Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial
BMJ 2023; 380 doi: https://doi.org/10.1136/bmj-2022-072133 (Published 06 February 2023) Cite this as: BMJ 2023;380:e072133
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Dear Editor
We would like to raise concerns regarding the interpretation of the non-inferiority trial and, more importantly, the radiobiological concepts of radiation dose distribution and its impact on a patient’s oncological outcomes, as reported in the recent work of Yan-Ping Mao et al.[1]
The biological effectiveness of elective radiotherapy in controlling regional micro-metastatic disease differs from that of treating gross disease. The dose-response relationship for the subclinical disease is actually linear and reflects the heterogeneity of occult metastatic tumor burden[2,3]. We have previously addressed similar concerns in another non-inferiority randomized trial[4,5]. However, this study shares, and in some ways more obviously, the same limitation. According to appendix 2 (Figure S3), the irradiated dose to the medial retropharyngeal lymph nodes (MRLN) region is around 40Gy in the MRLN-sparing RT group, and over 54Gy in the Standard RT group. The concept of “sparing” in the study does not mean that the MRLN was exposed to zero radiation. Instead, the radiation dose of around 35 to 40Gy is almost close to an elective dose for many disease sites. On top of the abovementioned logic, the study used a non-inferiority design with a margin of 8% to detect difference in local control. The study can lead to complacency, as both arms received a significant radiation dose, and the difference in irradiated MRLN volume was only one to two vertebral heights. The study highlights that limiting the radiation dose to adjacent anatomy can result in noticeable improvements in patient quality of life[6], but it does not establish a causal relationship between sparing the MRLN from radiation and equivalent oncological outcomes. It is essential to note that the dosimetry, not the target contour itself, impacts treatment outcomes.
In conclusion, we agree with the study that MRLN can be spared from target delineation in the elective treatment setting, reducing radiation dose and volume to adjacent anatomy, and alleviating post-treatment sequelae. However, this randomized study alone may not be sufficient proof that sparing the MRLN from radiation results in equivalent oncological outcomes.
1. Mao Y-P, Wang S-X, Gao T-S, et al. Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial. BMJ. 2023;380:e072133.
2. Withers HR, Peters LJ, Taylor J. Dose-response relationship for radiation therapy of subclinical disease. International journal of radiation oncology, biology, physics. 1995;31(2):353-359.
3. Withers HR, Suwinski R. Radiation dose response for subclinical metastases. Paper presented at: Seminars in radiation oncology1998.
4. Tang L-L, Huang C-L, Zhang N, et al. Elective upper-neck versus whole-neck irradiation of the uninvolved neck in patients with nasopharyngeal carcinoma: an open-label, non-inferiority, multicentre, randomised phase 3 trial. The Lancet Oncology. 2022.
5. Liu C-M, Cheng J-Y, Lin Y-H, Chen C-S, Wang Y-M. Elective upper-neck versus whole-neck irradiation of the uninvolved neck in patients with nasopharyngeal carcinoma. The Lancet Oncology. 2022;23(6):e240.
6. Lin Y-H, Cheng J-Y, Huang B-S, et al. Significant Reduction in Vertebral Artery Dose by Intensity Modulated Proton Therapy: A Pilot Study for Nasopharyngeal Carcinoma. Journal of Personalized Medicine. 2021;11(8):822.
Competing interests: No competing interests
Re: Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial
Dear Editor
We agree that, even intending to spare the medial retropharyngeal lymph nodes (MRLN) region in the MRLN-sparing group, the doses could not decrease steeply to zero in the MRLN region, because of a scattered dose from intensity-modulated radiation therapy (IMRT) plans of 9 equally-spaced coplanar fields which may have incident beams passing through the spared MRLN region (isodose dose of 35-40 Gy in our trial) (Appendix 2 Figure S3). However, the recommended prophylactic dose of CTV2 in NPC is 44-50Gy (2.0Gy/ fraction) to 54-63Gy (1.6-1.8Gy/ fraction) according to the NCCN guidelines [1]. Obviously, 35-40Gy/33 fractions (i.e., 1.06-1.21Gy/fraction) is not enough biologically effectiveness to prevent the recurrence of RLN.
Based on magnetic resonance imaging, observations from our group and others showed that RLN involvement mainly occurs in the lateral group, with less than 0.6% occurring in the medial group [2-4]. Taking the RLN metastasis pattern and the excellent local control of this study into account, we believe that excluding the MRLN region from the targets is feasible, even with more accurate radiotherapy technologies, such as proton or heavy particle therapy, to provide better sparing to region of interest. However, the safety and the efficacy of MRLN region sparing RT based on proton or heavy particle are still worthy of further verification in the future.
1. National Comprehensive Cancer Network guidelines. 2023. Version 1. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf Accessed 20 December. 2022.
2. Tang L, Li L, Mao Y, et al. Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma detected by magnetic resonance imaging: prognostic value and staging categories. Cancer 2008;113(2):347-54. doi: 10.1002/cncr.23555
3. Wang XS, Yan C, Hu CS, et al. Study of the medial group retropharyngeal node metastasis from nasopharyngeal carcinoma based on 3100 newly diagnosed cases. Oral Oncol 2014;50(11):1109-13. doi: 10.1016/j.oraloncology.2014.08.007
4. Lin L, Lu Y, Wang XJ, et al. Delineation of Neck Clinical Target Volume Specific to Nasopharyngeal Carcinoma Based on Lymph Node Distribution and the International Consensus Guidelines. Int J Radiat Oncol Biol Phys 2018;100(4):891-902. doi: 10.1016/j.ijrobp.2017.11.004
Competing interests: No competing interests