Intensity-Modulated Radiation Therapy and Intensity-Modulated Proton Therapy—2 Effective Treatment Modalities for Nasopharyngeal Cancer | Head and Neck Cancer | JAMA Network Open | JAMA Network
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Invited Commentary
June 18, 2021

Intensity-Modulated Radiation Therapy and Intensity-Modulated Proton Therapy—2 Effective Treatment Modalities for Nasopharyngeal Cancer

Author Affiliations
  • 1Department of Radiation Oncology, Memorial Cancer Institute, Memorial Healthcare System, Pembroke Pines, Florida
JAMA Netw Open. 2021;4(6):e2113650. doi:10.1001/jamanetworkopen.2021.13650

Elsewhere in JAMA Network Open, Li et al1 report their institutional experience to examine survival and toxic effects among patients with nasopharyngeal cancer treated with photon-based intensity-modulated radiation therapy (IMRT) or intensity-modulated proton radiotherapy (IMPT). The study found excellent disease control outcomes in patients treated with either modality. There was a modest reduction in grade 2 and higher toxic effects seen among patients treated with IMPT.

IMPT is a powerful technology with great promise to improve the delivery of radiation to tumors while sparing normal tissue. A largely unanswered question regarding IMPT is whether there is a significant benefit in terms of tumor control and toxic effects between it and IMRT. Ideally, large randomized clinical trials could be performed to directly determine what benefits, if any, exist for IMPT vs IMRT, but unfortunately, these studies have been difficult to perform.2 In recognition of the elusiveness of randomized clinical trials comparing IMPT with IMRT, other methods have been used to ascertain the potential clinical benefit of IMPT. This includes retrospective studies with statistical techniques to attempt to account for differences in patient and disease characteristics between treatment groups.

In the propensity score–matched survival analysis in the study by Li et al,1 there were no statistically significant differences in locoregional failure–free survival, progression-free survival, distant metastasis–free survival, or overall survival. These findings are reassuring that both IMRT and IMPT are highly effective at achieving the primary goal of treatment, which is disease control. These results are also concordant with other studies showing high rates of tumor control for nasopharyngeal cancer with IMRT techniques.3 Given the excellent disease control outcomes for IMRT and IMPT, improvement of treatment involves reducing toxic effects.

It is important to consider how Common Terminology Criteria for Adverse Events (CTCAE) toxic effect scoring was assessed in the present study. In prospective trials, CTCAE questionnaires are completed by physicians at regular intervals during and after treatment. This ensures consistent and objective measurement of toxic effects and facilitates comparison between treatment arms. In retrospective nonrandomized trials, toxicity assessment can be more difficult. In many cases, this assessment is done by medical record review, but this can be limited by incomplete or missing data. It is not clear how any missing toxicity data was handled in this analysis. Furthermore, recording of toxic effects could not be done in a blinded fashion (ie, the person assessing toxic effects was aware of which treatment modality the patient was receiving). This raises the potential for bias in scoring toxic effects between treatment modalities.

As the authors noted, differences in grade 3 or higher toxic effects appeared numerically lower in the IMPT group than the IMRT group, but this did not achieve statistical significance. A review of toxic effects between patient groups (eTable 2 in the Supplement) reveals a statistically significant benefit for IMPT in all toxicity domains except oral pain and dermatitis. Most notably, there was a statistically significant reduction in weight loss (grade ≥2 weight loss, IMRT group: 59%; IMPT group: 36%; P < .001). This is important because weight loss is a quantitative toxicity measurement that is not subject to many of the ascertainment issues described previously and, thus, is a very reliable indicator of patient toxic effects. Weight loss during radiation treatment for nasopharyngeal cancer has also been shown to be associated with inferior patient outcomes and, thus, is a highly clinically significant end point.4

When assessing toxic effects between the 2 treatment groups in the study by Li et al,1 an important consideration is that there was a statistically significant difference in the type of chemotherapy received by patients treated with IMPT vs IMRT. High-dose (bolus) cisplatin was used in 57% of patients in the IMPT group but only 25% of patients in the IMRT group. It has been shown that the toxic effects of high-dose cisplatin are greater than those of weekly cisplatin.5 The increased use of bolus cisplatin in the IMPT group makes the toxic effects results even more impressive, as it appears that the normal tissue-sparing benefit of IMPT treatment is able to overcome, at least to some extent, the greater toxic effects from more aggressive chemotherapy.

