Proton Beam, Gabapentin Improve Care in Head and Neck Cancer

Pam Harrison

November 06, 2020

Two new approaches are improving care for patients with head and neck cancer. One is proton beam therapy, which yields less toxicity and better swallowing and quality-of-life outcomes compared to conventional radiotherapy. The other is gabapentin used prophylactically before radiotherapy, which reduces the need for opioid pain relief afterward.

Both approaches were discussed at virtual American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, where two new studies were presented.

"As a head and neck cancer expert, I consider the combination of proton beam therapy and gabapentin to be the most significant change moving forward in terms of mitigating the acute and the chronic toxicity [from radiotherapy] in our patients," commented Gopal Bajaj, MD, associate professor of radiation oncology at the University of Maryland, in College Park, Maryland. He was senior author on the study of prophylactic gabapentin.

"We're now seeing a preponderance of human papillomavirus [HPV]–related oropharyngeal cancers, and these patients are in their 40s and 50s and are otherwise healthy and have a significant life span ahead of them," commented Samir Patel, MD, associate professor of radiation oncology, Mayo Clinic, Scottsdale, Arizona. He was lead author on the study of proton beam therapy.

The standard of care for such patients is surgery followed by radiotherapy or chemoradiotherapy.

"When you radiate the throat, you end up with significant taste changes and pain, and this can lead to opioid needs for pain management as well as feeding tubes to maintain weight, and these changes can linger on, especially taste alterations." Patel explained.

Because proton beam technology can more precisely focus radiation on the target area at risk in the neck, "we can avoid any radiation scatter to the throat," he continued. The new study showed that it was associated with less toxicity, and "we found benefits in pain, swallowing, senses, speech, contact, and mouth opening over time," he said.

Proton Beam Therapy vs IMRT

Patel's study was conducted in 61 patients with stage III/IVA oropharyngeal cancer (92% were men, and more than 98% tested positive for HPV 16). These patients underwent transoral surgical resection with neck dissection. Adjuvant radiotherapy was indicated, owing to pathologic nodal findings.

Three quarters of the patients (76%) were treated with adjuvant proton beam therapy delivered to the at-risk nodal regions only. The remaining 24% received conventional intensity-modulated radiotherapy (IMRT), owing to insurance denial.

Thirty-eight percent of patients also received concurrent chemotherapy.

Patient-reported outcomes were measured prior to administering radiotherapy and at 3 and 12 following treatment using the EORTC HN-QLQ 35 survey and modified barium swallow impairment profiles.

In virtually all measures of quality of life, the patients who were treated with proton beam therapy fared significantly better than those who received IMRT (P < .04), although the results for the symptom of dry mouth did not reach statistical significance.

Table. Grade 2 or Higher Adverse Events Over Time

  Baseline (%) During treatment proton beam therapy (%) During treatment IMRT therapy (%) Three months later, proton beam RT vs IMRT (%) Twelve months later, proton beam RT vs IMRT (%)
Dry mouth 3 11 53 9 vs 18 2 vs 13
Dysphagia 5 14 65 2 vs 0 0
Mucositis 0 18 29 0 0
Nausea 0 5 29 0 0
Dysgeusia 2 16 77 5 vs 6 0 vs 6
Dermatitis 0 82 59 5 vs 0 0
Fatigue 0 2 18 2 vs 0 0 vs 6
Weight loss 0 0 18 0 0


In total, there were only six grade 3 events among patients who received either form of radiotherapy, and none were reported 3 months or later after receiving radiotherapy.

The proton beam therapy was so well tolerated by one of the patients in the study that he went snowboarding a day after he completed the proton beam protocol. By contrast, with conventional radiotherapy, most patients typically need 1 month or longer to recover, Patel commented.

Gabapentin Reduces Opioid Use

The other study showed benefits from the prophylactic use of gabapentin in head and neck cancer patients who underwent radiotherapy. In particular, there was less need for opioids for pain relief.

This study evaluated 139 patients with head and neck cancer who were treated with radiotherapy/chemoradiotherapy plus prophylactic gabapentin. Outcomes for these patients were compared with those for 49 matched historical control patients who did not receive the prophylactic protocol.

