Reirradiation presents a significant challenge despite recent advances in modern radiation therapy. Carbon ion radiotherapy has garnered increasing attention among radiation oncologists due to its potentially superior physical dosimetric distribution and radiobiological advantages. This systematic review comprehensively evaluated clinical outcomes from 27 original studies on the use of carbon ion reirradiation for locoregional recurrent malignancies, including those affecting the central nervous system, lung, head and neck, pancreas, liver, rectum, and gynecological sites. The findings suggest that carbon ion reirradiation for locoregional recurrent malignancies yields favorable clinical outcomes with a relatively low incidence of high-grade toxicities. For recurrent nasopharyngeal carcinoma, the reported 2-year overall survival, local control, regional control, and metastasis-free survival rates were 83.7%, 58.0%, 87.3%, and 94.7%, respectively. Grade ≥3 late nasopharyngeal necrosis occurred in 16% (33/206) of cases. In the case of recurrent glioblastoma, median overall survival and local control survival were reported at 13 and 7 months, respectively, with minimal high-grade complications; observed low-grade toxicities included acute involuntary movements, incomplete hemiparesis, and late-onset dysphasia. For recurrent lung cancer, 2-year local control and overall survival rates were reported as 54.0% and 61.9%, respectively. Grade ≥3 toxicities included two cases of radiation pneumonitis and one case of bronchopleural fistula. In recurrent pancreatic cancer, 1-year local control, progression-free survival, and overall survival rates were 53.5%, 24.5%, and 48.7%, respectively. A high-grade complication of Grade 3 acute duodenal stenosis was observed in one patient. Additionally, concurrent chemotherapy with carbon ion reirradiation was associated with minimal high-grade additive toxicities. Overall, carbon ion reirradiation appears to be a potentially safe and effective reirradiation modality for treating locoregional recurrent malignancies, though data remains limited.

Head and neck cancer (HNC) is a complex, heterogeneous group of malignancies. In treatment a combined modality therapy with surgery, radiotherapy and chemotherapy is usually advised. The use of charged particles was a breakthrough in radiation oncology and allowed the initiation of cancer treatment with high-precision. The purpose of the work is to discuss the role of carbon ion radiotherapy in the treatment of head and neck cancers.

Heavy ions such as carbon have more favorable physical and radiobiological properties than photons. The unique properties of carbon ions enable radiotherapy with dose escalation to tumors, while reducing both, radiation dose to adjacent normal tissues and radiation area. Considering its exceptional features, carbon ion radiotherapy offers promising results with acceptable toxicity regarding treatment of uncommon and rare malignancies, especially treated for a recurrent disease. HNC patients with adenoid cystic carcinoma and mucosal melanoma of the head and neck, which are considered to be radiation resistant, should benefit more from carbon ion radiotherapy than proton beam therapy or conventional photon radiotherapy. Also selected patients with other head and neck malignancies can benefit form carbon ion radiotherapy including advanced salivary gland cancer and nasopharyngeal cancer patients. Carbon ion radiotherapy offers better dose distributions, higher tumor doses, and an increased odds of local control and prolonged survival. Carbon ion radiotherapy represents a promising alternative to conventional photon RT or even proton beam therapy especially in treatment of radioresistant tumors situated close to critical organs.

Heavy ion radiotherapy is an emerging technology for treating radioresistant solid tumors. Unlike current low-linear energy transfer techniques, heavy ion radiotherapy, such as carbon ion radiotherapy, enhances the biologic effects related to cancer therapy. Prospective clinical evidence has demonstrated feasibility and efficacy in several disease sites, including head and neck, thoracic, central nervous system, gastrointestinal, pelvic tumors, and sarcomas. Although presently unavailable in the Americas, Mayo Clinic is constructing a heavy ion facility in the United States that is planned for clinical operation in 2028.

To describe the role of hadrontherapy (HT) in treating radioresistant, rare, recurrent, and radio-induced tumors, which can be defined, in assonance with the 4Rs of radiobiology, the "4Rs" of HT indications.

