EFFECTS OF PROTON THERAPY COMBINED WITH CHEMOTHERAPY

Conventional chemotherapy stimulates anti‐tumor immunity in several ways: by initiating the release of immunostimulatory molecules from dying tumor cells, mediating off‐target effects on immune cell populations, and activating the whole‐body immune system. 134 Correspondingly, the combination of photon radiation with chemotherapy can improve anti‐tumor efficacy through additive effects, 135 which has been widely utilized in numerous tumors such as NSCLC, 136 lymphoma, 137 , 138 esophageal carcinoma, 139 and pancreatic cancer. 140 Given that proton therapy exerts excellent therapeutic effects alongside low radiation toxicity, the combination of proton therapy with chemotherapy has been proposed as a new treatment strategy (Table 3 ). Early studies have suggested that the main advantage of combining proton therapy with chemotherapy lies in reducing radiation toxicity instead of improving survival outcomes. For example, a large cohort study involving patients with Hodgkin's lymphoma showed that those who received proton therapy following standard chemotherapy experienced no early grade 3 toxicity. Additionally, the early relapse‐free survival rates were similar to those of photon radiation treatment. 121 Similarly, although combining proton therapy with capecitabine chemotherapy did not significantly improve the 1‐year OS of patients with unresectable, borderline resectable, or medically inoperable pancreatic cancer, it did significantly reduce the risk of surgical or perioperative complications in patients with borderline resectable disease. 120 In patients with central nervous system germ cell tumors, systemic chemotherapy (cisplatin, cyclophosphamide, etoposide, and/or bleomycin) followed by proton therapy did not result in better 5‐year EFS or OS rates than chemotherapy followed by photon therapy. This was true for both low‐risk (PEFS = 0.457, POS = 0.485) and high‐risk (PEFS = 0.605, POS = 0.392) groups. 114 Recent studies have indicated that combining proton therapy with chemotherapy can improve the survival outcomes of patients with cancer. For NSCLC, Contreras et al. reported that treatment involving large‐fraction proton beam radiation of 60 Gy delivered over 15 sessions, combined with cisplatin and paclitaxel chemotherapy, resulted in high rates of locoregional control and OS, along with good acute tolerability. 115 A phase I/II single‐arm nonrandomized prospective multicenter trial also reached similar conclusions. Researchers found that large‐fraction proton therapy, delivering doses ranging from 2.5 to 3.53 Gy per fraction and combined with platinum‐based treatment for stage II or III unresectable NSCLC, resulted in high overall survival rates. Specifically, the OS rates were 89% and 49% at 1 and 3 years, respectively, with PFS rates of 58% and 32%. 116 Additionally, a retrospective analysis of NSCLC with negative driver genes revealed that combination therapy including proton therapy and chemotherapy (albumin‐bound paclitaxel and cisplatin) provided a survival advantage over X‐ray treatment, particularly in the later stages, which eventually contributed to longer OS by the third year (51.6 ± 4.62 months, 95% CI, 42.5 ∼ 60.7 vs 33.1 ± 1.99 months; 95% CI, 29.2 ∼ 37.1; P<0.05). 117 Based on these findings, proton therapy combined with chemotherapy could not only minimize radiation‐related toxicity in NSCLC but also improve survival outcomes, especially in the late stages. IMPT, an efficient type of proton therapy, when used alongside chemotherapy (fluorouracil, taxanes, and/or platinum), could improve long‐term survival outcomes in patients with locally advanced esophageal cancer (5‐year OS rate: 41.1%; PFS: 34.6%; local regional recurrence‐free survival: 78.1%; distant metastasis‐free survival: 65.0%) and simultaneously reduced the risk of cardiopulmonary toxicity. 118 Differences in the survival outcomes of the combination of proton therapy and chemotherapy could be attributed to tumor heterogeneity and the relatively small sample size. Thus, large‐scale prospective multicenter clinical studies are necessary to better illustrate these therapeutic effects. In addition, research on the transcriptional profile and immune landscape after combination treatment is worthy of attention.