Particle therapy in gastrointestinal cancer—a narrative review

Introduction

With advances in cancer therapy, cancer survivors are living significantly longer. Acute and chronic side effects as well as quality of life play an increasingly important role in treatment of cancer. Thus, the minimization or avoidance of side effects is—besides tumor control—one of the main goals in modern radiation therapy.

Though pretty similar in their effect on tumor cells, there are vast differences between conventional photon (X-ray) radiation and charged particles such as protons or even heavy ions. Due to their physical properties, photons have a potentially infinite range. However, the penetration depth of any kind of radiation into matter is limited by a variety of interactions. The predominantly limiting effects for photons are the photoelectric effect, the Compton effect, scattering, pair formation and nuclear reactions depending on the energy of the photons as well as the material of the irradiated tissue. An exponential weakening begins from the moment the radiation hits matter; therefore, the main energy output already takes place in the entry area of the beam. In contrast, the deceleration of particle radiation (which, due to its physical properties has a finite range) happens through interactions with atomic nuclei and electrons of the atomic shell. The probability of interaction increases with decreasing velocity of the particle. Since ions of the same energy are used in medical applications, the main energy release takes place at a defined point, the so-called Bragg peak. This point of maximum energy release can be modified via the initial particle energy (velocity). Thus, a precise energy deposition in the tumor tissue with simultaneously very low energy release in the surrounding (normal) tissue is possible. Thus, very steep dose gradients and often significantly better dosimetric protection of organs at risk can be achieved. The biological rationale for heavy ions in radiation therapy is based on their higher energy output compared to protons or photons. This higher energy output results in a significantly increased ionization density, leading to a greater probability of interaction with DNA. As a result, heavy ions exhibit an increased relative biological effectiveness (RBE) compared to photon irradiation. This advantage seems particularly beneficial in treating hypoxic tissues that are resistant to conventional photon radiation, as heavy ions have more direct interactions with DNA and less dependence on radical formation based on oxygen. This is why heavy ions are used for the radiotherapy of normally radioresistant tumors.

While this sounds beneficial and easy in theory, the high precision may trigger other problems, especially in moving targets/organs like the luminal gastrointestinal (GI) system. The precision of particle radiotherapy can be heavily influenced by air in the beam direction and is prone to dose inhomogeneities, especially in tissues surrounded by structures with changing fillings of gases. Thus, the robustness of the particle-radiotherapy plan (i.e., if the dose can be applied as planned in every fraction) will be influenced much more profoundly by anatomical changes than photon radiation. Moreover, dosimetric advantages do not necessarily translate into clinically meaningful benefits.

Whilst there are ample dosimetric studies concerning the use of particle therapy in GI-cancers, clinical data are still rather scarce. Several review articles have been published, the latest in 2022 (1). Regarding randomized data only one trial concerning proton therapy in esophageal cancer has been published so far (2). In the following parts we will discuss the current literature on particle therapy for esophageal, pancreatic, liver and anorectal cancer. I present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-757/rc).

Methods

Publications (up to August 2023) in English language were searched in PubMed and Web of Science. After analysis, the references of the selected publications were also searched for further relevant publications. As specific data are scarce, no minimum of patients in the according publications could be defined. Nevertheless, case reports were excluded from review (Table 1).

