New Clinical Trial: Sentinel Lymph Node Biopsy as Management Option for Oral Cancer

Approximately 70% to 80% percent of patients who undergo elective neck dissection (END) for early-stage oral cavity cancer do not have cancer in their lymph nodes. This statistic begs the question: Is there a better way to detect the 20% to 30% of patients who do have cancer?

That’s what researchers hope to answer with clinical trial NRG-HN006, Randomized Phase II/III Trial of Sentinel Lymph Node Biopsy versus Elective Neck Dissection for Early-Stage Oral Cavity Cancer.

The answer may hinge, in part, on the definition of “better.”

Unlike many trials, HN006 will consider the patient perspective. “We’re considering quality of life and morbidity,” said Stephen Lai, MD, PhD, professor of head and neck surgery at The University of Texas MD Anderson Cancer Center in Houston and the primary investigator for NRG-HN006. The current standard of care—elective neck dissection (END) for nearly all patients with early-stage oral cavity cancer—can result in significant shoulder impairment for many patients. That’s why NRG-HN006 will assess patient-reported neck and shoulder function, scarring, and length of hospital stay in addition to disease-free and overall survival.

Current Practices in the Management of Early-Stage Oral Cancer

For nearly 40 years, debate regarding the management of patients with early-stage, node-negative oral cancer centered around END or “watchful waiting” followed by neck dissection if cancer spread to the neck. As studies have found that 20% to 30% of patients with early-stage oral cancer will develop lymphatic metastases (J Clin Oncol. 2010;28:1395–1400), which are associated with decreased survival, American surgeons have largely tended toward END.

However, evidence for the utility of sentinel lymph node biopsy (SLNB) has been growing. A prospective multi-institutional trial published in 2010 found that SLNB correctly predicted a pathologically negative neck in 95% of patients (J Clin Oncol. 2010;28:1395-1400). The study included 140 patients with stage T1 and T2, N0 invasive oral cancers; for T1 lesions, 100% of metastases were correctly identified.

By 2014, SLNB was included as a management option in the National Comprehensive Cancer Network (NCCN) Guidelines for cancer of the oral cavity. “The guidelines said you could do either elective neck dissection or sentinel lymph node biopsy; they didn’t say one is preferred, but either is an option,” said John D. Cramer, MD, assistant professor in the department of otolaryngology–head and neck surgery at Wayne State University School of Medicine in Detroit.

By 2019, after several single-arm prospective studies demonstrated the accuracy of SLNB and showed that the procedure was associated with positive cancer outcomes, SLNB was “pretty widely adopted in Europe,” Dr. Cramer said. Currently, SLNB is the preferred option for the management of early-stage oral cancer in Amsterdam, The Netherlands, and other parts of Europe. “I’ve had physicians there tell me, ‘Based upon our experience with sentinel lymph node biopsy for early-stage oral cavity cancer, we actually think it’s unethical to randomize patients in a trial for an elective neck dissection,’” Dr. Lai said. In other parts of Europe, he said, debate rages. “In the UK right now, there is a group of surgeons who are saying, ‘We should only do elective neck dissection. We shouldn’t even consider sentinel lymph node biopsies,’” Dr. Lai said.

In the United States, SLNB for early-stage oral cancer remains rare. Dr. Cramer and his colleagues conducted a retrospective cohort study of patients with stage I to II oral cavity squamous cell carcinoma who underwent staging of the neck between 2012 and 2015, and found that just 240 of 8,328 patients, or 2.9%, underwent SLNB (Laryngoscope. 2019;129:162-169). The study noted that although SLNB is associated with a reduced hospital stay and equivalent overall survival compared to END, “SLNB remains rarely used in the United States.”

Dr. Cramer said the slow uptake of SLNB in the U.S. (and in other parts of the world) may be due to the fact that, to date, there hasn’t been strong evidence to favor either SLNB or END. Additionally, physicians view SLNB as a “de-escalation of treatment,” he said. “The tendency in cancer treatment is often to do more. Any time that we do something that’s perceived as ‘less,’ people are hesitant.”

Logistical and economic factors may also be inhibiting the use of SLNB. Some hospitals require the surgeon to perform the nuclear medicine injection to map the lymph drainage, which may necessitate a trip to the nuclear medicine department and tack on additional time to the case. “And sentinel node biopsy pays less than an elective neck dissection,” Dr. Cramer said.

Patients helped fuel momentum for SLNB in the management of breast cancer, but to date, no such advocacy has been noted in oral cancer. “It’s a rare cancer that has worse overall survival than breast cancer, so there are fewer people around five or 10 years later to speak about their experiences,” Dr. Cramer said.

Quality of Life Issues After END

It’s unwise to ignore the patient experience, yet few studies have methodically examined the impact of END and SLNB on patients’ lives.

