Carbon ion radiation therapy for sinonasal malignancies: Promising results from 2282 cases from the real world.

The aim of this study is to compare the effectiveness of carbon ion radiation therapy (CIRT), proton radiation therapy (PRT), and photon-based intensity-modulated radiation therapy (IMRT) in the treatment of sinonasal malignancies. We identified studies through systematic review and divided them into three cohorts (CIRT group/PRT group/IMRT group). Primary outcomes of interest were overall survival (OS) and local control (LC). We pooled the outcomes with meta-analysis and compared the survival difference among groups using Chi2 (χ2 ) test. A representative sample of 2282 patients with sinonasal malignancies (911 in the CIRT group, 599 in the PRT group, and 772 in the IMRT group) from 44 observation studies (7 CIRT, 16 PRT, and 21 IMRT) was included. The pooled 3-year OS, LC, distant metastasis-free survival, and progression-free survival rates were 67.0%, 72.8%, 69.4%, and 52.8%, respectively. Through cross-group analysis, the OS was significantly higher after CIRT (75.1%, 95% CI: 67.1%-83.2%) than PRT (66.2%, 95% CI: 57.7%-74.6%; χ2  = 13.374, P < .0001) or IMRT (63.8%, 95% CI: 55.3%-72.3%; χ2  = 23.814, P < .0001). LC was significantly higher after CIRT (80.2%, 95% CI: 73.9%-86.5%) than PRT (72.9%, 95% CI: 63.7%-82.0%; χ2  = 8.955, P = .003) or IMRT (67.8%, 95% CI: 59.4%-76.2%; χ2  = 30.955, P < .0001). However, no significant difference between PRT and IMRT for OS and LC was observed. CIRT appeared to provide better OS and LC for patients with malignancies of nasal cavity and paranasal sinuses. A prospective randomized clinical trial is needed to confirm the superiority of CIRT in the treatment of sinonasal tumors.

Significant impact of biochemical recurrence on overall mortality in patients with high-risk prostate cancer after carbon-ion radiotherapy combined with androgen deprivation therapy.

BACKGROUND: Whether biochemical recurrence (BR) is a significant predictive factor of mortality after definitive radiation therapy for prostate cancer remains unknown. The aim of the current study was to investigate the relation between BR and overall mortality (OAM) in high-risk prostate cancer patients who were treated with carbon-ion radiotherapy (CIRT) and had long-term follow-up in 2 prospective trials. METHODS: In the 2 phase 2 clinical trials, which involved 466 prostate cancer patients who received 63.0 to 66.0 Gy of CIRT (relative biological effect) in 20 fractions between 2000 and 2007, 324 patients who were deemed to be at high risk on the basis of the modified D'Amico classification criteria and received CIRT along with androgen-deprivation therapy (ADT) were examined. The OAM rate was adjusted for the ADT duration, and multivariate analyses using a Cox proportional hazards model were performed for OAM with BR as a time-dependent covariate. RESULTS: The median follow-up period was 107.4 months, and the 5- and 10-year OAM rates after adjustments for the ADT duration were 7.0% (95% confidence interval [CI], 4.0%-9.4%) and 23.9% (95% CI, 16.4%-26.2%), respectively. A multivariate analysis revealed that the presence of BR (hazard ratio, 2.82; 95% Cl, 1.57-5.08; P = .001) was one of the predictive factors for OAM. On the other hand, the duration of ADT had no impact on OAM. CONCLUSIONS: BR after CIRT combined with ADT is an independent predictive factor for OAM in high-risk prostate cancer patients. The results of this study could be applied to other high-dose radiation therapies. Cancer 2016;122:3225-31. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Comparison of Oncologic Outcomes and Treatment-Related Toxicity of Carbon Ion Radiotherapy and En Bloc Resection for Sacral Chordoma.

