Implementable Changes Could Improve QOL With Radiation-Related Mucositis in Head and Neck Cancer

Anurag Singh, MD

Oral mucositis remains a challenging toxicity to manage in patients with head and neck cancers who are undergoing radiation therapy, said Anurag Singh, MD, who added that altering the time of day patients undergo therapy, improving prophylactic management strategies, and minimizing the use of narcotics could translate to improved quality of life (QOL) in this patient population.

“It remains important for all clinicians [who treat patients with] head and neck cancers to continue thinking about ways we can improve patient experience during as well as after therapy. Until patients have optimal QOL, there is still a need to develop new approaches,” said Singh, a professor of oncology, director of Radiation Research in the Department of Radiation Medicine, co-leader of the Cell Stress and Biophysical Therapies Program, and associate dean of graduate medical education and research at Roswell Park Comprehensive Cancer Center.

Findings from a retrospective analysis that were published in Cancer Epidemiology, Biomarkers & Prevention demonstrated a significant association between radiation treatment time and oral mucositis severity in patients with head and neck cancer.¹ The severity was lowest for patients treated between 8:30am and 9:30am, increased and peaked between 11:30am and 3:00pm, and decreased substantially after 3:00pm.

Historically, opioids were used for pain management from radiation-related oral mucositis in patients with head and neck cancer; however, to decrease the need for narcotics, prophylactic gabapentin (Gralise) was evaluated. The results of another retrospective study that were published in the International Journal of Radiation Oncology, Biology, Physics showed that prophylactic gabapentin was effective and safe in patients with head and neck cancer undergoing radiation therapy or chemoradiotherapy.² Moreover, a significant decline in opioid requirement during treatment was noted, with patients achieving similar pain improvements as observed with narcotics.

These findings supported the integration of prophylactic gabapentin into the National Comprehensive Cancer Network (NCCN) guidelines for pain related to oral mucositis in patients with head and neck cancer.³

In an interview with OncLive®, Singh, who is also a professor of medicine at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, discussed the potential advantage to treating patients with radiation therapy at specific times of day, how the utilization of prophylactic gabapentin has decreased the need for narcotics in managing oral mucositis in patients with head and neck cancer, and the potential use of single-fraction radiation therapy in oncology.

OncLive®: What was the rationale to evaluate time of day as a factor for outcomes and QOL in patients with head and neck cancer undergoing radiation therapy?

Singh: For many years, there has been quite a bit of interest as to [how] circadian rhythm or the daily variation in our sleep-wake cycles affects patients and the consequences of how those effects impact radiation therapy. Prior studies have looked at patients who were treated early in the morning or late in the afternoon to try to compare treatment outcomes, including toxicity. Although those studies did not find any significant differences [in outcomes], our experimental work [at Roswell Park suggests] there should be differences.

Therefore, we designed a retrospective [study] to look at the exact time of patients’ treatment. We didn’t just look at early in the morning vs late in the afternoon.

We found a strange variation where patients who were treated in the middle of the day had the worst adverse effects compared with patients who were treated early in the morning or late in the afternoon. In one sense, [these data] explain what the previous, randomized trials hadn’t shown: a difference between early morning and late afternoon. In another sense, they left us with more questions about what is happening in the middle of the day to cause increased toxicity.

How can the results of this study inform clinical decisions?

The study was run in patients with head and neck cancer where mucositis or radiation-related toxicity significantly affects QOL and a patient’s ability to tolerate treatment through the course. A significant impetus exists to try to understand what the consequences of treatment time are because that is something that, in theory, could be easily modified. We could change when the patient was being treated without changing their chemotherapy schedule or radiation intensity.

That is effectively what we’ve done. As a result of our study, we have tried to treat patients mostly early in the morning or late in the afternoon with a break in the middle of the day.

What questions are ongoing research efforts seeking to answer regarding radiation therapy?

Many unmet needs [exist] with radiation therapy, which is one of the pillars of cancer care along with medical oncology and surgery. However, so many aspects [factor into] what makes one patient respond and a patient with similar age, ethnicity, and tumor stage not respond. Trying to figure out what aspects of treatment are driving or mitigating that response is a key element of what we are trying to do so that we can improve cancer care for all patients.

How does oral mucositis affect patients’ QOL? What benefit can prophylactic gabapentin offer to patients with head and neck cancer who are at risk of developing oral mucositis?

In head and neck cancer, pain can be from the tumor itself, which has significant effects on the patient’s QOL. The best treatment for that is to shrink the tumor or remove it entirely, in which case we are talking about treatment.

