A new perspective on radiotherapy in the comprehensive treatment of cancer

Abstract

Radiotherapy (RT) has become an indispensable part of modern cancer treatment owing to its efficacy, precision, and safety. With continuous advances in clinical practice, the role of RT in comprehensive cancer treatment has been repositioned. Through a combination of chemotherapy, targeted therapy, and immunotherapy, RT can achieve multiple therapeutic goals, including disease cure, symptom relief, improved quality of life, and prolonged survival. Therefore, understanding the development of RT, its mechanisms, technological innovations, combined therapeutic strategies, and prospects is essential for advancing tumor treatment and improving patient survival.

Keywords

combination therapy / future directions / historical development / radiotherapy

References

[1] Wilhelm Konrad Roentgen-The Centennial of His Birth-Semicentennial of the X-Rays. JAMA. 2020; 323(15): 1512.

[2] Qiang YG. Discovery of X rays and its unjustificable application in its early years—Commemorating the 120 anniversary of discovery of X-rays by Rroentgen. Chin J Radiol Med Protect. 2016; 36 (2): 154–160. (in Chinese)

[3] Kemerink M, Dierichs TJ, Dierichs J, et al. First-generation x-ray system. Radiology. 2011; 260(2): 611-612.

[4] Jönsson BA. Henri Becquerel's discovery of radioactivity - 125 years later. Phys Med. 2021; 87: 144-146.

[5] Liu B, Liu YF. Jorio Curie couple and artificial radioactivity-Commemorating the 60th anniversary of the discovery of artificial radioactivity. University Chemistry. 1995; 10(3): 62–64. (in Chinese)

[6] Novak D. The early history of radiotherapy. Hist Sci Med. 1982; 17(Spec 2): 262-264.

[7] Laugier A. Le premier siècle de la radiothérapie en France [The first century of radiotherapy in France]. Bull Acad Natl Med. 1996; 180(1): 143-160.

[8] Hurlbert MA, Akpan J. Dialectic narratives, hostile actors, and Earth's resources in Saskatchewan, Canada. Sustain Sci. 2023; 18(1): 285-301.

[9] Thariat J, Carsuzaa F, Marcy PY, Verillaud B, de Gabory L, Ferrand FR. Precision Postoperative Radiotherapy in Sinonasal Carcinomas after Endonasal Endoscopic Surgery. Cancers (Basel). 2021; 13(19):4802.

[10] Bortfeld T. IMRT: a review and preview. Phys Med Biol. 2006; 51(13): R363-R379.

[11] Gedam VR, Pradhan A. Comparison of three Radiotherapy Techniques Volumetric Modulated Arc Therapy with Variable and Constant Dose Rate and Intensity-Modulated Radiotherapy for the Irradiation of Five Cancer Sites. J Biomed Phys Eng. 2024; 14(4): 335-346.

[12] Chen D, Cai SB, Soon YY, et al. Dosimetric comparison between Intensity Modulated Radiation Therapy (IMRT) vs dual arc Volumetric Arc Therapy (VMAT) for nasopharyngeal cancer (NPC): Systematic review and meta-analysis. J Med Imaging Radiat Sci. 2023; 54(1): 167-177.

[13] Solberg TD, Selch MT, Smathers JB, DeSalles AA. Fractionated stereotactic radiotherapy: rationale and methods. Med Dosim. 1998; 23(3): 209-219.

[14] Timmerman RD, Kavanagh BD. Stereotactic body radiation therapy. Curr Probl Cancer. 2005; 29(3): 120-157.

[15] Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015; 16(6): 630-637.

[16] Tang LL, Chen YP, Chen CB, et al. The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma. Cancer Commun (Lond). 2021; 41(11): 1195-1227.

[17] Lavrova E, Garrett MD, Wang YF, et al. Adaptive Radiation Therapy: A Review of CT-based Techniques. Radiol Imaging Cancer. 2023; 5(4):e230011.

[18] Glide-Hurst CK, Lee P, Yock AD, et al. Adaptive Radiation Therapy (ART) Strategies and Technical Considerations: A State of the ART Review From NRG Oncology. Int J Radiat Oncol Biol Phys. 2021; 109(4): 1054-1075.

[19] Greco C, Wolden S. Current status of radiotherapy with proton and light ion beams. Cancer. 2007; 109(7): 1227-1238.

[20] Yan S, Ngoma TA, Ngwa W, Bortfeld TR. Global democratisation of proton radiotherapy. Lancet Oncol. 2023; 24(6): e245-e254.

[21] Dell'Oro M, Short M, Wilson P, Bezak E. Normal tissue tolerance amongst paediatric brain tumour patients- current evidence in proton radiotherapy. Crit Rev Oncol Hematol. 2021; 164:103415.