"The majority of patients were treated comprehensively, with 70% receiving concurrent chemoradiation, at a median radiation dose of 70 Gy," commented lead author Jeremy Mandia, MD, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

For all patients, treatment with gabapentin was initiated during the first week of radiotherapy. Doses were titrated up to 300 mg three times a day by day 3. Doses were increased up to 1200 mg three times a day for those with pain scores of 3 or greater. (For slightly older patients, titration was similar, but the titration interval was slower). By week 7 of radiotherapy, 35% of patients required 3600 mg of gabapentin a day, given in three divided doses.

At the same point in time, "opioids were needed for pain control in 39% of the prophylactic gabapentin group compared with 78% of patients who did not receive prophylactic gabapentin," Mandia reported. This represents a 50% reduction in the need for opioids to achieve adequate pain control, he noted.

Prophylactic gabapentin was also associated with a longer median time to first narcotic requirement. First opioid use occurred 2 weeks later than was seen in the group that did not receive prophylactic gabapentuin. Also, for the patients who received prophylactic gabapentin, the median total duration of opiod use was less by 7.3 weeks.

At week 7, only 9% of patients in the gabapentin group required an opioid dose >100 morphine milligram equivalents, compared with 50% of the control group. No differences were noted in grade 3 or greater mucositis, dermatitis, or fatigue between the two groups, although there was slightly more pharyngitis in the prophylactic gabapentin group.

"Prophylactic gabapentin in head and neck cancer patients undergoing radiation therapy or chemoradiation therapy was found to be associated with markedly reduced incidence, duration, and quantity of opioid use," Mandia concluded. He noted that doses of up to 3600 mg/d were well tolerated, and there was not a significant increase in toxicity.

Bajaj, who was senor author on this study, put the findings into a larger context.

"Many head and neck cancers are cured with a combination of either radiation alone or radiation plus chemotherapy, so radiation is the backbone modality for most of these patients," he told Medscape Medical News. However, the standard course of radiotherapy involves treatment 5 days a week for a total of 7 weeks, and by week 7, daily radiotherapy can wreak havoc on the highly enervated tissues within the mouth, throat, and tongue.

"As the weeks of radiation therapy go on, there is a compounding effect of tissue and mucosal injury that is conferred by the treatment, and patients are in a lot of pain," Bajaj explained.

Early in the development of gabapentin, it was noted that the drug could treat pain involving atypical pathways, including pain mitigated through the nervous system pathway. In contrast, with the use of narcotics for mucosal pain, "we are actually treating it wrong, because the narcotics saturate pain receptors, but these pain receptors are not what are being activated through mucosal injury in head and neck cancer — it really is irritation of the nerve fibers," he noted.

Some time ago, Bajaj inadvertently discovered that patients who received gabapentin within the first week of undergoing radiotherapy were much more likely not to need any narcotics, in contrast to those who received it later in the course of therapy. "We would see them during the last week of treatment and saw very severe tocicity, but they would have a pain score of zero — it was amazing," he said.

Hence, Bajaj and colleagues started initiating treatment with prophylactic gabapentin early and in very high doses, much higher than the currently recommended maximum dose of 2700 mg/d.

"The main thing that sets our study apart is the timing of when we started it and the maximal dose of where we went with it," he added.

"And if clinics are not doing both of those things, they are not going to appreciate the full impact of this protocol in terms of narcotic reduction," Bajaj emphasized.

"Prevents the Need for Opioids"

Asked to comment on the use of prophylactic gabapentin in head and neck cancer patients, Anurag Singh, MD, Roswell Park Comprehensive Cancer Center, Buffalo, New York, told Medscape Medical News that prophylactic gabapentin prevents the need for opioids. "By the time the patient is experiencing pain, it is too late to start gabapentin and expect an effect on its own," he commented.

"That said, gabapentin can potentiate the effect of narcotics ― but that was not studied in this research," he added. In a study he led, Singh and colleagues treated 60 patients with stage II to IV head and neck cancer with either high-dose gabapentin (2700 mg/d), or the institutional standard of hydrocodone with or without acetaminophen, progressing to fentanyl as needed.

Only 7% of patients in the high-dose gabapentin arm required an opioid during treatment, compared with 42% of patients in the standard-of-care arm. "In my experience, some very elderly patients cannot tolerate dose escalation of gabapentin, due to gait instability," Singh cautioned. "So in these patients, we often restrict them to very low doses, like 300 mg/d," he said.

There is also a risk for renal toxicity, although it is rare. It can be corrected by lowering the dose, he added.

Patel, Baja, Mandia, and Singh have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting: Abstracts 1096 and 1094. Presented October 27, 2020.

For more from Medscape Oncology, join us on Twitter and Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.