Toxicity profile of patients treated with proton and carbon-ion therapy for primary nasopharyngeal carcinoma: A systematic review and meta-analysis
Corresponding Author
Noorazrul Yahya
Diagnostic Imaging and Radiotherapy, CODTIS, Faculty of Health Sciences, National University of Malaysia, Kuala Lumpur, Malaysia
Correspondence
Noorazrul Yahya, Diagnostic Imaging and Radiotherapy, CODTIS, Faculty of Health Sciences, National University of Malaysia, Jalan Raja Muda Aziz, 50300 Kuala Lumpur, Malaysia.
Email: [email protected]
Search for more papers by this authorSiti Athiyah Mohamad Salleh
Diagnostic Imaging and Radiotherapy, CODTIS, Faculty of Health Sciences, National University of Malaysia, Kuala Lumpur, Malaysia
Search for more papers by this authorNurul Faiqah Mohd Nasir
Functional Image Processing Laboratory, Department of Radiology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Search for more papers by this authorHanani Abdul Manan
Functional Image Processing Laboratory, Department of Radiology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Search for more papers by this authorCorresponding Author
Noorazrul Yahya
Diagnostic Imaging and Radiotherapy, CODTIS, Faculty of Health Sciences, National University of Malaysia, Kuala Lumpur, Malaysia
Correspondence
Noorazrul Yahya, Diagnostic Imaging and Radiotherapy, CODTIS, Faculty of Health Sciences, National University of Malaysia, Jalan Raja Muda Aziz, 50300 Kuala Lumpur, Malaysia.
Email: [email protected]
Search for more papers by this authorSiti Athiyah Mohamad Salleh
Diagnostic Imaging and Radiotherapy, CODTIS, Faculty of Health Sciences, National University of Malaysia, Kuala Lumpur, Malaysia
Search for more papers by this authorNurul Faiqah Mohd Nasir
Functional Image Processing Laboratory, Department of Radiology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Search for more papers by this authorHanani Abdul Manan
Functional Image Processing Laboratory, Department of Radiology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Search for more papers by this authorAbstract
Background
Proton and carbon-ion therapy may spare normal tissues in regions with many critical structures surrounding the target volume. As toxicity outcome data are emerging, we aimed to synthesize the published data for the toxicity outcomes of proton or carbon-ion therapy (together known as particle beam therapy [PBT]) for primary nasopharyngeal carcinoma (NPC).
Materials and methods
We searched PubMed and Scopus electronic databases to identify original studies reporting toxicity outcomes following PBT of primary NPC. Quality assessment was performed using NIH's Quality Assessment Tool. Reports were extracted for information on demographics, main results, and clinical and dose factors correlates. Meta-analysis was performed using the random-effects model.
Results
Twelve studies were selected (six using mixed particle-photon beams, five performed comparisons to photon-based therapy). The pooled event rates for acute grade ≥2 toxicities mucositis, dermatitis, xerostomia weight loss are 46% (95% confidence interval [95% CI]—29%–64%, I2 = 87%), 47% (95% CI—28%–67%, I2 = 87%), 16% (95% CI—9%–29%, I2 = 76%), and 36% (95% CI—27%–47%, I2 = 45%), respectively. Only one late endpoint (xerostomia grade ≥2) has sufficient data for analysis with pooled event rate of 9% (95% CI—3%–29%, I2 = 77%), lower than intensity-modulated radiotherapy 27% (95% CI—10%–54%, I2 = 95%). For most endpoints with significant differences between the PBT and photon-based therapies, PBT resulted in better outcomes. In two studies where dose distribution was studied, doses to the organs at risk were independent risk factors for toxicities.
Conclusion
PBT may reduce the risk of acute toxicities for patients treated for primary NPC, likely due to dose reduction to critical structures. The pooled event rate for toxicities derived in this study can be a guide for patient counseling.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
Supporting Information
| Filename | Description |
|---|---|
| ajco13915-sup-0001-SuppMat.pdf172 KB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Devi BC, Pisani P, Tang TS, Parkin DM. High incidence of nasopharyngeal carcinoma in native people of Sarawak, Borneo Island. Cancer Epidemiol Biomarkers Prev. 2004; 13(3): 482-486.