[22] Mohamad O, Yamada S, Durante M. Clinical Indications for Carbon Ion Radiotherapy. Clin Oncol (R Coll Radiol). 2018; 30(5): 317-329.

[23] Jang JY, Kim K, Chen MF, et al. A meta-analysis comparing efficacy and safety between proton beam therapy versus carbon ion radiotherapy. Cancer Med. 2024; 13(3):e7023.

[24] Huang RX, Zhou PK. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther. 2020; 5(1): 60.

[25] Mavragani IV, Nikitaki Z, Souli MP, et al. Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis. Cancers (Basel). 2017; 9(7):91.

[26] McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer. 2020; 20(4): 203-217.

[27] Fricke H. Effect of ionizing radiation on protein denaturation. Nature. 1952; 169(4310): 965-966.

[28] Tuieng RJ, Cartmell SH, Kirwan CC, Sherratt MJ. The Effects of Ionising and Non-Ionising Electromagnetic Radiation on Extracellular Matrix Proteins. Cells. 2021; 10(11):3041.

[29] Tang L, Wei F, Wu Y, et al. Role of metabolism in cancer cell radioresistance and radiosensitization methods. J Exp Clin Cancer Res. 2018; 37(1): 87.

[30] Yang P, Li J, Zhang T, et al. Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids. Cell Death Differ. 2023; 30(11): 2432-2445.

[31] Li J, Wang Y, Shen W, et al. Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer. Adv Sci (Weinh). 2024; 11(18):e2400845.

[32] Zhang Z, Liu X, Chen D, Yu J. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct Target Ther. 2022; 7(1): 258.

[33] Shang S, Liu J, Verma V, et al. Combined treatment of non-small cell lung cancer using radiotherapy and immunotherapy: challenges and updates. Cancer Commun (Lond). 2021; 41(11): 1086-1099.

[34] Obrador E, Salvador-Palmer R, Villaescusa JI, et al. Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry. Antioxidants (Basel). 2022; 11(6):1098.

[35] Wang Y, Li Y, Yang Y, et al. In situ vaccination caused by diverse irradiation-driven cell death programs. Theranostics. 2024; 14(3): 1147-1167.

[36] Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005; 104(6): 1129-1137.

[37] Chinese Association for Therapeutic Radiation Oncologists (CATRO), Chinese Society for Therapeutic Radiation Oncology (CSTRO). Chinese Guidelines for Radiotherapy of Nasopharyngeal Carcinoma (2022 Edition). Chin J Cancer Prev Treat. 2022; 29 (9): 611–622. (in Chinese)

[38] General Office of the National Health Commission, PRC. Clinical Practice Guideline for Primary Lung Cancer (2022 Version). Medical Journal of Peking Union Medical College Hospital. 2022; 13(4): 549–570. (in Chinese)

[39] Chinese Guidelines for Diagnosis and Treatment of Malignant Lymphoma (2018 Edition). J Multidiscip Cancer Manage (Electronic Version). 2019; 5(4): 50–71. (in Chinese)

[40] Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016; 17(8): 1047-1060.

[41] Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009; 92(1): 4-14.

[42] Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev. 2010; 2010(1):CD008285.

[43] Lim SB, Hong SM, Yu CS, et al. Prevalence and clinical significance of acellular mucin in locally advanced rectal cancer patients showing pathologic complete response to preoperative chemoradiotherapy. Am J Surg Pathol. 2013; 37(1): 47-52.

[44] Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001; 345(9): 638-646.

[45] Gao WF, Li HC. Clinical evaluation of rectal cancer after neoadjuvant chemoradio-therapy. Chin J Clin Oncol. 2015; 42(6): 360–362. (in Chinese)

[46] Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004; 351(17): 1731-1740.

[47] Chinese Association for Therapeutic Radiation Oncologists (CATRO), Chinese Society for Therapeutic Radiation Oncology (CSTRO), Chinese Anti-Cancer Association Committee on Radiation Oncology. Chinese Guidelines for Radiotherapy of Esophageal Cancer (2022 Edition). J Int Oncol. 2022; 49(11): 641-657. (in Chinese)

[48] Springfeld C, Ferrone CR, Katz MHG, et al. Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol. 2023; 20(5): 318-337.

[49] Wu Y, Yao Y, Zhang J, Gui H, Liu J, Liu J. Tumor-Targeted Injectable Double-Network Hydrogel for Prevention of Breast Cancer Recurrence and Wound Infection via Synergistic Photothermal and Brachytherapy. Adv Sci (Weinh). 2022; 9(24):e2200681.

