Investigators Seek to Supplant Oropharyngeal SOC With Proton Therapy

OncologyLive, Vol. 21/No. 9, Volume 21, Issue 09

Partner | Cancer Centers | <b>MD Anderson</b>

Hoping to minimize the off-target effects associated with radiation in patients with oropharyngeal cancer, investigators are testing the hypothesis that intensitymodulated proton therapy can deliver doses as effectively as the current standard of care with less damage to surrounding tissue.

Steven J. Frank, MD

Hoping to minimize the off-target effects associated with radiation in patients with oropharyngeal cancer, investigators are testing the hypothesis that intensitymodulated proton therapy (IMPT) can deliver doses as effectively as the current standard of care (SOC) with less damage to surrounding tissue.

In a phase 2/3 trial (NCT01893307), investigators will randomize 440 patients with advanced stage oropharyngeal cancer to IMPT or intensity-modulated x-ray therapy (IMRT), the therapeutic standard in this disease setting.1

“Oropharyngeal cancer is a very curable disease, but the toxicities associated with curative options are very high and can translate into loss of taste, feeding tube dependency, and potentially loss of life,” said Steven J. Frank, MD, principal investigator of the study’s site at The University of Texas MD Anderson Cancer Center in Houston.

Although the efficacy of IMRT in the treatment of head and neck malignancies such as oropharyngeal cancer has been established, this modality can be highly toxic and is known to induce grade 3 or 4 adverse events (AEs) in patients. Beyond loss of taste, feeding tube dependency due to dysphagia, and death, IMRT AEs include severe mucositis, trismus, aspiration pneumonia, and compromises in salivary function that can lead to difficulty in eating. These toxicities become long term in approximately 12% of patients, said Frank, who serves as the executive director of the Particle Therapy Institute at MD Anderson.1

The prevalence of high-grade AEs that follow IMRT can be attributed to the intervention’s delivery of radiation. “When radiation enters the patient, it enters at a higher dose [than IMPT] and affects normal tissues,” Frank said. “After the radiation hits the tumor, it continues to exit beyond the tumor, impacting surrounding tissues.” This emanating radiation causes “collateral damage” in the oral cavity, brain stem, salivary glands, and larynx, he added.

IMPT offers a targeted alternative to IMRT that can deliver curative radiation at a lower dose. Specifically, the advanced form of proton therapy can transmit radiation at 25 to 40 fewer Gy.1

“25 Gy is equivalent to roughly 12,500 CT [computed tomography] scans or 5 million oral dental x-rays. When we think about the amount of unnecessary radiation that we can eliminate, this is significant,” Frank said.

During IMPT treatment, protons are layered onto tumors, allowing radiation to strike these precisely defined target areas rather than extend beyond the tumor to healthy tissue. “Proton therapy is a unique form of radiation that has different physical properties than conventional x-rays, and these properties minimize the radiation that comes into the body and allow the radiation to maximize its effect on the tumor without an exit dose into patients’ normal tissues,” Frank said. Developing methods to de-intensify treatment is a priority in oropharyngeal cancer, and 1 way to attenuate therapy is to lower the dose of Gy that a patient receives. However, 15% to 20% of patients who receive the standard dose will nevertheless present with recurring disease, Frank said. “What we are aiming to do with protons is to deintensify by limiting dose to normal tissues, focusing on the tumor itself,” he added.

In the phase 2/3 study, patients will receive either IMPT or IMRT at 70 Gy once per day, 5 days per week, for a maximum of 33 treatments with chemotherapy. The primary end point is the 3 year progression- free survival (PFS). Secondary end points include the cumulative incidence of late-onset grade 3 to grade 5 toxcities with IMPT versus IMRT, patient reported outcomes, and overall cost-effectiveness (Figure).

Preclinical Data Show Promise

Figure. IMPT Versus IMRT in Oropharyngeal Cancer of the Head and Neck (Click to Enlarge)

Results showed that treatment with IMPT provided tumor control with fewer AEs than IMRT. Investigators observed a total of 22 events (specifically, recurrence or death) across both treatment groups. These events were lower in the IMPT group (7 vs 15), translating to a 3-year PFS rate of 86.4% in the IMPT arm and 85.8% in the IMRT group (HR, 1.02; 95% CI, 0.41-2.54; P = .96).2

There were no significant differences in acute grade ≥3 dermatitis or mucositis between the IMPT and IMRT arms, investigators said. Importantly, there was a trend toward lower prevalence of grade 3 weight loss 1 year after treatment among those who received IMPT (OR, 0.28; 95% CI, 0.08-1.05; P = .06).2

Findings indicated that patients in the IMRT group were more likely to have >20% weight loss or need a gastrostomy (G)-tube 3 months after therapy (34% vs 18%). This trend continued 1-year post RT, when 24.7% of IMRT recipients experienced these toxicities compared with 8% of patients in the IMPT arm. In the context of the study’s predefined composite index of G-tube use or grade 3 weight loss, the odds ratios were 0.44 at 3 months (95% CI, 0.19-1.0; P = .05) and 0.23 at 1 year (95% CI, 0.07-0.73, P = .01).