Esophageal cancer

Depending on the tumor staging, chemoradiotherapy is one of the standard treatments in esophageal cancer. Nevertheless, the incidence of late cardiopulmonary toxicities grade 3 and higher was found to be 29–45% in several clinical studies (3,4). The use of intensity modulated radiotherapy (IMRT) can reduce the heart dose with a significant sparing of the right coronary artery (5) or several other substructures (6) which results in a significantly reduced incidence of cardiac deaths compared to three-dimensional conformal radiotherapy (3D-CRT) (7). Taking abovementioned possible advantages of particle therapy into consideration, an even better sparing of organs at risk and a reduction of side effects seems possible, using charged particles. Also, the lungs can be spared significantly better, especially considering widespread low radiation doses. The first clinical studies to include proton therapy (as a boost in combination with a conventional therapy or proton only therapy) in esophageal cancer were performed in Japan and were mostly dose escalation studies with doses up to 80.4 Gy. Good disease specific survival rates of around 90% for superficial and around 35% for advanced lesions after 5 to 10 years could be found (8-10). Nevertheless, it needs to be mentioned, that a higher risk for esophageal ulcers was observed with doses >80 Gy in one study, which is not necessarily surprising (11). Furthermore, it needs to be discussed, that patients were treated with radiotherapy only. At least in comparison to photons, combined radiochemotherapy is superior to radiotherapy alone (12).

Even though radiochemotherapy has been a standard treatment for many years in esophageal cancer, data for the combination of a systemic therapy with particle radiotherapy are scarce.

Ishikawa et al. reported on 67 patients with squamous cell carcinoma who received 60 Gy (RBE) in 30 fractions (13). The 4-year overall survival (OS) rates for stages I, II and III were 96%, 73% and 40%, respectively.

The only prospective randomized study concerning neoadjuvant proton therapy in esophageal cancer was performed at MD Anderson Cancer Center (2). A total of 107 patients who received concurrent radiochemotherapy were randomized between proton therapy and IMRT with the same prescription dose of 50.4 Gy. There was no difference between the two groups in the 3-year OS and progression-free survival (PFS) rates. A significant difference could be determined in the total toxicity burden (TTB) which was also the primary endpoint of the trial. The TTB was 2.3 times higher in the IMRT arm. Furthermore, postoperative complications were 7.6 times higher in the IMRT arm. It needs to be mentioned, that the decrease in TTB in the proton arm was mainly driven by the decrease in postoperative complications. No significant differences could be determined when the individual adverse events were compared and analyzed. An overview of the study results can be found in Table 2.

The question may arise, why no dose escalation in this neoadjuvant setting was performed if this seems to be feasible as some of the abovementioned studies have shown. The reason is rather simple. Particle therapy may have dosimetric advantages concerning organs at risk that are close to the target volume. The main problem regarding radiation toxicity in esophageal irradiation is the esophagus itself, which in this particular case is target and organ at risk at the same time. If dose escalation creates significant side effects in the esophagus itself, consequent surgery may be compromised, delayed or in the worst case impossible.

Pancreatic cancer

Pancreatic cancer remains an oncological diagnosis with a grim prognosis as most patients present with metastatic disease and only about 10–20% are eligible for resection, which is the only curative treatment option. However, even more than 80% of patients who undergo surgery die due to local recurrence or metastatic disease (14,15).

The standard postoperative therapy includes chemotherapy, the role of concomitant radiochemotherapy is still subject to discussion though several studies described a possible benefit for local control (LC) when performing radiochemotherapy (16,17). Being surrounded by many radiosensitive organs at risk, the steep dose gradients of particle therapy are preferable over conventional photon therapy. Several plan comparison studies were able to show dosimetric advantages of proton therapy over photon therapy. For example, Thompson et al. were able to show reductions in the low and moderate doses to the stomach and the small bowel with the best results being achieved while using a pencil beam scanning technique (18). In a postoperative setting, Nichols et al. were able to show drastic dose reductions in the small bowel and stomach using protons (19).

Clinical data are scarce with no randomized trials comparing particle therapy to conventional radiotherapy. The existing data are limited to rather small, mostly retrospective, case series. For preoperative radiochemotherapy the larges cohort with 50 patients was reviewed by Hong et al. (20). Thirty-seven patients underwent pancreaticoduodenectomy. LC was achieved in 84% of patients with a 4.1% rate of grade 3 toxicity and 0% of grade 4 or 5 toxicity.