[50] Qian H, Jiang GL, Wang LJ, et al. An analysis of pre operative radiotherapy on 51 cases of non-small cell lung cancer (NSCLC). Chin J Radiat Oncol. 1995; 4(4): 223–225. (in Chinese)

[51] Chinese Association for Therapeutic Radiation Oncologists (CATRO), Chinese Society for Therapeutic Radiation Oncology (CSTRO), Chinese Anti-Cancer Association Committee on Radiation Oncology. Chinese Guidelines for Radiotherapy of Prostate Cancer (2020 Edition). Chin J Cancer Prevent Treat. 2021; 28 (5): 323–337. (in Chinese)

[52] Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006; 296(19): 2329-2335.

[53] Strojan P. Role of radiotherapy in melanoma management. Radiol Oncol. 2010; 44(1): 1-12.

[54] Ashby M. The role of radiotherapy in palliative care. J Pain Symptom Manage. 1991; 6(6): 380-388.

[55] Lutz ST, Jones J, Chow E. Role of radiation therapy in palliative care of the patient with cancer. J Clin Oncol. 2014; 32(26): 2913-2919.

[56] Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011; 79(4): 965-976.

[57] Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007; 25(11): 1423-1436.

[58] Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2012; 2(3): 210-225.

[59] Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014; 15(4): 387-395.

[60] Loblaw DA, Perry J, Chambers A, Laperriere NJ. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group. J Clin Oncol. 2005; 23(9): 2028-2037.

[61] Song J, Brown C, Dennis K, Gaudet M, Haddad A. Palliative Radiotherapy for Haemostasis in Malignancy: a Systematic Review. Clin Oncol (R Coll Radiol). 2023; 35(9): e478-e488.

[62] Ali A, Song YP, Mehta S, et al. Palliative Radiation Therapy in Bladder Cancer-Importance of Patient Selection: A Retrospective Multicenter Study. Int J Radiat Oncol Biol Phys. 2019; 105(2): 389-393.

[63] Yu J, Jung J, Park SR, et al. Role of palliative radiotherapy in bleeding control in patients with unresectable advanced gastric cancer. BMC Cancer. 2021; 21(1): 413.

[64] Veluthattil AC, Sudha SP, Kandasamy S, Chakkalakkoombil SV. Effect of Hypofractionated, Palliative Radiotherapy on Quality of Life in Late-Stage Oral Cavity Cancer: A Prospective Clinical Trial. Indian J Palliat Care. 2019; 25(3): 383-390.

[65] Johnson AG, Soike MH, Farris MK, Hughes RT. Efficacy and Survival after Palliative Radiotherapy for Malignant Pulmonary Obstruction. J Palliat Med. 2022; 25(1): 46-53.

[66] Martin EJ, Bruggeman AR, Nalawade VV, et al. Palliative Radiotherapy Versus Esophageal Stent Placement in the Management of Patients With Metastatic Esophageal Cancer. J Natl Compr Canc Netw. 2020; 18(5): 569-574.

[67] Buckley AM, Lynam-Lennon N, O'Neill H, O'Sullivan J. Targeting hallmarks of cancer to enhance radiosensitivity in gastrointestinal cancers. Nat Rev Gastroenterol Hepatol. 2020; 17(5): 298-313.

[68] Narayan RS, Fedrigo CA, Brands E, et al. The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures. BMC Cancer. 2017; 17(1): 204.

[69] Liu MB. Studies on the lung cancer cell death induced by radiotherapy combined with chemotherapy and related mechanisms. Changchun: Jilin University, 2011. (in Chinese)

[70] Hennequin C, Guillerm S, Quero L. Combination of chemotherapy and radiotherapy: A thirty years evolution. Cancer Radiother. 2019; 23(6-7): 662-665.

[71] Shi ZM, Lu LN, Shen HB. The effect of intensity modulated radiotherapy combined with adjuvant chemotherapy on esophageal cancer. China Contin Med Educ. 2017; 9(34): 72–73. (in Chinese)

[72] Gong MY, Xu H, Duan XH, et al. Clinical efficacy of irinotecan/tigio chemotherapy combined with concurrent radiotherapy for recurrent rectal cancer. J Clin Med Pract. 2014; 18(11): 114–115, 119. (in Chinese)

[73] de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019; 20(9): 1273-1285.

[74] McCormack M, Eminowicz G, Gallardo D, et al. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): an international, multicentre, randomised phase 3 trial. Lancet. 2024; 404(10462): 1525-1535.

[75] Fokas E, Williams H, Diefenhardt M, et al. Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Pooled analysis of the CAO/ARO/AIO-12 and the OPRA randomized phase 2 trials. Eur J Cancer. 2024; 210:114291.

[76] Zhang J, Li M, Zhang K, et al. Concurrent chemoradiotherapyof different radiation doses and different irradiation fields for locally advanced thoracic esophageal squamous cell carcinoma: A randomized, multicenter, phase III clinical trial. Cancer Commun (Lond). 2024; 44(10): 1173-1188.