This is a narrative review written by a multidisciplinary team consisting of radiation oncologists, radiobiologists, and physicists on the current literature on HT, particularly carbon ion radiation therapy. To refine HT indications within the context of the "4Rs" framework, we evaluated tumor histologies across different clinical indication settings and emphasized the radiobiological mechanisms contributing to the effectiveness of HT.

For rare, radioresistant, recurrent, and radio-induced tumors, HT has proven to be effective and safe, achieving high rates of local response with mild toxicity. The current review shows that the biological parameters can assist clinicians in identifying appropriate cases for HT treatment.

Biological characteristics of the tumor support the administration of HT in radioresistant, rare, recurrent, and radio-induced tumors and should be considered during multidisciplinary discussions.

Rectal cancer recurrence after prior radiation therapy presents a difficult treatment challenge. Salvage treatment can be curative; however, it often requires multimodality therapy which can come with significant treatment-related morbidity. Reirradiation is a common part of treatment considerations in this setting and presents challenges in balancing appropriately aggressive therapy to improve disease control and cure rates with the addition of excess toxicity. Surgery remains the mainstay of curative salvage therapy for locally recurrent rectal cancer (LRRC) after prior radiation. Preoperative reirradiation improves R0 resection rates and local control and is associated with improved disease control outcomes. Altered fractionation and intraoperative radiation therapy are often used to improve the therapeutic ratio in the setting of reirradiation for LRRC. Herein, we discuss the evidence supporting multimodality salvage therapy for LRRC, including the importance of surgical salvage, the benefits of reirradiation, various approaches for reirradiation, and treatment-associated toxicities. Finally, we provide our recommendations for how to approach reirradiation for locally recurrent rectal cancer.

Carbon Ion Radiation Therapy is operated in several countries because of its advantage to have high dose concentration and/or high linear energy transfer (LET). To estimate the beam performance of Carbon Ion Radiation Therapy, we target the 1% energy and 1 mm2 position resolutions of the beam monitoring system. The beam monitoring system consists of a scintillation crystal and fiber hodoscope. The scintillation crystal is 20 × 20 × 120mm3 and its candidates are LYSO, CsI and BGO. The fiber hodoscope is composed of 1 mm thickness scintillation fibers and the fibers are arranged vertically for 2D reconstruction. With GEANT4 simulation, we verify the performance of our beam monitoring system. The energy response of the LYSO and BGO scintillators is linear within ± 2%. The energy resolution of each crystal candidate achieves the goal; LYSO (0.061%), CsI (0.20%) and BGO (0.10%). The position is reconstructed via fiber hodoscope within 5% uncertainty.

In this editorial, I would like to comment on the article, recently published in the World Journal of Clinical Oncology. The article focuses on non-surgical treatments for locally recurrent rectal cancer, including the watch-and-wait (WW) strategy after total neoadjuvant therapy (TNT) and particle beam therapy. As treatment options for rectal cancer continue to evolve, the high complete response rate achieved with TNT has led to the development of a new non-surgical approach: WW. Chemoradiotherapy followed by consolidation chemotherapy, in particular, has a low rate of tumor growth and is a treatment aimed at achieving a cure without surgery. However, the risk of recurrence within two years is significant, necessitating careful follow-up. Establishing standardized follow-up methods that can be implemented by many physicians is essential. Carbon ion radiotherapy has demonstrated high local control with a low incidence of severe late toxicities, even after previous pelvic radiotherapy. While these new non-surgical curative treatments for rectal cancer require further investigation, future advancements in this field are anticipated.

This study aimed to compare the use of a rotating gantry in liver tumor carbon-ion radiotherapy using of a fixed-port for treatment planning.

Thirty patients with liver tumors were analyzed. Three treatment plans were developed for each case: one with a rotating gantry with a 360° angle, one with fixed ports of 0° and 90° with a ±20° couch rolling setting, and one with fixed ports of 45° and 90° with a ±20° couch rolling setting. The dose-volume histogram parameters of the clinical target volume (CTV) and organs at risk (OARs) for each treatment plan were compared.