Use of a G-tube at the acute phase correlated with decreased overall survival (OS) and PFS in both the univariable and multivariable analyses. However, there was no statistically significant difference in OS (HR, 0.55; 95% CI, 0.12-2.50; P = .44) or PFS (HR, 1.02; 95% CI, 0.41-2.54; P = .96) with IMPT or IMRT, investigators said.2

IMPT’s capacity to reduce the occurrence of AEs compared with IMRT was further demonstrated in a study of 26 patients with newly diagnosed oropharyngeal cancer who were treated with IMPT between 2011 and 2012. Investigators extracted 26 IMRTtreated controls from MD Anderson’s database of patients with the disease who received treatment between 2000 and 2009. Insertion of a G-tube was more common among patients treated with IMRT (49%) versus IMPT (19%; P = 0.039).3 “These preliminary data have driven our motivation and excitement over this trial,” Frank said.

Expanding the Oropharyngeal Tool Kit

Despite the potential benefit of this proton-driven approach, the modality has not been broadly adopted in head and neck cancer in part because IMPT’s ability to reduce the occurrence of AEs at its lower dose has not yet been demonstrated in a randomized trial. Historically, the disease was not treated with conventional means of proton delivery such as passive scattering, according to Frank.1

Of note, MD Anderson was the first cancer center in the nation to develop and deploy pencil beam scanning, which generates a pattern of protons specific to a patient’s tumor location, shape, and size. The precision therapy enables clinicians to “customize the proton beam” to the tumor: “We can increase the intensity of protons where there’s more volume of cancer and scale it back when there’s less,” Frank said.4

A “unique modality that allows IMPT to occur,” pencil beam scanning makes dose control—and dose reduction—possible. “We can deliver radiation that conforms with the tumor in a similar manner that we can with IMRT but at a lesser dose,” Frank said.

Another limitation to the widespread use of IMPT in oncology is the intervention’s higher cost compared with IMRT.1 “We see a lot of insurance companies balk at authorization for the treatment, therefore not allowing patients to receive IMPT,” Frank said.

Although IMPT is more expensive than IMRT, the less-toxic nature of the therapy could cause IMPT to be a more cost-effective option than IMRT. For example, IMPT could spare patients and insurance companies the cost of G-tubes, emergency department visits, and hospitalizations.1 Frank says he believes that data from the phase 2/3 trial can have practice-changing implications in oropharyngeal cancer, both from a therapeutic and a payer standpoint. “If we’re able to [show efficacy] and reduce [adverse] events, IMPT could have a major impact on this disease for patients,” Frank said.

As of March 2020, more than 270 patients have enrolled in the study. “We have [launched] this trial in collaboration with 11 other institutions, and we will have another 12 institutions coming on within the year that will include international sites in Holland,” Frank said. Investigators hope to complete the trial by September 2021 and subsequently report data, he added. The trial is currently recruiting patients nationwide.


  1. Strubberg BC. Intensity-modulated proton therapy for oropharyngeal cancer. The University of Texas MD Anderson Cancer Center. Published March 2017. Accessed March 30, 2020. modulated-proton-therapy-for-oropharyngeal-cancer. h12-1591413.html?_ga=2.154357688.1065647073.1585447002- 1715419394.1560784478
  2. Blanchard P, Garden AS, Gunn GB, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer — a case matched analysis. Radiother Oncol. 2016;120(1):48-55. doi:10.1016/j. radonc.2016.05.022
  3. Frank SJ, Rosenthal DI, Ang K, et al. Gastrotomy tubes decrease by over 50% with intensity modulated proton therapy (IMPT) during the treatment of oropharyngeal cancer patients: a case-control study. Int J Rad Oncol. 2013;87(2):S144. doi:10.1016/j.ijrobp.2013.06.371
  4. Carter D. Pencil beam proton therapy: what to know. The University of Texas MD Anderson Cancer Center. Published August 7, 2019. Accessed March 13, 2020. publications/cancerwise/2019/08/pencil-beam-proton-therapy- -what-to-know.html?_ga=2.208427610.935718343.1584035391- 1715419394.1560784478

The hypothesis that IMPT can provide tumor control with fewer AEs than IMRT is supported by data from an observational study of 50 adults with oropharyngeal cancer who were treated with spot-scanning IMPT. In the analysis, investigators performed a 1:2 matching of patients who received IMPT for their disease with patients who received IMRT (n = 100).2