[77] Epstein JB, Thariat J, Bensadoun RJ, et al. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA Cancer J Clin. 2012; 62(6): 400-422.

[78] Paice JA. Chronic treatment-related pain in cancer survivors. Pain. 2011; 152(3 Suppl): S84-S89.

[79] Baker KS, Chow EJ, Goodman PJ, et al. Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev. 2013; 22(11): 1954-1963.

[80] Huddart RA, Norman A, Shahidi M, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol. 2003; 21(8): 1513-1523.

[81] Bai JW, Qiu SQ, Zhang GJ. Molecular and functional imaging in cancer-targeted therapy: current applications and future directions. Signal Transduct Target Ther. 2023; 8(1): 89.

[82] Peng C, Wu Y, Yang Y, et al. Using ultrasound-targeted microbubble destruction to enhance radiotherapy of glioblastoma. J Cancer Res Clin Oncol. 2021; 147(5): 1355-1363.

[83] Rivero Belenchón I, Congregado Ruiz CB, Saez C, Osman García I, Medina López RA. Parp Inhibitors and Radiotherapy: A New Combination for Prostate Cancer (Systematic Review). Int J Mol Sci. 2023; 24(16):12978.

[84] Li MY, Liu JQ, Chen DP, et al. Radiotherapy induces cell cycle arrest and cell apoptosis in nasopharyngeal carcinoma via the ATM and Smad pathways. Cancer Biol Ther. 2017; 18(9): 681-693.

[85] Liu S, Wu F, Zhang Y, et al. Apatinib Combined With Radiotherapy Enhances Antitumor Effects in an In Vivo Nasopharyngeal Carcinoma Model. Cancer Control. 2020; 27(1):1073274820922553.

[86] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354(6): 567-578.

[87] Banna GL, Addeo A. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med. 2024; 391(16): 1555.

[88] Xing L, Wu G, Wang L, et al. Erlotinib Versus Etoposide/Cisplatin With Radiation Therapy in Unresectable Stage III Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter, Randomized, Open-Label, Phase 2 Trial. Int J Radiat Oncol Biol Phys. 2021; 109(5): 1349-1358.

[89] Sun H, Li M, Huang W, et al. Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial. J Clin Oncol. 2025; 43(4): 412-421.

[90] Nassar AH, Jayakrishnan R, Feng J, et al. Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC. J Thorac Oncol. 2025; 20(1): 109-118.

[91] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354(6): 567-578.

[92] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010; 11(1): 21-28.

[93] Zhuang H, Zhao X, Zhao L, Chang JY, Wang P. Progress of clinical research on targeted therapy combined with thoracic radiotherapy for non-small-cell lung cancer. Drug Des Devel Ther. 2014; 8: 667-675.

[94] Zhou R, Zheng S, Wang D, et al. Efficacy and safety of combining bevacizumab and fractionated stereotactic radiotherapy for extensive brain metastases in patients with non-small cell lung cancer: a prospective phase II study (GASTO-1053). Cancer Commun (Lond). 2025; 45(12): 1739-1754.

[95] Zheng S, Ding S, Liu B, et al. Efficacy and safety of online adaptive magnetic resonance-guided fractionated stereotactic radiotherapy for brain metastases in non-small cell lung cancer (GASTO-1075): a single-arm, phase 2 trial. EClinicalMedicine. 2025; 82:103189.

[96] Darragh LB, Gadwa J, Pham TT, et al. Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors. Nat Commun. 2022; 13(1): 7015.

[97] Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol. 2015; 25(1): 11-17.

[98] Shahabi V, Postow MA, Tuck D, Wolchok JD. Immune-priming of the tumor microenvironment by radiotherapy: rationale for combination with immunotherapy to improve anticancer efficacy. Am J Clin Oncol. 2015; 38(1): 90-97.

[99] Grapin M, Richard C, Limagne E, et al. Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination. J Immunother Cancer. 2019; 7(1): 160.

[100] Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004; 58(3): 862-870.

[101] Lin L, Kane N, Kobayashi N, et al. High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors. Clin Cancer Res. 2021; 27(5): 1505-1515.

[102] Goff PH, Zeng J, Rengan R, Schaub SK. Radiation and Modulation of the Tumor Immune Microenvironment in Non-Small Cell Lung Cancer. Semin Radiat Oncol. 2021; 31(2): 133-139.

[103] Sato H, Niimi A, Yasuhara T, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017; 8(1): 1751.

[104] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39(1): 1-10.

[105] Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009; 10(7): 718-726.

[106] Brix N, Tiefenthaller A, Anders H, Belka C, Lauber K. Abscopal, immunological effects of radiotherapy: Narrowing the gap between clinical and preclinical experiences. Immunol Rev. 2017; 280(1): 249-279.