Importance: Maximal resection is the preferred management for sacral chordomas but can be associated with unacceptable morbidity. Outcomes with radiotherapy are poor. Carbon ion radiotherapy (CIRT) is being explored as an alternative when surgery is not preferred. Objective: To compare oncologic outcomes and treatment-related toxicity of CIRT and en bloc resection for sacral chordoma. Design, Setting, and Participants: Univariable logistic regression was performed to evaluate the association between treatment type and oncologic and toxicity outcomes in this retrospective cohort study. Nearest-neighbor propensity score matching was used to match the CIRT cohort with the en bloc resection cohort and 10 National Cancer Database (NCDB) cohorts separately, with the objective of obtaining more homogeneous cohorts when comparing treatments. Patient- and tumor-related characteristics from 2 institutional cohorts were collected for patients diagnosed with sacral chordomas between April 1, 1994, and July 31, 2017. The NCDB was queried for data on patients with sacral chordoma from January 1, 2004, to December 31, 2016, as a comparator in overall survival (OS) analyses. Data analysis was conducted from February 24, 2020, to January 16, 2021. Exposures: En bloc resection, incomplete resection, photon radiotherapy, proton radiotherapy, and CIRT. Main Outcomes and Measures: Overall survival was estimated using the Kaplan-Meier method and compared using the Cox proportional hazards model. Peripheral motor nerve toxic effects were scored using Common Terminology Criteria for Adverse Events, version 4.03. Results: A total of 911 patients were included in the study (NCDB: n = 669; median age, 64 [IQR, 52-74] years; 410 [61.3%] men; CIRT: n = 188; median age, 66 [IQR, 58-71] years; 128 [68.1%] men; en bloc surgical resection: n = 54; median age, 53.5 [IQR 49-64] years, 36 [66.7%] men). Comparison of the propensity score-matched institutional en bloc resection and CIRT cohorts revealed no statistically significant difference in OS (CIRT: median OS, 68.1 [95% CI, 44.0-102.6] months; en bloc resection: median OS, 58.6 [95% CI, 25.6-123.5] months; P = .57; hazard ratio, 0.71 [95% CI, 0.25-2.06]; P = .53). The CIRT cohort experienced lower rates of peripheral motor neuropathy (odds ratio, 0.13 [95% CI, 0.04-0.40]; P < .001). On comparison of the propensity score-matched NCDB cohorts with the CIRT cohort, significantly higher OS was found for CIRT compared with margin-positive surgery without adjuvant radiotherapy (CIRT: median OS, 64.7 [95% CI, 57.8-69.7] months; margin-positive surgery without adjuvant radiotherapy: median OS, 60.6 [95% CI, 44.2-69.7] months, P = .03) and primary radiotherapy alone (CIRT: median OS, 64.9 [95% CI 57.0-70.5] months; primary radiotherapy alone: 31.8 [95% CI, 27.9-40.6] months; P < .001). Conclusions and Relevance: These findings suggest that CIRT can be used as treatment for older patients with high performance status and sacral chordoma in whom surgery is not preferred. CIRT might provide additional benefit for patients who undergo margin-positive resection or who are candidates for primary photon radiotherapy.

Carbon-ion Radiotherapy for Inoperable Head and Neck Bone and Soft-tissue Sarcoma: Prospective Observational Study.

BACKGROUND/AIM: Bone and soft-tissue sarcomas of the head and neck have very poor prognoses. This prospective study aimed to investigate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for bone and soft-tissue sarcoma of the head and neck. PATIENTS AND METHODS: The present study was a prospective clinical study that included 10 consecutive patients diagnosed with bone and soft-tissue sarcoma of the head and neck who were treated with C-ion RT between 2012 and 2018 at our institution. C-Ion RT consisted of 70.4 Gy (relative biological effectiveness) in 16 fractions. RESULTS: The 3-year local control, overall survival, and progression-free survival rates for patients overall were 72.9%, 77.8%, and 36%, respectively. CONCLUSION: The present study demonstrated the efficacy of C-ion RT for bone and soft-tissue sarcoma of the head and neck; adverse events were within the expected range.

Comparison of clinical outcomes between carbon ion radiotherapy and X-ray radiotherapy for reirradiation in locoregional recurrence of rectal cancer.

