How to Ensure Surgical Head and Neck Clinical Trials Are Beneficial to Patients

Randomized controlled trials can take a great deal of time, money, and effort. Hisham Mehanna, MD, chair of head and neck surgery at the Institute of Cancer and Genomic Sciences and director of the Institute of Head and Neck Studies and Education at the School of Cancer Sciences at the University of Birmingham in the U.K., wondered about their return on investment for patients with head and neck cancer and the healthcare systems that serve them.

In his Eugene N. Myers, MD International Lecture on Head and Neck Cancer, “What Have Head and Neck Clinical Trials Ever Done for Our Patients Anyway?” Dr. Mehanna covered the benefits and flaws in clinical trials in head and neck cancer over the past two decades.

He referenced the presidential address delivered by John Andrew Ridge, MD, PhD, at the 2010 American Head and Neck Society meeting, which spoke of medical oncologists and clinical radiologists having a history of participating in clinical trials, whereas surgical oncologists did not. In the decade preceding
2010, surgical oncologists had not conducted a single clinical trial, and Dr. Ridge asserted that surgeons were willing to change their practice without Level 1 evidence. “Dr. Ridge believed surgeons had been dismissed as an intellectual force, even by surgeons themselves,” Dr. Mehanna said.

In the aftermath of Dr. Ridge’s address, surgeons led four major head and neck trials between 2011 and 2019. “Things have changed,” Dr. Mehanna said. “I think this reflects the rise of the head and neck surgeon–scientist.”

The Last 10 Years

Here are the four major clinical trials in head and neck cancer led by surgeons over the past decade and their results:

1. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. Led by Anil D’Cruz, MD, in Mumbai and also known as the Tata Trial because it was run by the Tata Memorial Centre, this
   trial concluded that, among patients with early-stage oral squamous-cell cancer, elective neck dissection resulted in higher rates of overall and disease-free survival than therapeutic neck dissection (N Engl J Med. 2015;373:521–529).
2. PET-NECK. This multicenter randomized phase III non-inferiority trial compared a PET-CT–guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer. Led by Dr. Mehanna, the trial concluded that PET-CT–guided active surveillance showed similar survival outcomes with planned neck dissection but resulted in considerably fewer planned neck dissections, fewer complications, and lower costs, supporting its use in routine practice (N Engl J Med. 2016;374:1444–1454).
3. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Led by Bob Ferris, MD in Pittsburgh, this trial concluded that, among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-
   agent therapy (N Engl J Med. 2016;375:1856–1867).
4. De-ESCALaTE HPV. This open-label randomized controlled phase 3 trial looked at radiotherapy plus cisplatin or cetuximab in low-risk HPV-positive oropharyngeal cancer. Also led by Dr. Mehanna, this trial’s interpretation was that cetuximab, compared with the standard cisplatin regimen, showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumor control. It advised that cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin (Lancet. 2019;393:51–60).

Design Flaws

Dr. Mehanna said there are issues that come up regularly in surgical research that are important to consider carefully. Clinical trials are a good way of addressing these pitfalls. They include:

• Type 1 error/effect of multiple analyses;
• Type 2 error/effect of inadequate power (sample size); and
• Over-interpretation of data.

According to Dr. Mehanna, Type 1 errors can be adjusted for by making the p-value more stringent. “Multiple analyses have a high risk of Type I error, especially if you’re using p = 0.05 as the level of significance,” Dr. Mehanna said. “That can be an overestimation of the effect of the intervention. We do a lot of analyses in the hope that we can find something that is less than P = 0.05, and we consider that as the significant, and then we build our paper around it.”

Dr. Mehanna cites the nivolumab study as a clinical trial that did well in avoiding a Type 1 error: The protocol was set and published before the study started, detailing exactly what analyses would take place. “It built the sample size to be 0.05, or 0.001 or whatever depending on the size and the number of analyses that were going to take place,” he said, “and stated exactly every question they were going to look at.”

We are recruiting and supporting recruitment into trials, but only where the trials do not impinge on our decision making. —Hisham Mahanna, MD

Type 2 errors lead to incorrectly missing a true effect because the sample size of the clinical trial isn’t large enough to detect it. Dr. Mehanna pointed to two randomized studies, one in 1980 and the other in 2009, that showed no benefits from neck dissection in early oral cancer (Cancer. 1980;46:386–390; Head Neck. 2009;31:765–772). Each study looked at only approximately 75 patients, and surveillance became one of the standards of care for early oral cancer. In 2015, Dr. D’Cruz’s study looking at elective neck dissection versus surveillance involved nearly 600 patients. “The real shock,” Dr. Mehanna said, “was that there was a 12.5% absolute difference in overall survival between having an elective neck dissection and surveillance. That, to me, was an “oh dear” moment, because for many years our patients were being treated with surveillance.” The previous studies had been much too small to identify an effect reliably.

Over-interpretation of data is the third crime, according to Dr. Mehanna, who pointed to the 2009 study that confirmed HPV-positive patients did better than HPV-negative patients. It also suggested that there were three different risk categories. The question was, were they over treating by giving the low risk patients who were doing really well too much chemoradiotherapy?

Some clinicians extrapolated data from the Bonner study of 2006 (which showed that adding cetuximab to radiotherapy resulted in better outcomes than by radiotherapy alone) to conclude that using cetuximab and radiotherapy for HPV patients could benefit them, and they changed clinical practice on that basis (N Engl J Med. 2006;354:567–578).

“However, our De-ESCALaTE trials showed that out of every 13 patients who were treated with cetuximab, one died unnecessarily because they hadn’t been treated with cisplatin,” Dr. Mehanna said. “That has had a big effect on our practice. In fact, those studies have had a drastic reduction on the use of cetuximab for low-risk HPV patients worldwide, an almost overnight reduction in cetuximab for those patients.”

Furthermore, Dr. Mehanna said that trials also benefit healthcare systems. “The PET/CT arm resulted in a cost saving of £1,415 per person treated,” Dr. Mehanna said. “In the U.K., about 2,000 patients would have gotten a neck dissection before for this indication. That translates into almost £3 million a year of savings, which covers HPV vaccine for almost 10,000 children a year.” And there is a fair amount of data that shows the clinical outcomes of all patients treated within a healthcare system that does a lot of research are better than those outcomes at healthcare organizations with low to no research activity.

Looking Ahead

Traditional trial designs are wasteful, said Dr. Mehanna. The future holds adaptive, efficient clinical trial designs that are multi-arm and multi-modal, allowing for earlier assessment and substitution of arms, and assessing at successive stages to allow discarding arms that show no progress. International collaborations, such as the newly formed Head and Neck Cancer International Group, will allow delivery of trials to larger populations.

“But surgeons still need to do better, Dr. Mehanna said. “We are recruiting and supporting recruitment into trials,
but only where the trials do not impinge on our decision making.” While there are exciting developments in trials and research, Dr. Mehanna implores surgeons to do more to overcome their biases and lack of equipoise.

“As I’ve hopefully demonstrated,” he said, “please don’t change your management without good level 1 evidence from trials, because the effects can be pretty significant on our patients. 

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Renée Bacher is a freelance medical writer based in Louisiana.