Due to intensive treatments, severe side effects, and a high rate of recurrence, oral cavity squamous cell carcinoma (SCC) is a challenging disease associated with poor outcomes. According to a recent study, neoadjuvant nivolumab alone or in combination with ipilimumab may be a safe and effective treatment for patients with oral cavity SCC undergoing surgical resection. In this interview, Jonathan Schoenfeld, MD, MPH, Associate Professor of Radiation Oncology at Harvard Medical School and first author of the study, speaks with i3 Health about the benefits of neoadjuvant nivolumab/ipilimumab, discusses the future of treatment for oral cavity SCC, and shares his advice regarding how to optimize outcomes for patients with this disease.
What are some of the most challenging aspects of treating patients with oral cavity SCC who are undergoing surgical resection?
Jonathan Schoenfeld, MD, MPH: Oral cavity SCC is a challenging disease to treat. First, outcomes have been historically poor. Many patients have significant smoking or alcohol histories or other health problems such as cardiovascular diseases. Despite intense treatment, these patients have a high rate of recurrence. The tumors can come back and then be incurable, subsequently leading to high mortality rates over the first few years after treatment.
The second challenging aspect is that the treatment itself is very difficult for these patients. The current standard of care is upfront surgery followed by adjuvant treatment based on pathology, usually either radiation or a combination of radiation and chemotherapy. Surgery to this area in the oral cavity—often the tongue, the gums, or other areas of the mouth—can be very morbid. These areas and the oral cavities are obviously important for speaking and swallowing, and surgery can have permanent impacts on these functions and on quality of life. Then you add in the side effects of the subsequent radiation with or without chemotherapy, and we're talking about a significant effect on quality of life for these patients.
It's a long treatment, and the acute recovery period can last up to six months, if not longer. This is time that patients have to take off from work, and they may need help from their families or be unable to take care of their families. The radiation can cause permanent effects in terms of dry mouth and dental effects. Chemotherapy typically has side effects that can include permanent neuropathy, hearing issues, or kidney issues.
These patients have a really intense treatment, in terms of both short-term effects and reduced quality of life for the rest of their lives. Ultimately, despite all of these intensive treatments, many of them will still relapse. It really is a challenging disease to treat.
What is the significance of your results regarding the efficacy of neoadjuvant nivolumab alone or in combination with ipilimumab for patients with oral cavity SCC?
Dr. Schoenfeld: Our study was a phase 2 randomized trial testing either two doses of nivolumab alone or two doses of nivolumab in combination with one dose of ipilimumab, a CTLA-4 inhibitor, over a period of about three weeks prior to surgery. The first thing that we found is that both regimens were tolerated prior to surgery, and neither of them delayed the surgery date in any of the patients enrolled in the trial. This was significant because we obviously want to get these patients to surgery, as it's potentially curative. There was a concern that the side effects and toxicities from the two regimens would prevent patients from undergoing surgery, but we didn't see any delays with this schedule and were able to get patients to the operating room on time, in a similar time span to what would have occurred if they had not enrolled in the study.
That was particularly significant with the patients who received the combination of nivolumab and ipilimumab, because the addition of ipilimumab has historically increased the rates of toxicity, particularly severe toxicities, in patients who had undergone this treatment. We really didn't see that: while there were some increased toxicities, none of them delayed the time to the operating room. In all of these patients, the treatment was well tolerated.
The other significant aspect is that even in a relatively short treatment window of about three weeks or so, we saw evidence of response in most patients. This ranged from evidence of tumor shrinkage on exam to shrinkage on scans. In a lot of patients, we also saw evidence of pathologic response. In a few patients, particularly those treated with the combination of nivolumab and ipilimumab, we actually saw a near complete or even a complete pathologic response: the study shows evidence that even in just a few weeks, the immune system was able to cause regression of most, if not all, of some of these oral cavity cancers in a few patients. Even though the study wasn't designed to prove that the immunotherapy had a beneficial effect on disease recurrence rates and overall survival, early follow-up shows that those rates of recurrence and survival look very promising.
How do you see the treatment of oral cavity SCC evolving in the coming years?
Dr. Schoenfeld: One thing that we know is that immunotherapies such as nivolumab work for patients with oral cavity cancer who have metastatic disease. We're currently studying how best to integrate immunotherapy earlier in the disease process. This study and others are looking at giving immunotherapy prior to surgery, and there are actually large phase 3 trials now underway to test that approach. Other studies are looking at adding immunotherapy after surgery or after chemotherapy and radiation. I think one of the ways in which we can try to improve results for these patients is by adding in immunotherapy earlier in their treatment.
The other way that I see oral cavity cancer treatment changing is the development of more targeted treatments: new surgical approaches, use of sentinel lymph node biopsy for earlier stage cancers, and more targeted radiation approaches. Surgical and radiation approaches, as well as technology, are becoming more targeted, and hopefully we can integrate additional immune and genetic biomarkers to help guide treatment even further.
Do you have any words of advice for members of the cancer care team treating patients with oral cavity SCC?
Dr. Schoenfeld: This study and others like it really highlight the importance of treating these patients in a multidisciplinary setting, even early on in their treatment. Historically, these patients have been treated upfront by surgeons with surgical resection, but as new options become available over the next few years, it will be important for them to be seen in a multidisciplinary setting—not just by surgeons, but also by radiation oncologists and medical oncologists—in order to think about how to best integrate radiation, chemotherapy, and immunotherapy earlier on. Because treating these patients is very challenging, a multidisciplinary team that includes a speech language pathologist, nutritionist, dentist, and social worker really helps to maximize their care. There is a lot of variability in head and neck cancer and oral cavity cancer. It's really important to consider each case individually. In the context of our study, we discussed all of our patients in a multidisciplinary tumor board and reviewed their progress as they were going through their treatment. As new approaches are developed, it's becoming even more important to have good communication across the multidisciplinary treatment team.
About Dr. Schoenfeld
Jonathan Schoenfeld, MD, MPH, is an Associate Professor of Radiation Oncology at Harvard Medical School and a senior physician at Dana-Farber Cancer Institute. He specializes in the treatment of melanoma and head and neck cancers, including salivary gland cancer, throat cancer, thyroid cancer, and oral cavity carcinoma. Dr. Schoenfeld's research interests include tumor immunology, cancer epidemiology, immunological effects of radiation therapy, and the development of novel therapies combining immunotherapy and radiation. He has authored or coauthored numerous peer-reviewed publications focused on improving outcomes in patients with melanoma and head and neck cancers.
For More Information
Schoenfeld JD, Hanna GJ, Jo VY, et al (2020). Neoadjuvant nivolumab or nivolumab/ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2020.2955
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.