Carbon ion radiotherapy (CIRT) has garnered interest for the treatment of locoregional rectal cancer recurrence. No study has compared CIRT and X-ray radiotherapy (XRT) for reirradiation (reRT) in such cases. We analyzed and compared the clinical outcomes such as local control, overall survival, and late toxicity rate between CIRT and XRT, for treating locoregional rectal cancer recurrence. Patients with rectal cancer who received reRT to the pelvis by CIRT or XRT from March 2005 to July 2019 were included. The CIRT treatment schedule was 70.4 Gy (relative biological effectiveness) in 16 fractions. For the XRT group, the median reRT dose was 50 Gy (range 25-62.5 Gy) with a median of 25 fractions (range 3-33). Thirty-five and 31 patients received CIRT and XRT, respectively. Tumour and treatment characteristics such as recurrence location and chemotherapy treatment differed between the two groups. CIRT showed better control of local recurrence (adjusted hazard ratio [HR] 0.17; p = 0.002), better overall survival (HR 0.30; p = 0.004), and lower severe late toxicity rate (HR 0.15; p = 0.015) than XRT. CIRT was effective for treating locoregional rectal cancer recurrence, with high rates of local control and survival, and a low late severe toxicity rate.

Clinical impact of Hypofractionated carbon ion radiotherapy on locally advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) involving a major branch of the portal or hepatic vein is in a locally advanced stage and remains difficult to cure. This study aimed to evaluate the clinical effects of carbon ion radiotherapy (C-ion RT) in locally advanced HCC (LAHCC). METHODS: The data of 11 consecutive patients with LAHCC who received C-ion RT were analyzed. The C-ion RT doses of 52.8 Gy (relative biological effectiveness [RBE]) and 60.0 Gy (RBE) were delivered in 4 fractions for standard cases, and the 60.0 Gy dose was delivered in 12 fractions for close-to-gastrointestinal-tract cases. Survival and local control probabilities were calculated using the Kaplan-Meier method. RESULTS: The median follow-up duration after C-ion RT was 36.4 months. The median age at the time of registration for C-ion RT was 76 years. The median tumor size was 53 mm. The numbers of treatment-naive and recurrent HCC patients were 1 and 10, respectively. Direct invasion of the major branch of the portal vein, hepatic vein, or both portal and hepatic veins was observed in three, five, and three patients, respectively. The 3-year overall survival, local control, and progression-free survival rates were 64, 78, and 18%, respectively. No patient developed radiation-induced liver diseases or grade 3 or higher toxicities in the acute and late phases. CONCLUSIONS: C-ion RT showed favorable clinical outcomes with a high rate of local control and minimal toxicities in LAHCC. Our findings suggest that C-ion RT is a promising multidisciplinary treatment option in LAHCC.

Particle beam radiation therapy for sinonasal malignancies: Single institutional experience at the Shanghai Proton and Heavy Ion Center.

BACKGROUND: Sinonasal malignancies (SNM) include malignant neoplasms of various histologies that originate from the paranasal sinuses or nasal cavity. This study reported the safety and efficacy of particle-beam radiation therapy (PBRT) for the treatment of sinonasal malignancies. METHODS AND MATERIALS: One-hundred-and-eleven patients with nonmetastatic sinonasal malignancies received definitive (82.9%) or salvage (31.5%) PBRT. The majority (85.6%) of patients presented with T3/4 disease, and only 19 (17.1%) had R0 or R1 resection. Seventy (63.1%) patients received carbon-ion radiotherapy (CIRT), 37 received proton radiotherapy (PRT) followed by CIRT boost, and 4 received PRT alone. Prognostic factors were analyzed using Cox regression for univariate and multiple regression. Toxicities were reported using the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: The median follow-up was 20.2 months for the entire cohort. The 2-year local progression-free survival (LPFS), regional progression-free survival (RPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) rates were 83%, 97.2%, 85.9%, 66%, and 82%, respectively. Re-irradiation and large GTV were the significant factors for OS. Melanoma and sarcoma patients had significantly higher distant metastatic rate, and poorer OS and PFS. Late toxicity occurred in 22 (19.8%) patients, but only 4 (3.6%) patients experienced grades 3-4 late toxicity. CONCLUSIONS: Particle-beam radiation therapy results in excellent local-regional control with extremely low serve toxicities for patients with SNM. Sarcoma and melanoma were featured with a greater risk of death from distant dissemination. Patients who underwent re-irradiation had significantly worse OS. PBRT is feasible and safe in the management of SNM.

Health Technology Assessment of Carbon-ion Beam Radiotherapy: A Systematic Review of Clinical Effectiveness and Safety for 54 Oncological Indications in 12 Tumour Regions.

