab (Erbitux, Eli Lilly) — an antibody against the epidermal growth factor — reduced treatment toxicity without impacting high survival rates..

Gillison and colleagues evaluated 805 adults from 182 health care facilities in the U.S. and Canada with histologically documented HPV-positive oropharyngeal carcinoma; classification in American Joint Committee on Cancer seventh edition clinical categories T1-T2, N2a-N3 MO or T3-T4, NO-N3 MO; Zubrod performance status score of 0 or 1; and sufficient bone marrow, hepatic and renal function.
Researchers randomly assigned participants to radiotherapy with cisplatin (n = 406; mean age, 57.7 years; 92% men) or with cetuximab (n = 399; mean age, 57.4 years; 89% men).

Participants in the cetuximab group received a loading dose of IV 400 mg/m2 5 to 7 days prior to radiotherapy initiation, followed by 250 mg/m2 weekly for seven doses (total 2,150 mg/m2). Participants in the cisplatin group received 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients underwent accelerated intensity-modulated radiotherapy administered at 70 Gy in 35 fractions over 6 weeks, at six fractions per week.


OS — with a noninferiority margin of 1.45 — served as the primary endpoint. The modified intention-to-treat approach was used as the basis for the primary analysis.

Results showed after median follow-up of 4.5 years, radiotherapy plus cetuximab failed to meet the noninferiority criteria for OS (HR = 1.45; one-sided 95% upper CI, 1.94; one-sided log-rank, P = .0163).

Five-year OS was 77.9% (95% CI, 73.4-82.5) in the cetuximab group vs. 84.6% (80.6-88.6) in the cisplatin group.

Compared with the cisplatin group, the cetuximab group had significantly lower 5-year PFS (67.3% vs. 78.4%; HR = 1.72; 95% CI, 1.29-2.29), and significantly higher rates of locoregional failure (5-year proportions, 17.3% vs. 9.9%; HR = 2.05; 95% CI, 1.35-3.1).

The two groups had similar rates of acute moderate to severe toxicity (77.4% vs. 81.7%) as well as late moderate to severe toxicity (16.5% vs. 20.4%).


Toxicity , tumor control

In the open-label, randomized, controlled phase 3 De-ESCALaTE trial, Hisham Mehanna, PhD, chair of head and neck surgery at Institute of Head and Neck Studies and Education at University of Birmingham in the United Kingdom, and colleagues found that, compared with standard cisplatin therapy, cetuximab yielded no improvements in toxicity, poorer OS and higher rates of locoregional recurrence and distant metastases.

Mehanna and colleagues evaluated 334 adults — nonsmokers or lifetime smokers with a smoking history of less than 10 pack-years — with HPV-positive low-risk oropharyngeal cancer who were treated at 32 head and neck treatment centers in Ireland, the Netherlands and the U.K.
Gy in 35 fractions) and either IV cisplatin (100 mg/m2 on days 1, 22 and 43 of radiotherapy; n = 166) or IV cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2; n = 168).
served as the study’s primary outcome. Researchers used intention-to-treat and per-protocol analyses to evaluate the primary outcome.
; 95% CI, 27.3-31 with cisplatin vs. 30.1; 95% CI, 28.3-32.9 with cetuximab) or severe toxicity (mean events per patient in each group, 4.8; 95% CI, 4.2-5.4).

However, a significant difference occurred between the cisplatin and cetuximab groups in 2-year OS (97.5% vs. 89.4%; HR = 5; 95% CI, 1.7-14.7) and 2-year recurrence (6% vs. 16.1%; 95% CI, 1.6-7.2). Cisplatin was associated with significantly fewer locoregional occurrences (3% vs. 12%; P = .0026) and fewer distant metastases (3% vs. 9%; P =.0092) than cetuximab.
and Doody wrote in the accompanying editorial. “This recommendation is pertinent, as there is emerging evidence showing a substantial increase in HPV-positive oropharyngeal squamous cell carcinoma in older patient groups. These results also serve as a timely reminder that although HPV-positive oropharyngeal squamous cell carcinoma has an excellent prognosis with existing, well-established treatment protocols, treatment de-intensification strategies should only be evaluated within the confines of well-designed clinical trials.” – by Jennifer Bryne


Disclosures: Gillison reports grants from the NCI and Oral Cancer Foundation during the course of the study; consulting fees from Amgen, Aspyrian, AstraZeneca, Bristol-Myers Squibb, Celgene Corp., Eli Lilly, EMD Serono, Genocea Biosciences, Merck, New Link Genetics Corp., Roche and TRM Oncology, all outside the submitted work; and a Damon-Runyon Clinical Investigator Award from 2000-05, which was supported by a grant from Eli Lilly. Mehanna reports personal fees from AstraZeneca, Merck, Sanofi Pasteur and Warwickshire Head and Neck Clinic Ltd.; grants from AstraZeneca, GlaxoSmithKline Biologicals, GlaxoSmithKline, Merck, Sanofi Pasteur, Silence Therapeutics and several academic funders, including Cancer Research UK, the Medical Research Council and NIHR Health Technology Assessment Unit; and travel expenses from Merck and Sanofi Pasteur outside the submitted work. Please see the studies for all other authors’ relevant financial disclosures. Oosthuizen and Doody report no relevant financial disclosures.