- 2Liu Q, Chen J-O, Huang Q-H, Li Y-H. Trends in the survival of patients with nasopharyngeal carcinoma between 1976 and 2005 in Sihui, China: a population-based study. Chin J Cancer. 2013; 32(6): 325-333. doi:10.5732/cjc.012.10189
- 3Adham M, Kurniawan AN, Muhtadi AI, et al. Nasopharyngeal carcinoma in Indonesia: epidemiology, incidence, signs, and symptoms at presentation. Chin J Cancer. 2012; 31(4): 185-196. doi:10.5732/cjc.011.10328
- 4Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: Cancer J Clin. 2015; 65(2): 87-108. doi:10.3322/caac.21262
- 5Luo J, Chia KS, Chia SE, Reilly M, Tan CS, Ye W. Secular trends of nasopharyngeal carcinoma incidence in Singapore, Hong Kong and Los Angeles Chinese populations, 1973–1997. Eur J Epidemiol. 2007; 22(8): 513-521. doi:10.1007/s10654-007-9148-8
- 6Wang Y, Zhang Y, Ma S. Racial differences in nasopharyngeal carcinoma in the United States. Cancer Epidemiol. 2013; 37(6): 793-802. doi:10.1016/j.canep.2013.08.008
- 7Pan JJ, Ng WT, Zong JF, et al. Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer. 2016; 122(4): 546-558. doi:10.1002/cncr.29795
- 8Newhauser WD, Zhang R. The physics of proton therapy. Phys Med Biol. 2015; 60(8): R155-R209. doi:10.1088/0031-9155/60/8/r155
- 9Ando K, Kase Y. Biological characteristics of carbon-ion therapy. Int J Radiat Biol. 2009; 85(9): 715-728. doi:10.1080/09553000903072470
- 10Voon NS, Lau FN, Zakaria R, et al. MRI-based brain structural changes following radiotherapy of nasopharyngeal carcinoma: a systematic review. Cancer Radiother. 2021; 25(1): 62-71. doi:10.1016/j.canrad.2020.07.008
- 11Hsieh JC-H, Du T, Xiao J, Qiu Z, Wu K. The effectiveness of intensity-modulated radiation therapy versus 2D-RT for the treatment of nasopharyngeal carcinoma: a systematic review and meta-analysis. PLoS One. 2019; 14(7):e0219611. doi:10.1371/journal.pone.0219611
- 12Wang L, Hu J, Liu X, Wang W, Kong L, Lu JJ. Intensity-modulated carbon-ion radiation therapy versus intensity-modulated photon-based radiation therapy in locally recurrent nasopharyngeal carcinoma: a dosimetric comparison. Cancer Manage Res. 2019; 11: 7767-7777. doi:10.2147/cmar.S205421
- 13Minatogawa H, Yasuda K, Dekura Y, et al. Potential benefits of adaptive intensity-modulated proton therapy in nasopharyngeal carcinomas. J Appl Clin Med Phys. 2020; 22(1): 174-183. doi:10.1002/acm2.13128
- 14Holliday EB, Frank SJ. Proton therapy for nasopharyngeal carcinoma. Chin Clin Oncol. 2016; 5(2): 25. doi:10.21037/cco.2016.03.05
- 15Moon SH, Cho KH, Lee C-G, et al. IMRT vs. 2D-radiotherapy or 3D-conformal radiotherapy of nasopharyngeal carcinoma. Strahlenther Onkol. 2016; 192(6): 377-385. doi:10.1007/s00066-016-0959-y
- 16Ibrahim MS, Attalla EM, El Naggar M, Elshemey WM. Dosimetric comparison between three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in the treatment of different stages of nasopharyngeal carcinoma. J Radiother Pract. 2018; 18(1): 46-51. doi:10.1017/s1460396918000377
- 17Ramaekers BLT, Pijls-Johannesma M, Joore MA, et al. Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons. Cancer Treat Rev. 2011; 37(3): 185-201. doi:10.1016/j.ctrv.2010.08.004
- 18Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009; 339:b2535. doi:10.1136/bmj.b2535
- 19Beddok A, Feuvret L, Noël G, et al. Boost in proton for locally advanced nasopharyngeal carcinoma: a Curie Institute experience. Cancer Radiother. 2019; 23(4): 304-311. doi:10.1016/j.canrad.2019.01.003