[107] Onate AJ, Clark PA, Morris ZS. Using Radiation Therapy to Prime and Propagate an Anti-tumor Immune Response Against Brain Tumors. Neuromolecular Med. 2022; 24(1): 3-7.

[108] Meric-Bernstam F, Larkin J, Tabernero J, Bonini C. Enhancing anti-tumour efficacy with immunotherapy combinations. Lancet. 2021; 397(10278): 1010-1022.

[109] Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014; 3:e28518.

[110] Zeng H, Zhang W, Gong Y, Xie C. Radiotherapy activates autophagy to increase CD8⁺ T cell infiltration by modulating major histocompatibility complex class-I expression in non-small cell lung cancer. J Int Med Res. 2019; 47(8): 3818-3830.

[111] Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers. Int J Mol Sci. 2014; 15(1): 927-943.

[112] Lin W, Xu Y, Chen X, et al. Radiation-induced small extracellular vesicles as “carriages” promote tumor antigen release and trigger antitumor immunity. Theranostics. 2020; 10(11): 4871-4884.

[113] Sharabi AB, Nirschl CJ, Kochel CM, et al. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol Res. 2015; 3(4): 345-355.

[114] Gupta A, Probst HC, Vuong V, et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol. 2012; 189(2): 558-566.

[115] Zhou Z, Zhao J, Hu K, et al. Single High-Dose Radiation Enhances Dendritic Cell Homing and T Cell Priming by Promoting Reactive Oxygen Species-Induced Cytoskeletal Reorganization. Int J Radiat Oncol Biol Phys. 2021; 109(1): 95-108.

[116] Anitei MG, Zeitoun G, Mlecnik B, et al. Prognostic and predictive values of the immunoscore in patients with rectal cancer. Clin Cancer Res. 2014; 20(7): 1891-1899.

[117] Kovács A, Stenmark Tullberg A, Werner Rönnerman E, et al. Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of the SweBCG91RT Randomized Trial. J Clin Oncol. 2019; 37(14): 1179-1187.

[118] Marciscano AE, Ghasemzadeh A, Nirschl TR, et al. Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy. Clin Cancer Res. 2018; 24(20): 5058-5071.

[119] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014; 124(2): 687-695.

[120] Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015; 520(7547): 373-377.

[121] Wang J, Zhang J, Wen W, et al. Exploring low-dose radiotherapy to overcome radio-immunotherapy resistance. Biochim Biophys Acta Mol Basis Dis. 2023; 1869(7):166789.

[122] Demaria S, Coleman CN, Formenti SC. Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer. 2016; 2(6): 286-294.

[123] Theelen WSME, Chen D, Verma V, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med. 2021; 9(5): 467-475.

[124] Correction to Lancet Oncol 2017; 18: e143-52. Lancet Oncol. 2019; 20(5):e242.

[125] Chen D, Menon H, Verma V, et al. Response and outcomes after anti-CTLA4 versus anti-PD1 combined with stereotactic body radiation therapy for metastatic non-small cell lung cancer: retrospective analysis of two single-institution prospective trials. J Immunother Cancer. 2020; 8(1):e000492.

[126] Lin Z, Cai M, Zhang P, et al. Phase II, single-arm trial of preoperative short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer. J Immunother Cancer. 2021; 9(11):e003554.

[127] Hiniker SM, Reddy SA, Maecker HT, et al. A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. Int J Radiat Oncol Biol Phys. 2016; 96(3): 578-588.

[128] Luke JJ, Lemons JM, Karrison TG, et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol. 2018; 36(16): 1611-1618.

[129] Yang H, Jin T, Li M, Xue J, Lu B. Synergistic effect of immunotherapy and radiotherapy in non-small cell lung cancer: current clinical trials and prospective challenges. Precis Clin Med. 2019; 2(1): 57-70.

[130] Xia WY, Feng W, Zhang CC, et al. Radiotherapy for non-small cell lung cancer in the immunotherapy era: the opportunity and challenge-a narrative review. Transl Lung Cancer Res. 2020; 9(5): 2120-2136.

[131] Chen D, Zou B, Li B, et al. Adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC): a phase II trial. EClinicalMedicine. 2024; 75:102795.

[132] Nakamichi S, Kubota K, Misumi T, et al. Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non-small Cell Lung Cancer: TORG1937 (DATE Study). Clin Cancer Res. 2024; 30(6): 1104-1110.

[133] Ross HJ, Kozono D, Wang XF, et al. Atezolizumab Before and After Chemoradiation for Unresectable Stage III Non-Small Cell Lung Cancer: A Phase II Nonrandomized Controlled Trial. JAMA Oncol. 2024; 10(9): 1212-1219.

[134] Ohri N, Jolly S, Cooper BT, et al. Selective Personalized RadioImmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial (SPRINT). J Clin Oncol. 2024; 42(5): 562-570.