Significant differences in the volume of the liver-gross tumor volume (GTV) of normal liver irradiated with 5 Gy to 15 Gy were found between the gantry treatment plans and fixed-port treatment plans. There were no significant differences in the OARs, except for the CTV and liver GTV, between the gantry and fixed-port treatment plans.

The study results support the potential of using a rotating gantry to reduce liver doses, especially in the low-to-medium dose range, while maintaining target and OAR doses except for the liver. A rotating gantry could be especially useful in cases in which the relationship between the tumor and OAR is complicated by location.

Radiotherapy (RT) remodels the tumor immune microenvironment (TIME) and modulates the immune response to indirectly destroy tumor cells, in addition to directly killing tumor cells. RT combined with immunotherapy may significantly enhance the efficacy of RT in colorectal cancer by modulating the microenvironment. However, the molecular mechanisms by which RT acts as an immunomodulator to modulate the immune microenvironment remain unclear. Further, the optimal modalities of RT combined with immunotherapy for the treatment of colorectal cancer, such as the time point of combining RT and immunization, the fractionation pattern and dosage of radiotherapy, and other methods to improve the efficacy, are also being explored parallelly. To address these aspects, in this review, we summarized the mechanisms by which RT modulates TIME and concluded the progress of RT combined with immunization in preclinical and clinical trials. Finally, we discussed heavy ion radiation therapy and the efficacy of prediction markers and other immune combination therapies. Overall, combining RT with immunotherapy to enhance antitumor effects will have a significant clinical implication and will help to facilitate individualized treatment modalities.

It is difficult to effectively cure patients with unresectable locally recurrent colorectal cancers (LRCRCs) using conventional chemotherapy or chemoradiation therapy. Furthermore, treatment options vary depending on the patient's history of radiation therapy. Carbon-ion radiation therapy (CIRT) is a potentially curative treatment for these patients. Here, we compare the treatment outcomes of radiation therapy-naïve cases (nRT) and re-irradiation cases (reRT).

Patients with LRCRC treated with CIRT at QST Hospital between 2003 and 2019 were eligible. CIRT was administered daily 4 d/wk for 16 fractions. The total irradiated dose was set at 73.6 Gy (relative biologic effectiveness-weighted dose [RBE]) for nRT and 70.4 Gy (RBE) for reRT patients.

We included 390 nRT cases and 83 reRT cases. The median follow-up period from the initiation of CIRT was 48 (5-208) months. The 3-year overall survival (OS) rates for nRT and reRT were 73% (95% CI, 68%-77%) and 76% (65%-84%), respectively. The 5-year OS rates were 50% (45%-55%) and 50% (38%-61%), respectively. These rates did not differ significantly (P = .55). The 3-year local control (LC) rates for nRT (73.6 Gy) and reRT (70.4 Gy) cases were 80% (75%-84%) and 80% (68%-88%), respectively. The 5-year LC rates were 72% (67%-78%) and 69% (55%-81%), respectively, without a significant difference (P = .56).

Our results suggest that CIRT for LRCRC is a very effective and promising treatment for both nRT and reRT cases.

Carbon-ion radiotherapy (CIRT) has unique radiobiological properties that cause increased radiobiological effect and tumour control, especially with hypoxic tissues. This critical review aimed to evaluate clinical response to CIRT across all published tumour sites to establish if there is a clinical need for a CIRT centre in the UK.

A critical review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature searching was undertaken in November 2022 within the PubMed, Science Direct, SCOPUS and Web of Science databases using the term 'carbon ion radiotherapy' in the title, abstract or author keywords.

After critical appraisal, data was extracted from 78 primary study papers. Strong evidence supported use of CIRT for chondrosarcoma, chordoma, nasopharyngeal, non-small cell lung cancer (NSCLC), oral cavity, prostate, rectal and salivary gland tumours. Further research is needed to strengthen the evidence base for some other tumour types.

The UK's incidence and mortality rates suggest a clinical need for CIRT for chondrosarcoma, chordoma, NSCLC, oral cavity, prostate, and rectal tumours. There is a need to improve survivorship amongst pancreatic, liver, and oesophageal cancer patients. Data published relating to CIRT for these tumours is promising but of lower quality and more research is needed in these areas.