- 20Lewis GD, Holliday EB, Kocak-Uzel E, et al. Intensity-modulated proton therapy for nasopharyngeal carcinoma: decreased radiation dose to normal structures and encouraging clinical outcomes. Head Neck. 2016; 38: E1886-95. doi:10.1002/hed.24341 Suppl 1:E1886-95
- 21McDonald MW, Liu Y, Moore MG, Johnstone PAS. Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy. Radiat Oncol. 2016; 11(1): 32. doi:10.1186/s13014-016-0600-3
- 22Akbaba S, Held T, Lang K, et al. Bimodal Radiotherapy with Active Raster-Scanning Carbon Ion Radiotherapy and Intensity-Modulated Radiotherapy in High-Risk Nasopharyngeal Carcinoma Results in Excellent Local Control. Cancers 2019; 11(3): 379. https://doi.org/10.3390/cancers11030379
- 23Hu J, Huang Q, Gao J, et al. Mixed Photon and Carbon-Ion Beam Radiotherapy in the Management of Non-Metastatic Nasopharyngeal Carcinoma. Front Oncol. 2021; 11. https://doi.org/10.3389/fonc.2021.653050
- 24Alterio D, D'Ippolito E, Vischioni B, et al. Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy. Acta Oncol. 2020; 59(5): 541-548. doi:10.1080/0284186x.2020.1730001
- 25Chan AW, Liebsch LJ, Deschler DG, et al. Proton radiotherapy for T4 nasopharyngeal carcinoma. J Clin Oncol. 2004; 22(14_suppl): 5574–5574. https://doi.org/10.1200/jco.2004.22.90140.5574
- 26Park SG, Ahn YC, Oh D, et al. Early clinical outcomes of helical tomotherapy/intensity-modulated proton therapy combination in nasopharynx cancer. Cancer Sci. 2019; 110(9): 2867-2874. doi:10.1111/cas.14115
- 27Chan A, Adams JA, Weyman E, et al. A Phase II Trial of Proton Radiation Therapy With Chemotherapy for Nasopharyngeal Carcinoma. Int J Radiat Oncol Biol Phys. 2012; 84(3): S151–S152. https://doi.org/10.1016/j.ijrobp.2012.07.391
- 28Chou Y-C, Fan K-H, Lin C-Y, et al. Intensity modulated proton beam therapy versus volumetric modulated arc therapy for patients with nasopharyngeal cancer: a propensity score-matched study. Cancers. 2021; 13(14): 3555. doi:10.3390/cancers13143555
- 29Holliday EB, Garden AS, Rosenthal DI, et al. Proton Therapy Reduces Treatment-Related Toxicities for Patients with Nasopharyngeal Cancer: A Case-Match Control Study of Intensity-Modulated Proton Therapy and Intensity-Modulated Photon Therapy. Int J Particle Ther. 2015; 2(1): 19–28. https://doi.org/10.14338/ijpt-15-00011.1
10.14338/IJPT-15-00011.1 Google Scholar
- 30Jiří K, Vladimír V, Michal A, et al. Proton pencil-beam scanning radiotherapy in the treatment of nasopharyngeal cancer: dosimetric parameters and 2-year results. Eur Arch Otorhinolaryngol. 2020; 278(3): 763–769. https://doi.org/10.1007/s00405-020-06175-5
- 31Li 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.2021.13205
- 32Sanford NN, Lau J, Lam MB, et al. Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience. Int J Radiat Oncol Biol Phys. 2019; 103(3): 654–668. https://doi.org/10.1016/j.ijrobp.2018.10.006
- 33Zhang B, Mo Z, Du W, Wang Y, Liu L, Wei Y. Intensity-modulated radiation therapy versus 2D-RT or 3D-CRT for the treatment of nasopharyngeal carcinoma: a systematic review and meta-analysis. Oral Oncol. 2015; 51(11): 1041-1046. doi:10.1016/j.oraloncology.2015.08.005
- 34Holliday EB, Kocak-Uzel E, Feng L, et al. Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: a case-matched control analysis. Med Dosim. 2016; 41(3): 189-194. doi:10.1016/j.meddos.2016.01.002
- 35Yahya N, Roslan N. Estimating radiotherapy demands in South East Asia countries in 2025 and 2035 using evidence-based optimal radiotherapy fractions. Asia Pac J Clin Oncol. 2018; 14(5): e543-e547. doi:10.1111/ajco.12831
- 36Yahya N, Sukiman NK, Suhaimi NA, Azmi NA, Manan HA. How many roads must a Malaysian walk down? Mapping the accessibility of radiotherapy facilities in Malaysia. PLoS One. 2019; 14(3):e0213583. doi:10.1371/journal.pone.0213583
