Surgery vs Chemoradiation in Head and Neck Cancer

Kristin Jenkins

January 16, 2017

The first large-scale analysis to compare upfront surgery to definitive chemoradiation (CRT) in patients with human papilloma virus (HPV)-negative oropharyngeal squamous cell cancer (OPSCC) found no difference in overall survival between the two groups.

Patients receiving CRT had a 3-year overall survival of 79.2% compared with 81.4% for those who underwent primary surgery, report Zain A. Husain, MD, of Smilow Cancer Hospital, Yale Cancer Center, New Haven, Connecticut, and colleagues.

However, nearly 60% of patients treated with upfront surgery also received adjuvant CRT, which is notable, say the authors, as trimodal therapy likely worsens toxic effects without a discernable survival benefit.

"Given that upfront surgical intensification is not associated with improved overall survival, further research should focus on better selection of surgical patients who are less likely to require adjuvant CRT, as trimodal therapy increases treatment-related toxic effects," the researchers emphasize.

The new findings were published online January 5 in JAMA Oncology.

The lack of overall survival benefit with upfront surgery was also observed following a subset analysis of patients with margin-negative resection (P = .88). This was not because of poor quality of surgery, the researchers say, but rather the fact that CRT patients were more likely to have poorer prognostic features such as a higher T and N stage.

Equivalent overall survival was re-demonstrated in a cohort identified using propensity score matching (P = .46).

In addition, the study shows that 59.1% of surgical patients received trimodal therapy with adjuvant CRT, which is indicated for patients with positive margins and/or extracapsular extension (ECE).

"That nearly 60% of patients treated with upfront surgery received trimodal therapy is notable given the lack of overall survival benefit and probable increased toxic effects," the researchers say.

The odds of receiving CRT increased with a number of factors, including nonprivate insurance status, higher T and N stage, absence of comorbid conditions, proximity to a treatment facility, and unknown histologic grade, the study indicates.

The results suggest that upfront surgery doesn't help overcome resistance of HPV-negative disease to CRT, so it shouldn't be recommended to intensify therapy or overcome perceived resistance of tumors to CRT, the researchers say.

"Decisions about surgery and radiation should be based on things like patient preference, the availability of local expertise, medical comorbidities which may affect the ability to operate or give chemotherapy, and factors like tumor extent and presence of radiographic extracapsular extension," lead author Dr Husain said in an email.

"Surgery remains an important tool in the arsenal for oropharyngeal cancer, and there are many clinical scenarios where surgery is important," he emphasized.

However, he also acknowledged that there are scenarios in which surgery in HPV-negative patients with OPSCC is discussed "solely as a means to increase the aggressiveness of therapy in hopes that this will translate into improved oncologic outcomes.

"Unfortunately," he added, "this does not appear to improve survival."

Currently, treatment of HPV-negative OPSCC shows resistance to CRT and carries a poor prognosis relative to HPV-positive disease, the authors note. Treatment intensification with induction chemotherapy, CRT with accelerated fractionation, or the addition of cetuximab (Erbitux, Eli Lilly) has not improved survival, they add.

On the other hand, treatment intensification with minimally invasive transoral robotic surgery (TORS) has become "an enticing option" for improving quality of life in patients requiring minimal adjuvant therapy.

For the study, researchers identified 1044 patients diagnosed with HPV-negative OPSCC in 2010 to 2012 using the National Cancer Database.

Median age of the cohort was 59 years and 812 patients were male (77.8%). A total of 460 (44.1%) received upfront surgery and 584 (55.9%) received CRT. Median follow-up was 30 months.

Although surgery plus chemoradiation is thought to be more toxic than chemoradiation alone, how the toxicity of chemoradiation compares with surgery plus radiation "is an ongoing question," Dr Husain said.

Noting that it has proven difficult to predict prior to surgery which patients will have positive margins or extracapsular extension, he pointed to another published review in which his team found that patients with a larger preoperative lymph node appeared more likely to have extracapsular extension and be treated with chemoradiation after TORS, with a potentially higher rate of toxicity.

The researchers concluded that lymph node size should be taken into account when deciding treatment approaches.

"This has not been found across all studies," Dr Husain noted. In future, he added, radiomics or genomic markers may provide insight into preoperative patient characteristics associated with positive surgical margins or extracapsular extension requiring adjuvant chemoradiation after TORS.

In yet another study — an open-label Phase 2 randomized trial of adjuvant radiotherapy with or without cisplatin for patients with surgically resected SCC — Dr Husain and his team are looking at whether patients with a p53 mutation could benefit from chemoradiation after surgery.

"This will hopefully allow us to learn more about how to incorporate tumor-specific mutation information into our treatment paradigms," he said.

The authors declare no outside funding for this study. Dr Husain reports a relationship with Merck, and coauthor Henry S. Park, MD, reports a relationship with Varian Medical Systems.

JAMA Oncol. Published online January 5, 2017. Full text

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