The clinical response to CIRT for certain tumours suggests the need for a carbon-ion centre in the UK. Demand for further research [phase III trials] has been identified, giving the UK opportunity to establish a research centre, with opportunity to treat, contributing to world-renowned research whilst improving patient outcomes.

Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT.

A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion.

The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

This study aimed to evaluate the oncological outcomes and safety of carbon ion re-irradiation with pencil beam scanning (PBS) delivery technique for previously irradiated and unresectable locally recurrent rectal cancer (LRRC). Between June 2017 and September 2021, 24 patients of unresectable LRRC with prior pelvic photon radiotherapy who underwent carbon ion re-irradiation at our institute were retrospectively analyzed. Carbon ion radiotherapy was delivered by raster scanning with a median relative biological effectiveness-weighted dose of 72 Gy in 20 fractions. Weekly CT reviews were carried out, and offline adaptive replanning was performed whenever required. The median follow-up duration was 23.8 months (range, 6.2-47.1 months). At the last follow-up, two patients had a local disease progression, and 11 patients developed distant metastases. The 1- and 2-year local control, progression-free survival and overall survival rates were 100 and 93.3%, 70.8 and 45.0% and 86.7 and 81.3%, respectively. There were no Grade 3 or higher acute toxicities observed. Three patients developed Grade 3 late toxicities, one each with gastrointestinal toxicity, skin reaction and pelvic infection. In conclusion, definitive carbon ion re-irradiation with PBS provided superior oncologic results with tolerable toxicities and may be served as a curative treatment strategy in unresectable LRRC.

Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research.

To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT.

The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types.

After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

Radiotherapy (RT) plays an important role in the treatment of patients with previously irradiated locally recurrent rectal cancer (LRRC). Over the years, numerous technologies and different types of RT have emerged. The aim of our systematic literature review was to determine whether the new techniques have led to improvements in both outcomes and toxicities.

A computerized search was performed by MEDLINE and the Cochrane database. The studies reported data from patients treated with carbon ion radiotherapy (CIRT), intensity-modulated photon radiotherapy (IMRT), and stereotactic radiotherapy (SBRT).

Seven publications of the 126 titles/abstracts that emerged from our search met the inclusion criteria and presented outcomes of 230 patients. OS was reported with rates of 90.0% and 73.0% at 1 and 2 years, respectively; LC was 89.0% and 71.6% at 1 and 2 years after re-RT, respectively. Toxicity data vary widely, with emphasis on acute and chronic gastrointestinal and urogenital toxicity, even with modern techniques.

data on toxicity and outcomes of re-RT for LRRC with new technologies are promising compared with 3D techniques. Comparative studies are needed to define the best technique, also in relation to the site of recurrence.

Radical resection (R0) represents the best curative treatment for local recurrence (LR) rectal cancer. Re-irradiation (re-RT) can increase the rate of R0 resection. Currently, there is a lack of guidelines on Re-RT for LR rectal cancer. The Italian Association of Radiation and clinical oncology for gastrointestinal tumors (AIRO-GI) study group released a national survey to investigate the current clinical practice of external beam radiation therapy in these patients.

In February 2021, the survey was designed and distributed to members of the GI working group. The questionnaire consisted of 40 questions regarding center characteristics, clinical indications, doses, and treatment techniques of re-RT for LR rectal cancer.

A total of 37 questionnaires were collected. Re-RT was reported as an option for neoadjuvant treatment in resectable and unresectable disease by 55% and 75% of respondents, respectively. Long-course treatment with 30-40 Gy (1.8-2 Gy/die, 1.2 Gy bid) and hypofractionated regimen of 30-35 Gy in 5 fractions were used in most centers. A total dose of 90-100 Gy as EqD2 dose (α/β = 5 Gy) was delivered by 46% of the respondents considering the previous treatment. Modern conformal techniques and daily image-guided radiation therapy protocols were used in 94% of centers.