The main application for particle therapy may be unresectable pancreatic carcinomas, in which dose escalation may be of advantage considering local tumor control. Combined approaches with particle therapy after neoadjuvant chemotherapy also seem possible. Albeit being a promising field of research data are also scarce. For unresectable pancreatic carcinoma a larger cohort of 50 patients was reviewed by Terashima et al. (21). The 1-year LC rate was 81.7% with a rate of late toxicity grade 3+ of 10%. Ami et al. recently reported retrospectively on 200 patients who were treated with protons [67.5 Gy (RBE)] with or without chemotherapy. LC rate after 2 years was 44.3% and OS after 2 years was 35.4% (22).

Concerning a definitive treatment in locally recurrent pancreatic cancer, a collective of 13 patients was irradiated with carbon ions at Heidelberg. Though most patients developed distant metastases, the estimated 1-year LC and locoregional control rates were 87.5% and 75%, respectively. One patient suffered from G3 toxicity (GI bleeding). Apart from that no further higher-grade acute or late toxicities were observed (23). Table 3 contains an overview of the study results.

Generally speaking, because of the surrounding bowels, dose uncertainties are a relevant point concerning particle therapy. Due to the bowel movement and changing filling (especially changes in gas load), significant changes in anatomy and therefore dose distribution can occur, even between two fractions and close monitoring under radiotherapy is necessary. So far, the clinical data imply that particle therapy for pancreatic cancer is safe and effective, though larger analyses or even randomized studies could augment the use of particle therapy in the treatment of pancreatic cancer.

Liver cancer

In 2020 primary liver cancer was the sixth most common neoplasm and the third leading cause of cancer-related death worldwide. Rates of incidence as well as mortality are 2 to 3 times higher among men. Hepatocellular carcinoma (HCC) account for the majority of liver cancer cases (75–85%) (24).

Still, surgical resection or orthotopic liver transplantation (OLT) are the therapies of choice with a 5-year survival up to 60–70% (25). Nevertheless, only a minority of patients are suitable for resection or OLT due to medical or anatomical reasons. Other local therapies like transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) may be used in a palliative setting. Radiation therapy has played a minor role historically, as the dose required for sufficient tumor control surpasses the dose tolerance of the liver, especially as those tumors mostly occur in damaged livers with impaired function (26). The technical improvements in IMRT and stereotactic body radiotherapy (SBRT) concerning dose conformity have established new possibilities for photon radiotherapy of the liver (27). Nevertheless, the cumulative entry and exit doses of conventional radiotherapy may still exceed the dose tolerance of the healthy liver tissue. Because of the abovementioned properties with superior target conformation, particle therapy may be of particular interest in the treatment of liver tumors (28,29).

Several studies have been published on the use of particle therapy in HCC, especially for the use of protons. Kawashima et al. performed one of the first prospective trials, which included 30 patients with solitary tumors and liver cirrhosis (30). Patients had a median tumor size of 4.5 cm and were treated with 76 Gy (RBE) in 20 fractions. During the median follow-up of 31 months, only one patient experienced a local recurrence and the 2-year OS was 66% with minimal acute toxicity. In another prospective trial 51 patients with a median tumor size of 2.8 cm and Child-Pugh class A or B cirrhosis were treated with 66 Gy (RBE) in 10 fractions (31). The 5-year LC rate was 87.8% and OS was 38.7%, in patients with Child-Pugh class A cirrhosis OS was 42.1%. Patients experienced only minor toxicities. Bush et al. reported on 76 patients of which 54% were outside of Milan criteria, 24% had Child-Pugh class C cirrhosis and 16% had a model of end-stage liver disease (MELD) score >15 (32). Patients received 63 Gy (RBE) in 25 fractions. The median PFS was 36 months with a 3-year PFS rate of 60% for patients within the Milan criteria. Median time to failure was 18 months with a LC rate of 80%. Acute toxicity was again minimal. The same group performed an interesting randomized trial comparing TACE with proton therapy [70.2 Gy (RBE) in 15 fractions] (33). Total number of hospitalization days within 30 days of the procedures (62 vs. 2, P<0.001) as well as total hospitalization days (166 vs. 24, P<0.001) were in favor of proton therapy. There was no difference concerning median survival (32 months) or 2-year OS (65% vs. 68%, P=0.8). Nevertheless, there was a significantly better 2-year LC and PFS in patients who received proton therapy. Komatsu et al. reported on 343 patients treated with protons and carbon-ions (34). Dose and fractionation schemes were rather widespread [52.8–84.0 Gy (RBE)/4–38 fractions for protons; 52.8–76.0/4–20 for carbon ions]. LC rate after 5 years was reported to be 90.8% and OS 38.2%. Three patients experienced grade 3 toxicities. Radiation induced hepatic dysfunction was found in four patients.