[135] Markussen A, Johansen JS, Larsen FO, et al. Nivolumab with or without Ipilimumab Combined with Stereotactic Body Radiotherapy in Patients with Metastatic Biliary Tract Cancer: A Randomized Phase 2 Study. Clin Cancer Res. 2024; 30(16): 3428-3437.

[136] Zhou R, Liu F, Zhang H, et al. Fraction Dose Escalation of Hypofractionated Radiotherapy with Concurrent Chemotherapy and Subsequent Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer: A Phase I Study. Clin Cancer Res. 2024; 30(13): 2719-2728.

[137] Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014; 15(7): 700-712.

[138] Morisada M, Clavijo PE, Moore E, et al. PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. Oncoimmunology. 2017; 7(3):e1395996.

[139] McBride S, Sherman E, Tsai CJ, et al. Randomized Phase II Trial of Nivolumab With Stereotactic Body Radiotherapy Versus Nivolumab Alone in Metastatic Head and Neck Squamous Cell Carcinoma. J Clin Oncol. 2021; 39(1): 30-37.

[140] Twardowski P, Wong JYC, Pal SK, et al. Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer. Cancer Treat Res Commun. 2019; 19:100116.

[141] Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison?. Nat Rev Clin Oncol. 2017; 14(6): 365-379.

[142] Rodríguez-Ruiz ME, Vanpouille-Box C, Melero I, Formenti SC, Demaria S. Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect. Trends Immunol. 2018; 39(8): 644-655.

[143] Kho VM, Mekers VE, Span PN, Bussink J, Adema GJ. Radiotherapy and cGAS/STING signaling: Impact on MDSCs in the tumor microenvironment. Cell Immunol. 2021; 362:104298.

[144] Yu JB, DeStephano DM, Jeffers B, et al. Updated Analysis of Comparative Toxicity of Proton and Photon Radiation for Prostate Cancer. J Clin Oncol. 2024; 42(16): 1943-1952.

[145] Hu J, Huang Q, Gao J, et al. Clinical outcomes of carbon-ion radiotherapy for patients with locoregionally recurrent nasopharyngeal carcinoma. Cancer. 2020; 126(23): 5173-5183.

[146] Jin JY, Gu A, Wang W, Oleinick NL, Machtay M, Spring Kong FM. Ultra-high dose rate effect on circulating immune cells: A potential mechanism for FLASH effect?. Radiother Oncol. 2020; 149: 55-62.

[147] Zou W, Zhang R, Schüler E, et al. Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps. Int J Radiat Oncol Biol Phys. 2023; 116(5): 1202-1217.

[148] Hall WA, Paulson E, Li XA, et al. Magnetic resonance linear accelerator technology and adaptive radiation therapy: An overview for clinicians. CA Cancer J Clin. 2022; 72(1): 34-56.

[149] Schwartz DL, Garden AS, Thomas J, et al. Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial. Int J Radiat Oncol Biol Phys. 2012; 83(3): 986-993.

[150] Deig CR, Kanwar A, Thompson RF. Artificial Intelligence in Radiation Oncology. Hematol Oncol Clin North Am. 2019; 33(6): 1095-1104.

[151] Goodman KA, Ou FS, Hall NC, et al. Randomized Phase II Study of PET Response-Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial. J Clin Oncol. 2021; 39(25): 2803-2815.

[152] Kong FS, Hu C, Pryma DA, et al. Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer. J Clin Oncol. 2024; 42(33): 3935-3946.

[153] Verkooijen HM, Kerkmeijer LGW, Fuller CD, et al. R-IDEAL: A Framework for Systematic Clinical Evaluation of Technical Innovations in Radiation Oncology. Front Oncol. 2017; 7:59.

[154] Takayama Y, Kadoya N, Yamamoto T, et al. Evaluation of the performance of deformable image registration between planning CT and CBCT images for the pelvic region: comparison between hybrid and intensity-based DIR. J Radiat Res. 2017; 58(4): 567-571.

[155] Cao X, Zhang R, Esipova TV, et al. Quantification of Oxygen Depletion During FLASH Irradiation In Vitro and In Vivo. Int J Radiat Oncol Biol Phys. 2021; 111(1): 240-248.

[156] Vozenin MC, Montay-Gruel P, Tsoutsou P, Limoli CL. Mechanisms, challenges and opportunities for FLASH radiotherapy in cancer. Nat Rev Cancer. 2026; 26(1): 62-75.

[157] Nachbar M, Lo Russo M, Gani C, et al. Automatic AI-based contouring of prostate MRI for online adaptive radiotherapy. Z Med Phys. 2024; 34(2): 197-207.

[158] Xiao C, Jin J, Yi J, et al. RefineNet-based 2D and 3D automatic segmentations for clinical target volume and organs at risks for patients with cervical cancer in postoperative radiotherapy. J Appl Clin Med Phys. 2022; 23(7):e13631.