In any nonrandomized study, there is always concern for an inherent difference in patient groups that may explain differences in outcome (confounding) that may otherwise be ascribed to the intervention being studied. One potential source of confounding in this study is patient socioeconomic status (SES). Patients with higher SES and better access to resources could have better access to nutritional support, dental care, speech pathology, and other home care services. This higher level of support could result in improved tolerance of treatment and less overall toxic effects. As the authors indicated, insurance coverage did play a role in determining treatment modality for some patients. Additionally, the authors stated that some patients were unable to make travel arrangements to the IMPT facility and therefore received IMRT. These factors support the possibility that SES may be a confounding variable between patients receiving IMRT and IMPT in this study.

Despite the apparent benefit of reduced toxic effects among patients receiving IMPT and IMRT in this study, the results need to be viewed in context. These results are based on a small sample of only 28 patients in the IMPT group. Most of the toxic effects seen in the study were grade 1 or 2, and minimal grade 3 toxic effects were noted in either the IMRT or IMPT group. Does a modest reduction in grade 2 or higher toxic effects justify the significantly increased cost of proton therapy? Furthermore, do these modest reductions in acute grade 2 or higher toxic effects during treatment result in any significant long-term benefit to patients or meaningful impact on patient quality of life?

The results of this study do not support the conclusion that IMPT is superior to IMRT for nasopharyngeal cancer, nor that IMPT is the new standard of care for nasopharyngeal cancer. What the study does demonstrate is that both IMPT and IMRT modalities are highly effective in the treatment of nasopharyngeal cancer, and that IMPT may be associated with a modest reduction in grade 2 or higher toxic effects. The findings of this study highlight the need for prospective research to better inform treatment decisions. While large phase 3 trials comparing IMPT and IMRT for nasopharyngeal cancer may never be performed, there would be substantial benefit in the enrollment of patients in robust phase 2 trials of IMPT to collect detailed patient outcome and toxicity data. Incorporation of patient-reported outcomes should be included in these trials to provide a more complete picture of patient toxic effects.6 These types of studies will help quantify the role that IMPT may have in the future treatment of head and neck cancer.

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Article Information

Published: June 18, 2021. doi:10.1001/jamanetworkopen.2021.13650

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Falchook A. JAMA Network Open.

Corresponding Author: Aaron Falchook, MD, Department of Radiation Oncology, Memorial Cancer Institute, Memorial Healthcare System, 801 N Flamingo Road, Pembroke Pines, FL 33028 (

Conflict of Interest Disclosures: None reported.

Li  X, Kitpanit  S, Lee  A,  et al.  Toxicity profiles and survival outcomes among patients with nonmetastatic nasopharyngeal carcinoma treated with intensity-modulated proton therapy vs intensity-modulated radiation therapy.   JAMA Netw Open. 2021;4(6):e2113205. doi:10.1001/jamanetworkopen.2021.13205Google Scholar
Miller  RC, Lodge  M, Murad  MH, Jones  B.  Controversies in clinical trials in proton radiotherapy: the present and the future.   Semin Radiat Oncol. 2013;23(2):127-133. doi:10.1016/j.semradonc.2012.11.004PubMedGoogle ScholarCrossref
Gupta  T, Kannan  S, Ghosh-Laskar  S, Agarwal  JP.  Systematic review and meta-analyses of intensity-modulated radiation therapy versus conventional two-dimensional and/or or three-dimensional radiotherapy in curative-intent management of head and neck squamous cell carcinoma.   PLoS One. 2018;13(7):e0200137. doi:10.1371/journal.pone.0200137PubMedGoogle Scholar
Shen  LJ, Chen  C, Li  BF, Gao  J, Xia  YF.  High weight loss during radiation treatment changes the prognosis in under-/normal weight nasopharyngeal carcinoma patients for the worse: a retrospective analysis of 2433 cases.   PLoS One. 2013;8(7):e68660. doi:10.1371/journal.pone.0068660PubMedGoogle Scholar
Szturz  P, Wouters  K, Kiyota  N,  et al.  Weekly low-dose versus three-weekly high-dose cisplatin for concurrent chemoradiation in locoregionally advanced non-nasopharyngeal head and neck cancer: a systematic review and meta-analysis of aggregate data.   Oncologist. 2017;22(9):1056-1066. Published online May 22, 2017. doi:10.1634/theoncologist.2017-0015PubMedGoogle ScholarCrossref
Falchook  AD, Green  R, Knowles  ME,  et al.  Comparison of patient- and practitioner-reported toxic effects associated with chemoradiotherapy for head and neck cancer.   JAMA Otolaryngol Head Neck Surg. 2016;142(6):517-523. doi:10.1001/jamaoto.2016.0656PubMedGoogle ScholarCrossref
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