Because END involves identifying and working around the spinal accessory nerve, which innervates the trapezius muscle, shoulder-related morbidity isn’t uncommon after the procedure. Some patients are unable to raise their arm above their head, which may seem like a relatively trivial matter given the gravity of cancer, but movement impairments can cause significant challenges in patients’ lives.

“There are people here in Michigan who have to shovel snow, people who work on a horse farm who have to shovel manure, and people who perform construction work. If they can’t clear their driveway, or care for their horses, or work, that can be an enormous economic problem for these patients,” said Steven S. Chang, MD, director of the Head and Neck Cancer Program at the Henry Ford Cancer Institute in Detroit. “Recovery can take up to two years, and two years of a nonfunctional shoulder or decreased function matters to patients.”

In patients’ view, the value of sentinel lymph node-guided biopsy is that it allows them to avoid a bigger surgery that may not be necessary. —Steven S. Chang, MD

END is generally considered a low morbidity procedure, but Dr. Cramer believes this may not be the case. “I think if we study the outcomes in comparison and ask patients about their experience, we may realize that there are other options that might have lower morbidity, or that patients would prefer,” he said.

NRG-HN006, the current clinical trial comparing SLNB and END, is novel in that it will explicitly examine quality of life issues, an emphasis that’s patient driven. “At Henry Ford, we have a patient advisory council specifically focused on head and neck cancer. I brought the trial concept to the patients, and they told me that value in this trial isn’t survival outcomes but morbidity from these two different operations,” Dr. Chang said. “In their view, the value of sentinel lymph node-guided biopsy is that it allows them to avoid a bigger surgery that may not be necessary.”

Changing the Paradigm: SLNB versus END

Recent studies out of France and Japan provide additional support for SLNB as a management strategy for early-stage oral cancer. The French study, published in December 2020, randomly assigned 307 patients to either SLNB or END. Neck node recurrence-free survival was 89.6% at two years in the group that underwent END and 90.7% in the group that underwent SLNB. The authors concluded that the study “demonstrated oncologic equivalence” of the two approaches, while noting that functional outcomes were worse in the END group until six months after surgery (J Clin Oncol. 2020;38:4010-4018).

The Japanese study included 271 patients who were also randomized to either SLNB or END. Three-year overall survival (OS) in the SLNB group was 87.9%; disease-free survival (DFS) was 78.7%. Three-year OS in the END group was 86.6%, while DFS was 81.3%. Neck functionality was significantly better in the SLNB group (J Clin Oncol. 2021;39:2025-2036).

Although both trials seem to affirm the noninferiority of SLNB to END as a management strategy for early-stage oral cavity cancer while highlighting the functional benefits of SLNB, the studies may not be persuasive enough to change practice. The French trial used a noninferiority margin of 10%, which is unlikely to influence SLNB adoption, Dr. Lai said. The Japanese study used a 12% percent noninferiority margin.

“What they’re essentially saying is that sentinel lymph node biopsy is no worse than 10% to 12% of what we can do with elective neck dissection,” Dr. Lai said. “Most clinicians will tell you they want to see a noninferiority margin of 5% before changing practice. They’d want to see that sentinel lymph node biopsy is no worse than 5% for patient outcomes than elective neck dissection.”

Of course, it’s difficult to accrue a large enough sample size to attain a 5% noninferiority margin. Statistically speaking, clinical trial NRG-HN006 will need a patient population of at least 618 to achieve a 5% noninferiority margin. That’s why the trial is open to patients in the United States and abroad.

“We aren’t interested in recruiting only patients from head and neck surgeons at tertiary academic institutions,” Dr. Lai said. “We also want patients from otolaryngologists at a variety of centers who are taking care of patients with early-stage oral cavity cancer.”

Patients will be randomized to either the SLNB arm or the END arm after undergoing a PET/CT scan. Phase II of the trial will examine the quality-of-life impact of SLNB and END. “Once we hit 228—roughly 114 patients in each arm—we’re going to stop the study and look at the Neck Dissection Impairment Index (NDII) at six months after dissection or sentinel lymph node biopsy,” Dr. Lai said. “We’ll be looking to see if there’s a potentially clinically meaningful difference.”

If the evidence at that point suggests an advantage for SLNB, the trial will proceed to Phase III, which will test the hypothesis that SLNB is noninferior to END in terms of disease-free survival and superior to END in functionality of the neck and shoulder.

It will take time to determine the results. The study is currently accruing patients. Dr. Lai expects that Phase II may take four to five years, while it may be a decade or more until Phase III results are available.

It’s a significant, but worthwhile, time investment, according to Dr. Lai.

“We owe it to our patients to run high-quality studies so that we actually address our clinical questions with definitive answers,” he said. “We’re looking to potentially change the standard of care based upon high-quality data acquired in a well-designed study. I’m not here to champion sentinel lymph node biopsy if it turns out it’s no better for our patients. We’re in a great position to determine if sentinel lymph node biopsy may be better than elective neck dissection on multiple fronts, including overall survival.”

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Jennifer Fink is a freelance medical writer based in Wisconsin.