[159] Buchner JA, Kofler F, Etzel L, et al. Development and external validation of an MRI-based neural network for brain metastasis segmentation in the AURORA multicenter study. Radiother Oncol. 2023; 178:109425.

[160] Liu G, Zhao L, Li X, et al. A Novel Ultrahigh-Dose-Rate Proton Therapy Technology: Spot-Scanning Proton Arc Therapy + FLASH (SPLASH). Int J Radiat Oncol Biol Phys. 2023; 117(3): 730-737.

[161] Bourhis J, Sozzi WJ, Jorge PG, et al. Treatment of a first patient with FLASH-radiotherapy. Radiother Oncol. 2019; 139: 18-22.

[162] Mascia AE, Daugherty EC, Zhang Y, et al. Proton FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases: The FAST-01 Nonrandomized Trial. JAMA Oncol. 2023; 9(1): 62-69.

[163] Daugherty EC, Mascia AE, Sertorio MGB, et al. FAST-01: Results of the First-in-Human Study of Proton FLASH Radiotherapy. Int J Radiat Oncol Biol Phys. 2022; 114(3, Supplement): S4.

[164] Daugherty EC, Zhang Y, Xiao Z, et al. FLASH radiotherapy for the treatment of symptomatic bone metastases in the thorax (FAST-02): protocol for a prospective study of a novel radiotherapy approach. Radiat Oncol. 2024; 19(1): 34.

[165] Klaver YLB, Hoogeman MS, Lu QR, et al. Requirements and Study Design for the Next Proton FLASH Clinical Trials: an International Multidisciplinary Delphi Consensus. Int J Radiat Oncol Biol Phys. 2025; 123(1): 296-305.

[166] Gao F, Yang Y, Zhu H, et al. First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays. Radiother Oncol. 2022; 166: 44-50.

[167] Shi X, Yang Y, Zhang W, et al. FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy. Proc Natl Acad Sci USA. 2022; 119(43):e2208506119.

[168] Liu F, Shi J, Zha H, et al. Development of a compact linear accelerator to generate ultrahigh dose rate high-energy X-rays for FLASH radiotherapy applications. Med Phys. 2023; 50(3): 1680-1698.

[169] Yang Y, Wang J, Gao F, et al. FLASH radiotherapy using high-energy X-rays: Current status of PARTER platform in FLASH research. Radiother Oncol. 2023: 109967.

[170] Yuan J, Liu H, Zheng Y. Radiation therapy delivered in 0.03 seconds! Our hospital leads domestic e-Flash clinical trial results [in Chinese]. West China Hospital of Sichuan University. Published October 14, 2025. Accessed January 20, 2026. https://www.wchscu.cn/comprehensive/88619.html?utm_source=chatgpt.com

[171] Zhao X, Huang S, Lin H, et al. A Novel Dose Rate Optimization Method to Maximize Ultrahigh-Dose-Rate Coverage of Critical Organs at Risk Without Compromising Dosimetry Metrics in Proton Pencil Beam Scanning FLASH Radiation Therapy. Int J Radiat Oncol Biol Phys. 2024; 120(4): 1181-1191.

[172] Fang W-C, Huang X-X, Tan J-H, et al. Proton linac-based therapy facility for ultra-high dose rate (FLASH) treatment. Nuclear Science and Techniques. 2021; 32(4): 34.

[173] Stark LS, Andratschke N, Baumgartl M, et al. Dosimetric and geometric end-to-end accuracy of a magnetic resonance guided linear accelerator. Phys Imaging Radiat Oncol. 2020; 16: 109-112.

[174] McDonald BA, Dal Bello R, Fuller CD, Balermpas P. The Use of MR-Guided Radiation Therapy for Head and Neck Cancer and Recommended Reporting Guidance. Semin Radiat Oncol. 2024; 34(1): 69-83.

[175] Westerhoff JM, Daamen LA, Christodouleas JP, et al. Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy. JAMA Netw Open. 2024; 7(5):e2410819.

[176] Zhan B, Xiao J, Cao C, et al. Multi-constraint generative adversarial network for dose prediction in radiotherapy. Med Image Anal. 2022; 77:102339.

[177] Kajikawa T, Kadoya N, Ito K, et al. A convolutional neural network approach for IMRT dose distribution prediction in prostate cancer patients. J Radiat Res. 2019; 60(5): 685-693.

[178] Kida S, Kaji S, Nawa K, et al. Visual enhancement of Cone-beam CT by use of CycleGAN. Med Phys. 2020; 47(3): 998-1010.

[179] Zhou D, Nakamura M, Mukumoto N, Matsuo Y, Mizowaki T. Feasibility study of deep learning-based markerless real-time lung tumor tracking with orthogonal X-ray projection images. J Appl Clin Med Phys. 2023; 24(4):e13894.