Our survey showed that re-RT treatment is performed with advanced technology that allow a good management of LR rectal cancer. Significant variations were observed in terms of dose and fractionation, highlighting the need for a consensus on a common treatment strategy that could be validated in prospective studies.

Neoadjuvant concurrent chemoradiotherapy (nCCRT) is a standard treatment for locally advanced rectal cancer (LARC). The gut microbiome may be reshaped by radiotherapy through its effects on microbial composition, mucosal immunity, and the systemic immune system. We sought to clarify dynamic, longitudinal changes in the gut microbiome and blood immunomodulators throughout nCCRT and to explore the relationship of such changes with outcomes after nCCRT.

A total of 39 patients with LARC were recruited for this study. Fecal samples and peripheral blood samples were collected from all 39 patients before nCCRT, during nCCRT (at week 3), and after nCCRT (at week 5). The gut microbiota and the microbial community structure were analyzed by 16S rRNA sequencing of the V3-V4 region. Levels of blood immunomodulatory proteins were measured with a Millipore HCKPMAG-11 K kit and Luminex 200 platform (Luminex, USA).

Cross-sectional and longitudinal analyses revealed that the gut microbiome profile and enterotype exhibited characteristic variations that could distinguish patients with good response (AJCC TRG classification 0-1) vs poor response (TRG 2-3) to nCCRT. Sparse partial least squares regression and canonical correspondence analyses showed multivariate associations between specific microbial taxa, host immunomodulatory proteins, immune cells, and outcomes after nCCRT. An integrated model consisting of baseline Clostridium sensu stricto 1 levels, fold changes in Intestinimonas, blood levels of the herpesvirus entry mediator (HVEM/CD270), and lymphocyte counts could predict good vs poor outcome after nCCRT [area under the receiver-operating characteristics curve (AUC)= 0.821; area under the precision-recall curve [AUPR] = 0.911].

Our results showed that longitudinal variations in specific gut taxa, associated host immune cells, and immunomodulatory proteins before and during nCCRT could be useful for early predictions of the efficacy of nCCRT, which could guide the choice of individualized treatment for patients with LARC.

We compared the dose distributions of carbon-ion pencil beam scanning (C-PBS), proton pencil beam scanning (P-PBS) and Volumetric Modulated Arc Therapy (VMAT) for locally recurrent rectal cancer. The C-PBS treatment planning computed tomography (CT) data sets of 10 locally recurrent rectal cancer cases were randomly selected. Three treatment plans were created using identical prescribed doses. The beam angles for C-PBS and P-PBS were identical. Dosimetry, including the dose received by 95% of the planning target volume (PTV) (D95%), dose to the 2 cc receiving the maximum dose (D2cc), organ at risk (OAR) volume receiving > 15Gy (V15) and > 30Gy (V30), was evaluated. Statistical significance was assessed using the Wilcoxon signed-rank test. Mean PTV-D95% values were > 95% of the volume for P-PBS and C-PBS, whereas that for VMAT was 94.3%. However, PTV-D95% values in P-PBS and VMAT were < 95% in five and two cases, respectively, due to the OAR dose reduction. V30 and V15 to the rectum/intestine for C-PBS (V30 = 4.2 ± 3.2 cc, V15 = 13.8 ± 10.6 cc) and P-PBS (V30 = 7.3 ± 5.6 cc, V15 = 21.3 ± 13.5 cc) were significantly lower than those for VMAT (V30 = 17.1 ± 10.6 cc, V15 = 55.2 ± 28.6 cc). Bladder-V30 values with P-PBS/C-PBS (3.9 ± 4.8 Gy(RBE)/3.0 ± 4.0 Gy(RBE)) were significantly lower than those with VMAT (7.9 ± 8.1 Gy). C-PBS provided superior dose conformation and lower OAR doses compared with P-PBS and VMAT. C-PBS may be the best choice for cases in which VMAT and P-PBS cannot satisfy dose constraints. C-PBS could be another choice for cases in which VMAT and P-PBS cannot satisfy dose constraints, thereby avoiding surgical resection.