Concerning carbon ion therapy, 24 patients were treated in a phase I/II trial by Kato et al. (35). Total dose was 49.5–79.5 Gy (RBE) in 15 fractions. LC rate after 3 years was 81% and OS after 5 years 25%. No severe liver injury was observed. Shibuya et a retrospectively reported on 174 patients treated in ultra-hypofractionated settings with either 52.8 Gy (RBE)/4 fractions, 60.0/4 or 48/2, respectively (36). LC rate and OS at 3 years were 87.7% and 73.3%, respectively. The rate of grade 3–4 toxicities was 5.7%.

Hiroshima et al. retrospectively analyzed 58 patients with Child B cirrhosis who underwent carbon-ion therapy with doses between 45 and 60 Gy (RBE) in 2 to 4 fractions (37). LC rate after 2 years was 96.4% and OS 46%. Another retrospective analysis was published by Tomizawa et al. (38). In a recurrent situation, 41 patients were treated with 52.8–60.0 Gy (RBE) in 4–12 fractions. The 2-year OS and LC rate were 83.0% and 56%, respectively.

Regarding the comparison between carbon-ion therapy and TACE, Shiba et al. published the results of a propensity score matching study in 2019 (39). After 3 years, carbon ion therapy was significantly better in OS (88% vs. 58%; P<0.05), LC rate (80% vs. 26%; P<0.01) and PFS (51% vs. 15%; P<0.05).

An overview of the study results can be found in Table 4.

In summary, the level of evidence for particle therapy in HCC is much better than in other GI-tumors with encouraging results concerning OS and LC and low rates of side effects. Nevertheless, most studies are retrospective and further (especially randomized) evidence is needed.

Anorectal cancer

Radiochemotherapy is traditionally one of the cornerstones in the treatment of anorectal cancer. As LC rates are rather high in anorectal cancer, the main rationale for particle therapy may be the minimization of side effects or the treatment of local relapses.

Dosimetric studies were able to show better sparing of the organs at risk (OARs) while using proton therapy (40-42).

Clinical data go back to 1977 when Suit et al. reported on patients with different types of cancer. Patients with anorectal cancer were included and the treatment was tolerated well (43). Jeans et al. reported on the use of a neoadjuvant short-term proton therapy, which was tolerated very well with no side effects > grade 2 (44). The only comparative study was conducted by Mohiuddin et al. (45). Two hundred and eight patients with anal squamous cell carcinoma who received either proton or photon therapy were compared. There was no difference in LC or toxicity; proton therapy was dosimetrically superior compared to the photon therapy. In 2011, Lee et al. reported on 67 patients with locally recurrent rectal cancer. It was noted that in the four patients who received protons as a part of the concurrent chemoradiation therapy, higher doses could be prescribed even with OARs in close proximity (46).

Meanwhile, the therapy regimen has changed significantly with total neoadjuvant therapy (TNT) offering the chance of better disease-free survival and lower risk of distant metastasis (47) in rectal cancer. A randomized study from Sweden (PRORECT) is comparing preoperative short-course radiotherapy with protons to photons as part of a TNT approach. So far only dosimetric results have been published, showing significantly less dose in the organs at risk using protons (48).

