Treatment deintensification in HPV oropharynx cancer
There appears to be a large proportion of patients with human papillomavirus (HPV)-associated oropharyngeal cancer who would benefit from treatment modification or deintensification, according to an expert who spoke at the European Society for Medical Oncology (ESMO) Asia 2016 Congress held in Singapore. This is in line with the use of chemoradiotheraphy in the current treatment paradigm in head and neck cancer.
HPV oropharynx cancer emerged as a new disease entity, seen predominantly in younger Caucasian individuals, said Dr Anil D’Cruz MS, DNB, FRCS, director of the Tata Memorial Hospital in India. “The performance status of these patients was much better because they were younger. They presented with small stage T but a propensity for metastasis, and [their disease] was biologically very different from the HPV-negative cancers.”
“At the same time, the treatment of head and neck cancers was evolving, and there was a shift towards chemoradiotherapy,” Dr D’Cruz added.
He noted from a previous study that as treatment changed from standard-protocol radiotherapy to platinum-based chemoradiotherapy, acute toxicity doubled.
Specifically, in three trials that looked at long-term toxicity following concurrent chemoradiation for locally advanced head and neck cancer, nearly a third of oropharyngeal cancer patients had a severe late toxicity. [J Clin Oncol 2008;26:3582–9]
Severe chemoradiotherapy-related toxicity was defined as chronic grade 3 to 4 pharyngeal/laryngeal toxicity, requirement of a feeding tube 2 years after registration, and potential treatment-related death (eg, pneumonia) within 3 years.
New staging system makes case for treatment de-escalation
A novel staging system for HPV oropharynx cancer addressed the need to have a system that was different from that derived from tobacco-related cancers, making the case for treatment de-escalation and treating the favourable groups better, Dr D’Cruz said.
Developed by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S), the proposed classification designated T1–T2/N0–N1 as stage I, T1–T2/N2 or T3/N0–N2 as stage II, and T4 or N3 as stage III. Only metastatic disease was designated as stage IV. [Lancet Oncol 2016;17:440–451]
Dr D’Cruz cited three strategies to de-escalate treatment. First was to modify the radiotheraphy, either reducing radiation dose and volumes or having better delivery system. Second was to modify the chemotheraphy by replacing it with biologics or omitting/reducing it. Third was to integrate surgery into the treatment algorithm, or to identify unfavourable subsets of patients who could not be de-escalated.
Specifically, radiation dose/volume and delivery system proved crucial to certain outcomes. For example, dysphagia increased for every 10-Gy rise in total dose above 55 Gy, while standard IMRT offer moderate sparing of anatomic strictures compared with 3D radiotherapy.
Chemotherapy also contributed to an increased toxicity when added to radiation, with several studies reporting an increase of around 30 percent in grade III/IV toxicity and in non-cancer deaths.
Dr D’Cruz cited a number of phase III trials and comparison studies that provided a rationale for the other deintensification strategies, including those that reported the efficacy of replacing chemotherapy with biologics and those that demonstrated better swallowing outcomes with microsurgery vs chemoradiotherapy alone. [N Engl J Med 2006;354:567–578; Head & Neck 2015;37:1488–1494]
The decreased EGFR expression and less hypoxic areas in HPV-positive cancers could be targeted in different approaches to reduce treatment-related complications, he added.
Treatment intensification warranted in some patients
Meanwhile, the high-risk group in oropharyngeal cancer does very poorly, with a 3-year overall survival rate of only 46 percent vs 93 percent in the low-risk group and 70.8 percent in the intermediate-risk group. This high-risk group comprise patients with HPV-negative cancers, those who are high smokers, and those who are low smokers but with T4 disease. [N Engl J Med 2010;363:24-35]
“Obviously this group needs to have intensification of therapy,” Dr D’Cruz said, adding that this was where smoking comes into the equation of oropharyngeal cancer.
Another group that can benefit from intensification is those of HPV-positive patients who are at high risk of distinct metastasis. These patients have N3, N2c or N2b disease but with greater than 10-pack years of smoking.
“One of the approaches for local control is hyperfractionation,” he said. “We have the MARCH meta-analysis showing that [the therapy] gives an 8-percent absolute benefit.”
Intensification with the use of surgery may also be an attractive approach, with the 2008 study from Walvekar et al demonstrating that surgery altered T stage in 26 percent, N stage in 23 percent, and clinical stage in 40 percent of patients, Dr D’Cruz continued.
Induction chemotherapy is yet another alternative.
Given the range of approaches to both treatment intensification and deintensification, Dr D'Cruz said clinical trials should provide the answer to what clinicians could appropriately give for their patients.