- 37Yahya N, Manan HA. Neurocognitive impairment following proton therapy for paediatric brain tumour: a systematic review of post-therapy assessments. Support Care Cancer. 2020; 29(6): 3035-3047. doi:10.1007/s00520-020-05808-z
- 38Thomas H, Timmermann B. Paediatric proton therapy. Br J Radiol. 2020; 93(1107):20190601. doi:10.1259/bjr.20190601
- 39Romesser PB, Cahlon O, Scher E, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiother Oncol. 2016; 118(2): 286-292. doi:10.1016/j.radonc.2015.12.008
- 40Moskvin V, Lasley FD, Ray GL, et al. Acute skin toxicity associated with proton beam therapy in spine and brain patients. J Radiat Oncol. 2013; 3(2): 195-203. doi:10.1007/s13566-013-0128-1
10.1007/s13566-013-0128-1 Google Scholar
- 41Kern A, Bäumer C, Kröninger K, Wulff J, Timmermann B. Impact of air gap, range shifter, and delivery technique on skin dose in proton therapy. Med Phys. 2020; 48(2): 831-840. doi:10.1002/mp.14626
- 42Bressan V, Stevanin S, Bianchi M, Aleo G, Bagnasco A, Sasso L. The effects of swallowing disorders, dysgeusia, oral mucositis and xerostomia on nutritional status, oral intake and weight loss in head and neck cancer patients: a systematic review. Cancer Treat Rev. 2016; 45: 105-119. doi:10.1016/j.ctrv.2016.03.006
- 43Simone CB, Ly D, Dan TD, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol. 2011; 101(3): 376-382. doi:10.1016/j.radonc.2011.05.028
- 44Nguyen M-L, Cantrell JN, Ahmad S, Henson C. Intensity-modulated proton therapy (IMPT) versus intensity-modulated radiation therapy (IMRT) for the treatment of head and neck cancer: a dosimetric comparison. Med Dosim. 2021; 46(3): 259-263. doi:10.1016/j.meddos.2021.02.001
- 45Brown AP, Urie MM, Chisin R, Sui HD. Proton therapy for carcinoma of the nasopharynx: a study in comparative treatment planning. Int J Radiat Oncol Biol Phys. 1989; 16(6): 1607-1614. doi:10.1016/0360-3016(89)90970-x
- 46Li K, Yang L, Xin P, et al. Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy. Oral Oncol. 2017; 72: 32-37. doi:10.1016/j.oraloncology.2017.06.026
- 47Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016; 122(10): 1483-1501. doi:10.1002/cncr.29882
- 48Mee T, Kirkby NF, Kirkby KJ. Mathematical modelling for patient selection in proton therapy. Clin Oncol. 2018; 30(5): 299-306. doi:10.1016/j.clon.2018.01.007
- 49Yahya N, Manan HA. Utilisation of diffusion tensor imaging in intracranial radiotherapy and radiosurgery planning for white matter dose optimization: a systematic review. World Neurosurg. 2019; 130: e188-e198. doi:10.1016/j.wneu.2019.06.027
- 50Langendijk JA, Lambin P, De Ruysscher D, Widder J, Bos M, Verheij M. Selection of patients for radiotherapy with protons aiming at reduction of side effects: the model-based approach. Radiother Oncol. 2013; 107(3): 267-273. doi:10.1016/j.radonc.2013.05.007
- 51Tambas M, Steenbakkers RJHM, van der Laan HP, et al. First experience with model-based selection of head and neck cancer patients for proton therapy. Radiother Oncol. 2020; 151: 206-213. doi:10.1016/j.radonc.2020.07.056
- 52Langendijk JA, Boersma LJ, Rasch CRN, et al. Clinical trial strategies to compare protons with photons. Semin Radiat Oncol. 2018; 28(2): 79-87. doi:10.1016/j.semradonc.2017.11.008
- 53Li WF, Chen NY, Zhang N, et al. Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: long-term results of phase 3 randomized controlled trial. Int J Cancer. 2019; 145(1): 295-305. doi:10.1002/ijc.32099
Citing Literature