BACKGROUND/AIM: Due to the unique physical dose distribution of carbon-ion radiotherapy (CIRT), CIRT can be regarded as a novel tumour irradiation technique - potentially advantageous for various tumour types. Yet it is unclear in how far, superiority or inferiority can be claimed when comparing CIRT to standard irradiation. This study aimed to assess the scientific evidence regarding the effectiveness and safety of CIRT. MATERIALS AND METHODS: A systematic literature review was performed using the European Network for Health Technology Assessment (EUnetHTA) Core Model® for rapid relative effectiveness assessment. The literature search for clinical outcome studies on CIRT was performed using four databases [Cochrane (Central), Centre for Research and Dissemination (CRD), Embase and OVID MEDLINE]. The Cochrane Risk of Bias Tool (for randomised controlled trials) and the Institute of Health Economics (IHE-18) Checklist (for observational studies) were used to assess the risk of bias of the included studies. The evidence synthesis was restricted to 54 oncological indications in 12 broad tumour regions and studies with a low or moderate risk of bias, published between 2005 and 2017. RESULTS: Twenty-seven studies were eligible for the qualitative synthesis of the evidence regarding the effectiveness and safety of CIRT: One randomised controlled trial that primarily focused on the feasibility of CIRT, three case-control studies, three before- and after- studies with a focus on quality of life, and 20 further studies of case series. Overall, insufficient scientific evidence was found for superiority or inferiority of CIRT when compared to standard irradiation for 13/54 oncologicaI indications in 7/12 tumour regions (skull base tumours, brain cancer, cancer in the ear-nose-throat region, bone and soft-tissue tumours, lung cancer, prostate cancer, gastrointestinal tumours). No scientific evidence was found for the remaining 41/54 oncological indications. CONCLUSION: CIRT is undoubtedly, theoretically, a promising cancer treatment. To date, however, it lacks randomised controlled trials assessing the long-term effectiveness and harms associated with the use of CIRT. CIRT must be considered as an experimental treatment due to the lack of high-quality clinical research.

A comparison of carbon ion radiotherapy and transarterial chemoembolization treatment outcomes for single hepatocellular carcinoma: a propensity score matching study.

BACKGROUND: We compared clinical outcomes of carbon ion radiotherapy and transarterial chemoembolization in the treatment of hepatocellular carcinoma. METHODS: Data of 477 patients with hepatocellular carcinoma who had undergone carbon ion radiotherapy or transarterial chemoembolization between April 2007 and September 2016 were retrospectively reviewed. Treatment naïve patients with single HCC, who underwent carbon ion radiotherapy or transarterial chemoembolization as a primary treatment were included. Clinical outcomes of the treatments were compared after utilizing propensity score matching. RESULTS: Of 124 patients who received carbon ion radiotherapy and 353 patients who received transarterial chemoembolization, 31 and 23 patients met our inclusion criteria, respectively. After utilizing propensity score matching, 17 matched pairs of patients from each treatment group were analyzed. The median follow-up durations after carbon ion radiotherapy and transarterial chemoembolization were 43 and 32 months, respectively. The 3-year overall survival, local control, and progression-free survival rates in the carbon ion radiotherapy versus transarterial chemoembolization groups were 88% versus 58% (p < 0.05), 80% versus 26% (p < 0.01), and 51% versus 15% (p < 0.05), respectively. CONCLUSIONS: Carbon ion radiotherapy showed more favorable clinical outcomes than did transarterial chemoembolization for patients with single hepatocellular carcinoma after matching patient characteristics utilizing propensity score matching. Further studies with larger patient numbers are required to confirm our results. TRIAL REGISTRATION: UMIN000036455 : date of registration 22 March 2019, retrospectively registered.

Carbon-ion radiotherapy for locoregional recurrence after primary surgery for pancreatic cancer.

The efficacy and safety of carbon ion radiotherapy (C-ion RT) for locoregional recurrence after surgery for pancreatic cancer were retrospectively evaluated. The results for 30 patients showed that C-ion RT was performed safely with relatively long overall survival, good local control, and minimal toxicity.

Multicenter Study of Carbon-Ion Radiation Therapy for Mucosal Melanoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN).

