MUNICH- A "salutary lesson" was reported by researchers investigating therapy for oropharyngeal cancer at the 2018 ESMO Annual Congress. It came from results of the De-ESCALaTE HPV study that found patients with low-risk head and neck cancer who tested positive for human papilloma virus (HPV+) did better if they had been treated with standard platinum-based chemotherapy (added to their radiotherapy) rather than the EGFR inhibitor cetuximab.
"One of the big lessons is that you really need phase III trials-even when treatments are already approved-as in [the] case [of] head and neck cancer," said Hisham Mehanna, PhD, BMedSc, FRCS, Chair of Head and Neck Surgery at the Institute for Head and Neck Studies Education in the University of Birmingham, U.K. "You need phase III trials to compare new treatments to standards of care to really be able to take [them] into the clinic.
"Clinical practice should not be changed without these phase III trials," he emphasized.
De-ESCALaTE HPV Details
The De-ESCALaTE HPV study-reported at ESMO by Mehanna and his colleagues-found there had been "significant detriment from the use of cetuximab instead of cisplatin in terms of tumor control and no benefit in terms of reduced toxicity." They concluded that: "Cisplatin and radiotherapy remained the standard of care in this setting."
"What we found was that cetuximab had the same overall level of [all grades of] toxicities, the same quality of life, the same swallowing and function." While the most severe toxic events were more frequent with cisplatin. "But the real surprise was that cetuximab resulted in worse survival than cisplatin-driven by more recurrences. And therefore cetuximab is just not as good as cisplatin in terms of survival and control of disease," said Mehanna.
In the study, patients with low-risk HPV-positive oropharyngeal cancer were randomized to receive radiotherapy plus either cisplatin or cetuximab. The outcome measures were the total numbers of grade 3-5 toxicity events, overall survival, and quality of life.
Since the incidence of HPV-positive oropharyngeal cancer had been rapidly rising, and since it was judged to be a distinct disease entity affecting younger patients who had much better outcomes, the researchers wanted to look into ways of de-escalating treatment. Standard cisplatin with radiotherapy caused significant toxicities that many patients faced the prospect of enduring for decades. In the absence of previous studies comparing (the already-approved agent) cetuximab head-to-head with cisplatin, the data for clinical decision-making were absent for this subgroup of patients.
De-ESCALaTE HPV randomized 334 patients-166 to cisplatin therapy and 168 to cetuximab-at 32 head and neck treatment centers in the U.K., Ireland, and the Netherlands. There were 10 recurrences and six deaths in the cisplatin arm of the study compared to 29 recurrences and 20 deaths in the cetuximab arm.
Patients lived longer with cisplatin treatment. There was a significant difference in 2-year overall survival between the arms-97.5 percent for cisplatin compared with 89.4 percent with cetuximab with a p value of 0.001 and a hazard ratio (HR) of 4.99.
The 2-year recurrence rate was significantly lower with cisplatin than cetuximab-6.0 percent compared to 16.1 percent-with a p-value of 0.0007 and HR of 3.39. But although there were no differences between the cisplatin and cetuximab arms in the overall mean number of toxicity events, there were significantly more serious adverse events (162) in cisplatin-treated patients compared to those receiving cetuximab (95).
"The clinical implications are that patients who [have] low-risk HPV-positive head and neck cancer should be treated with cisplatin and radiotherapy wherever possible-and not with cetuximab," said Mehanna.
Looking Forward
Branislav Bystricky, MD, Head of the Medical and Radiation Oncology Department at University Hospital Trencin, Slovakia, said it had previously been believed that cetuximab caused fewer side effects (overall) and was therefore a good option for treating HPV-positive patients with head and neck cancer-especially as many of them were young and expected to survive for several decades.
Patients who were less able to tolerate chemotherapy were also considered for cetuximab therapy, he noted. "This study shows that the best treatment choice for patients with HPV-positive throat cancer is cisplatin and radiotherapy. This combination gives double the benefit since it is more effective in terms of survival and does not worsen all-grade toxicity compared to cetuximab with radiotherapy."
Bystricky noted that the results were in agreement with interim findings from the NCI's RTOG 1016 trial. "We now have two studies showing that these patients should not be given cetuximab. Future research should examine whether genotyping for the KRAS-variant can select a group of patients that will benefit from cetuximab treatment with radiotherapy," he said.
Peter M. Goodwin is a contributing writer.