This leaves the treatment of locally recurrent anorectal cancer as a field of special interest regarding the use of particle therapy. Nevertheless, only little data are available let alone randomized data. A large collective consists of 235 patients that were treated in a phase I/II dose escalation study with carbon ions in Japan. Total dose ranged from 67.2 to 73.6 Gy (RBE). Patients were treated over the course of 4 weeks with a low number of adverse events (one GI ulcer grade 3 was described, no further acute reactions > grade 2). The overall LC rate was 90% at 3 years and 88% at 5 years (49).

Concerning the use of protons in recurrent anorectal cancer, Hiroshima et al. reported on 12 patients, who received a proton therapy with a 3-year LC rate of 80.2% (50).

With good LC rates and low side effects, reirradiation to the pelvis with particles seems to be a treatment alternative worth considering in patients with recurrent anorectal cancer. Nevertheless, randomized trials are urgently needed as the level of evidence is still rather low.

The results of the studies are summarized in Table 5.

Conclusions

The use of particle therapy in GI cancer seems promising, though clinical data are scarce for most tumor entities. Dosimetric analyses were able to show clear advantages over conventional photon therapy, which can result in lower toxicity rates. The few available clinical trials suggest that particle therapy is safe and effective in the therapy of GI cancers. Solid clinical data are only available for HCC; yet randomized phase III trials are still lacking. Nevertheless, particle therapy is considerably more laborious in terms of work and cost. This can only be justified, if the dosimetric advantages translate into meaningful clinical advantages—either improved tumor control or reduced toxicity. Both have not been shown yet for most GI indications. Further clinical evidence, especially randomized trials, is crucial to augment the role of particle therapy in the treatment of GI cancer.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Falk Roeder and Thomas Brunner) for the series “Precision Radiation Oncology in GI Cancers” published in Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-757/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-757/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-757/coif). The series “Precision Radiation Oncology in GI Cancers” was commissioned by the editorial office without any funding or sponsorship. M.M. receives travel grants from Pharmamar. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kobeissi JM, Simone CB 2nd, Hilal L, et al. Proton Therapy in the Management of Luminal Gastrointestinal Cancers: Esophagus, Stomach, and Anorectum. Cancers (Basel) 2022;14:2877. [Crossref] [PubMed]
2. Lin SH, Hobbs BP, Verma V, et al. Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer. J Clin Oncol 2020;38:1569-79. [Crossref] [PubMed]
3. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167-74. [Crossref] [PubMed]
4. Morota M, Gomi K, Kozuka T, et al. Late toxicity after definitive concurrent chemoradiotherapy for thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys 2009;75:122-8. [Crossref] [PubMed]
5. Kole TP, Aghayere O, Kwah J, et al. Comparison of heart and coronary artery doses associated with intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for distal esophageal cancer. Int J Radiat Oncol Biol Phys 2012;83:1580-6. [Crossref] [PubMed]
6. Shiraishi Y, Xu C, Yang J, et al. Dosimetric comparison to the heart and cardiac substructure in a large cohort of esophageal cancer patients treated with proton beam therapy or Intensity-modulated radiation therapy. Radiother Oncol 2017;125:48-54. [Crossref] [PubMed]