Mucositis is inflammation of the mucosa that results from therapy, such as chemotherapy or radiation therapy. The mucosa is damaged, then inflamed, and patients experience pain as a result. Our approach [to utilizing] gabapentin [was based on the question of]: What happens if those nerve endings never turn on? It turns out that most of the nerve endings in the body are quiescent at most times. However, when there is injury, they become active. Therefore, the thought was that if we started with the gabapentin early, that could prevent the nerve endings from ever turning on.

Prior to instituting gabapentin, 90% of patients or more would need narcotic therapy by the end of treatment. We were trying to see if we could lessen the need for narcotics.

We found that increasing doses of gabapentin in the way we [gave gabapentin] in the study, decreased the times narcotics were necessary and the total amount of narcotics utilized. Since that study, we have escalated the dose of gabapentin further. Now we are giving 1200 mg [of gabapentin] 3 times a day. We haven’t done the formal analysis yet, but anecdotally, we’ve found that this further decreased the need for narcotics. In our prior study, about half of patients could [be spared] narcotics, whereas now, almost 90% of patients can be treated throughout the duration of therapy without needing narcotics.

How often are opioids misused in patients with head and neck cancer?

That is a difficult question for me to answer because, in my personal experience, the number of long-term patients who have had difficulty with narcotic abuse has been vanishingly small. However, it must be remembered that I wasn’t testing patients. Of course, a significant number of patients in the population are at risk for developing abuse [of narcotics]. Any exposure [to narcotics] increases those risks.

The best information we have is that some percentage of patients who are exposed to narcotics for cancer therapy will develop a dependence on them that will persist beyond the duration of their cancer therapy. It is a real issue and one that we take very seriously.

[Limiting narcotic use] was one of the main factors that animated our initial gabapentin study. We wanted to avoid exposing patients to narcotics while maintaining their QOL during therapy.

Why is it important to develop alternative methods to address pain in patients with head and neck cancer?

Multiple methods are necessary because going through cancer therapy, particularly in the head and neck where there are so many nerve endings, is an inherently difficult process. [It is also] one that can be exceptionally lengthy when we factor in the time that chemotherapy is given, as well as surgery, radiation, and recovery thereafter. We are talking about a potentially very long time that now with [the integration of] immunotherapy could span years. Therefore, QOL during cancer therapy is very important.

Beyond opioids and gabapentin, what alternative strategies could patients experiencing radiation therapy–related oral mucositis turn to for pain management?

Acupuncture has been tried. We are trying cranial electrical stimulation in our clinic as well to determine whether electro-mechanical methods can improve pain. Our recently completed study looked at anti-depressants in patients with head and neck cancer to see if that could optimize QOL and pain control. Patients can look at a variety of other aspects, as well as biofeedback, to improve QOL.

How could the integration of single-fraction stereotactic body radiation therapy (SBRT) further refine the use of radiation therapy in patients with cancer?

We have developed novel ways of treating localized lung cancer using high-dose, targeted radiation therapy. Because this is a new technique, it wasn’t intuitively obvious what the right number of treatments were, so we looked at anywhere from 12 treatments, down to 5, and down to 1.

We were interested in how we could develop this single treatment because many of our patients at Roswell Park [travel] many hours from quite a distance for treatment. If we are giving them 5 or 12 treatments, it is inconvenient and a significant burden to them.

We developed single-fraction SBRT for these patients through a variety of studies comparing single-fraction with 3- or 4-fraction SBRT in a prospective fashion. We also did retrospective comparisons with 5-fraction treatments.

We found that in each case the single-fraction SBRT was as good as the more than 1–fraction treatment. As a result, we were able to develop a therapy that is as good for the patient, has lower costs, and is far more convenient.

Additionally, we think there are advantages to the immune system in terms of giving a tumor-vaccinating dose. We are excited to take this concept from localized lung cancer [and bring it] to other types of cancers that have potentially spread to up to 5 sites. We can now approach [those patients] with a single radiation treatment to see if we can improve that patient’s total lifespan while maintaining their QOL by utilizing these local therapies, even in the metastatic setting without many sites of disease.

References

1. Gu F, Farrugia MK, Duncan WD, et al. Daily time of radiation treatment is associated with subsequent oral mucositis severity during radiotherapy in head and neck cancer patients. Cancer Epidemiol Biomarkers Prev. 2020;29(5):949-955. doi:10.1158/1055-9965.EPI-19-0961
2. Mandia JJ, Wang H, Padmanabhan R, et al. Prophylactic gabapentin results in dramatic reduction of narcotic utilization in head and neck cancer patients undergoing radiotherapy. Int J Radiat Oncol Biol Phys. 2020;108(3):S160-S161. doi:10.1016/j.ijrobp.2020.07.924
3. Pfister DG, Spencer S, Adelstein D, et al. Head and neck cancers, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(7):873-898. doi:10.6004/jnccn.2020.0031