[180] Mayerhoefer ME, Materka A, Langs G, et al. Introduction to Radiomics. J Nucl Med. 2020; 61(4): 488-495.

[181] Calvaruso M, Pucci G, Alberghina C, Minafra L. Radiation Therapy Personalization in Cancer Treatment: Strategies and Perspectives. Int J Mol Sci. 2025; 26(13):6375.

[182] Lee NY, Sherman EJ, Schöder H, et al. Intra-treatment hypoxia directed major radiation de-escalation as definitive treatment for human papillomavirus-related oropharyngeal cancer. J Clin Oncol. 2024; 42(16_suppl): 6007.

[183] Harary PM, Rajaram S, Chen MS, Hori YS, Park DJ, Chang SD. Genomic predictors of radiation response: recent progress towards personalized radiotherapy for brain metastases. Cell Death Discov. 2024; 10(1): 501.

[184] Dang Y, Qi T, Gao H, Huang S. Radiotherapy combined with cytokine-induced killer cell therapy for liver metastasis from rectal cancer: A case report. Medicine (Baltimore). 2019; 98(43):e17636.

[185] Kuhnl A, Roddie C, Kirkwood AA, et al. Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK. Br J Haematol. 2024; 205(2): 483-494.

[186] Imber BS, Sadelain M, DeSelm C, et al. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy. Br J Haematol. 2020; 190(1): 45-51.

[187] Zhou M, Chen M, Shi B, et al. Radiation enhances the efficacy of EGFR-targeted CAR-T cells against triple-negative breast cancer by activating NF-κB/Icam1 signaling. Mol Ther. 2022; 30(11): 3379-3393.

[188] Murty S, Haile ST, Beinat C, et al. Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model. Oncoimmunology. 2020; 9(1):1757360.

[189] DeSelm C, Palomba ML, Yahalom J, et al. Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape. Mol Ther. 2018; 26(11): 2542-2552.

[190] Lin X, Liu Z, Dong X, et al. Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma. J Transl Med. 2024; 22(1): 929.

[191] Dymova MA, Taskaev SY, Richter VA, Kuligina EV. Boron neutron capture therapy: Current status and future perspectives. Cancer Commun (Lond). 2020; 40(9): 406-421.

[192] Takeno S, Yoshino Y, Aihara T, et al. Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period. Cancer Med. 2024; 13(11):e7250.

[193] Miyatake S, Kawabata S, Yokoyama K, et al. Survival benefit of Boron neutron capture therapy for recurrent malignant gliomas. J Neurooncol. 2009; 91(2): 199-206.

[194] Kawabata S, Miyatake S, Kuroiwa T, et al. Boron neutron capture therapy for newly diagnosed glioblastoma. J Radiat Res. 2009; 50(1): 51-60.

[195] Hiratsuka J, Kamitani N, Tanaka R, et al. Long-term outcome of cutaneous melanoma patients treated with boron neutron capture therapy (BNCT). J Radiat Res. 2020; 61(6): 945-951.

[196] Barth RF, Mi P, Yang W. Boron delivery agents for neutron capture therapy of cancer. Cancer Commun (Lond). 2018; 38(1): 35.

[197] Kong FM, Ten Haken RK, Schipper M, et al. Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2017; 3(10): 1358-1365.

[198] Tucker SL, Liu HH, Liao Z, et al. Analysis of radiation pneumonitis risk using a generalized Lyman model. Int J Radiat Oncol Biol Phys. 2008; 72(2): 568-574.

[199] Nie T, Chen Z, Cai J, et al. Integration of dosimetric parameters, clinical factors, and radiomics to predict symptomatic radiation pneumonitis in lung cancer patients undergoing combined immunotherapy and radiotherapy. Radiother Oncol. 2024; 190:110047.

[200] Dong Y, Zhang J, Lam S, et al. Multimodal Data Integration to Predict Severe Acute Oral Mucositis of Nasopharyngeal Carcinoma Patients Following Radiation Therapy. Cancers (Basel). 2023; 15(7):2032.

[201] Dona Lemus OM, Cao M, Cai B, Cummings M, Zheng D. Adaptive Radiotherapy: Next-Generation Radiotherapy. Cancers (Basel). 2024; 16(6):1206.

[202] Salako O, Fagbenro G, Joseph A, Enyi AF, Adegboyega BC, Okunade KS. An ehealth intervention during radical radiotherapy: Patient-Reported Outcome Side effects (PROSE) study—An emerging approach from sub-Saharan Africa. J Clin Oncol. 2023; 41(16_suppl): 6628-6628.

Rights & permissions

2026 The Author(s). Precision Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Shandong Cancer Hospital & Institute.