7. Lin SH, Wang L, Myles B, et al. Propensity score-based comparison of long-term outcomes with 3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2012;84:1078-85. [Crossref] [PubMed]
8. Koyama S, Tsujii H, Yokota H, et al. Proton beam therapy for patients with esophageal carcinoma. Jpn J Clin Oncol 1994;24:144-53. [PubMed]
9. Koyama S, Tsujii H. Proton beam therapy with high-dose irradiation for superficial and advanced esophageal carcinomas. Clin Cancer Res 2003;9:3571-7. [PubMed]
10. Sugahara S, Tokuuye K, Okumura T, et al. Clinical results of proton beam therapy for cancer of the esophagus. Int J Radiat Oncol Biol Phys 2005;61:76-84. [Crossref] [PubMed]
11. Mizumoto M, Sugahara S, Nakayama H, et al. Clinical results of proton-beam therapy for locoregionally advanced esophageal cancer. Strahlenther Onkol 2010;186:482-8. [Crossref] [PubMed]
12. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-8. [Crossref] [PubMed]
13. Ishikawa H, Nonaka T, Ohnishi K, et al. Long-Term Follow-Up Results of Concurrent Chemo-Proton Therapy for Esophageal Cancer. Int J Radiat Oncol Biol Phys 2018;102:E31. [Crossref]
14. Esposito I, Kleeff J, Bergmann F, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 2008;15:1651-60. [Crossref] [PubMed]
15. Kleeff J, Reiser C, Hinz U, et al. Surgery for recurrent pancreatic ductal adenocarcinoma. Ann Surg 2007;245:566-72. [Crossref] [PubMed]
16. Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 2016;315:1844-53. [Crossref] [PubMed]
17. Groot VP, Gemenetzis G, Blair AB, et al. Implications of the Pattern of Disease Recurrence on Survival Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 2018;25:2475-83. [Crossref] [PubMed]
18. Thompson RF, Mayekar SU, Zhai H, et al. A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas. Med Phys 2014;41:081711. [Crossref] [PubMed]
19. Nichols RC Jr, Huh SN, Prado KL, et al. Protons offer reduced normal-tissue exposure for patients receiving postoperative radiotherapy for resected pancreatic head cancer. Int J Radiat Oncol Biol Phys 2012;83:158-63. [Crossref] [PubMed]
20. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys 2014;89:830-8. [Crossref] [PubMed]
21. Terashima K, Demizu Y, Hashimoto N, et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol 2012;103:25-31. [Crossref] [PubMed]
22. Ami K, Terashima K, Ishida J, et al. Proton radiotherapy as a treatment strategy to increase survival in locally advanced pancreatic cancer in the body and tail: a retrospective study. Radiat Oncol 2023;18:131. [Crossref] [PubMed]
23. Liermann J, Ben-Josef E, Syed M, et al. Carbon ion radiotherapy as definitive treatment in locally recurrent pancreatic cancer. Strahlenther Onkol 2022;198:378-87. [Crossref] [PubMed]
24. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
25. Hansen EK, Roach M. Handbook of evidence-based radiation oncology. New York: Springer; 2010.
26. Pan CC, Kavanagh BD, Dawson LA, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 2010;76:S94-100. [Crossref] [PubMed]
27. Gerum S, Heinz C, Belka C, et al. Stereotactic body radiotherapy in patients with hepatocellular carcinoma in a multimodal treatment setting. Strahlenther Onkol 2020;196:334-48. [Crossref] [PubMed]
28. Krishnan S, Dawson LA, Seong J, et al. Radiotherapy for hepatocellular carcinoma: an overview. Ann Surg Oncol 2008;15:1015-24. [Crossref] [PubMed]
29. Zurlo A, Lomax A, Hoess A, et al. The role of proton therapy in the treatment of large irradiation volumes: a comparative planning study of pancreatic and biliary tumors. Int J Radiat Oncol Biol Phys 2000;48:277-88. [Crossref] [PubMed]
30. Kawashima M, Furuse J, Nishio T, et al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 2005;23:1839-46. [Crossref] [PubMed]
31. Fukumitsu N, Sugahara S, Nakayama H, et al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2009;74:831-6. [Crossref] [PubMed]
32. Bush DA, Kayali Z, Grove R, et al. The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial. Cancer 2011;117:3053-9. [Crossref] [PubMed]
33. Bush DA, Volk M, Smith JC, et al. Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial. Cancer 2023;129:3554-63. [Crossref] [PubMed]
34. Komatsu S, Fukumoto T, Demizu Y, et al. Clinical results and risk factors of proton and carbon ion therapy for hepatocellular carcinoma. Cancer 2011;117:4890-904. [Crossref] [PubMed]
35. Kato H, Tsujii H, Miyamoto T, et al. Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis. Int J Radiat Oncol Biol Phys 2004;59:1468-76. [Crossref] [PubMed]
36. Shibuya K, Ohno T, Terashima K, et al. Short-course carbon-ion radiotherapy for hepatocellular carcinoma: A multi-institutional retrospective study. Liver Int 2018;38:2239-47. [Crossref] [PubMed]
37. Hiroshima Y, Wakatsuki M, Kaneko T, et al. Clinical impact of carbon-ion radiotherapy on hepatocellular carcinoma with Child-Pugh B cirrhosis. Cancer Med 2023;12:14004-14. [Crossref] [PubMed]
38. Tomizawa K, Shibuya K, Shiba S, et al. Repeated Carbon-Ion Radiation Therapy for Intrahepatic Recurrent Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys 2023;116:1100-9. [Crossref] [PubMed]
39. Shiba S, Shibuya K, Katoh H, et al. A comparison of carbon ion radiotherapy and transarterial chemoembolization treatment outcomes for single hepatocellular carcinoma: a propensity score matching study. Radiat Oncol 2019;14:137. [Crossref] [PubMed]
40. Palmer M, Mok H, Ciura K, et al. Dose Reduction to Small Bowel and Other Relevant Structures in Rectal Carcinoma With Proton Therapy. Int J Radiat Oncol 2012;84:S846. [Crossref]
41. Kronborg CJS, Jørgensen JB, Petersen JBB, et al. Pelvic insufficiency fractures, dose volume parameters and plan optimization after radiotherapy for rectal cancer. Clin Transl Radiat Oncol 2019;19:72-6. [Crossref] [PubMed]
42. Radu C, Norrlid O, Brændengen M, et al. Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients. Acta Oncol 2013;52:528-37. [Crossref] [PubMed]
43. Suit HD, Goitein M, Tepper JE, et al. Clinical experience and expectation with protons and heavy ions. Int J Radiat Oncol Biol Phys 1977;3:115-25. [Crossref] [PubMed]
44. Jeans EB, Jethwa KR, Harmsen WS, et al. Clinical Implementation of Preoperative Short-Course Pencil Beam Scanning Proton Therapy for Patients With Rectal Cancer. Adv Radiat Oncol 2020;5:865-70. [Crossref] [PubMed]
45. Mohiuddin JJ, Jethwa KR, Grandhi N, et al. Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus. Adv Radiat Oncol 2021;6:100744. [Crossref] [PubMed]
46. Lee JH, Kim DY, Kim SY, et al. Clinical outcomes of chemoradiotherapy for locally recurrent rectal cancer. Radiat Oncol 2011;6:51. [Crossref] [PubMed]
47. Liu S, Jiang T, Xiao L, et al. Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis. Oncologist 2021;26:e1555-66. [Crossref] [PubMed]
48. Pedone C, Sorcini B, Staff C, et al. Preoperative short-course radiation therapy with PROtons compared to photons in high-risk RECTal cancer (PRORECT): Initial dosimetric experience. Clin Transl Radiat Oncol 2022;39:100562. [Crossref] [PubMed]
49. Yamada S, Takiyama H, Isozaki Y, et al. Carbon-ion Radiotherapy for Colorectal Cancer. J Anus Rectum Colon 2021;5:113-20. [Crossref] [PubMed]
50. Hiroshima Y, Ishikawa H, Murakami M, et al. Proton Beam Therapy for Local Recurrence of Rectal Cancer. Anticancer Res 2021;41:3589-95. [Crossref] [PubMed]