PURPOSE: To evaluate the efficacy and safety of carbon-ion radiation therapy (RT) for mucosal melanoma of the head and neck (MMHN) in the Japan Carbon-Ion Radiation Oncology Study Group study. METHODS AND MATERIALS: Patients with MMHN with N0-1M0 status who were treated with carbon-ion RT at 4 institutions in Japan between November 2003 and December 2014 were analyzed retrospectively. Two hundred sixty patients (male, 111; female, 149; median age, 68 years) with histologically proven MMHN were enrolled. RESULTS: Primary sites included the nasal cavity in 178 patients, paranasal sinuses in 43, oral cavity in 27, and pharynx in 12. Eighty-six patients had T3 tumors, 147 had T4a tumors, and 27 had T4b tumors. Two hundred fifty-one patients were diagnosed with N0 disease, and 9 with N1 disease. The median total dose and number of fractions were 57.6 Gy RBE (relative biological effectiveness) and 16, respectively. Chemotherapy including dimethyl traizeno imidazole carboxamide was used concurrently in 129 patients. The median follow-up duration was 22 months (range, 1-132 months). The 2-year overall survival and local control rates were 69.4% and 83.9%, respectively. Multivariate analysis showed that gross tumor volume and concurrent chemotherapy were significant prognostic factors for overall survival. Grade 3 and grade 4 late morbidities were observed in 27 and 7 patients (5 developed ipsilateral blindness, 1 mucosal ulcer, and 1 second malignant disease in the irradiated volume), respectively. No patients developed grade 5 late morbidities. CONCLUSION: Carbon-ion RT is a promising treatment option for MMHN.

Clinical Impact of Re-irradiation with Carbon-ion Radiotherapy for Lymph Node Recurrence of Gynecological Cancers.

BACKGROUND/AIM: To evaluate the safety and efficacy of re-irradiation with carbon-ion radiotherapy (C-ion RT) for lymph node recurrence of gynecological cancers after definitive radiotherapy. PATIENTS AND METHODS: Data regarding patients with unresectable and isolated recurrent lymph node from gynecological cancer after definitive radiotherapy were analyzed. Total dose of C-ion RT was 48-57.6 Gy (RBE) in 12 or 16 fractions. RESULTS: Sixteen patients received re-irradiation by C-ion RT were analyzed. Median follow-up was 37 months. Median tumor size was 27 mm. None developed Grade 1 or higher acute toxicities and Grade 3 or higher late toxicities. The 3-year overall survival, local control and disease-free survival rates after C-ion RT were 74%, 94% and 55%, respectively. CONCLUSION: Re-irradiation with C-ion RT for lymph node recurrence of gynecological cancers after definitive radiotherapy can be safe and effective. This result suggested that C-ion RT could be a curative treatment option for conventionally difficult-to-cure patients.

Carbon-Ion Radiation Therapy for Pelvic Recurrence of Rectal Cancer.

PURPOSE: Investigation of the treatment potential of carbon-ion radiation therapy in pelvic recurrence of rectal cancer. METHODS AND MATERIALS: A phase 1/2 dose escalation study was performed. One hundred eighty patients (186 lesions) with locally recurrent rectal cancer were treated with carbon-ion radiation therapy (CIRT) (phase 1/2: 37 and 143 patients, respectively). The relapse locations were 71 in the presacral region, 82 in the pelvic sidewalls, 28 in the perineum, and 5 near the colorectal anastomosis. A 16-fraction in 4 weeks dose regimen was used, with total dose ranging from 67.2 to 73.6 Gy(RBE); RBE-weighted absorbed dose: 4.2 to 4.6 Gy(RBE)/fraction. RESULTS: During phase 1, the highest total dose, 73.6 Gy(RBE), resulted in no grade >3 acute reactions in the 13 patients treated at that dose. Dose escalation was halted at this level, and this dose was used for phase 2, with no other grade >3 acute reactions observed. At 5 years, the local control and survival rates at 73.6 Gy(RBE) were 88% (95% confidence interval [CI], 80%-93%) and 59% (95% CI, 50%-68%), respectively. CONCLUSION: Carbon-ion radiation therapy may be a safe and effective treatment option for locally recurrent rectal cancer and may serve as an alternative to surgery.

Carbon Ion irradiation in the treatment of grossly incomplete or unresectable malignant peripheral nerve sheaths tumors: acute toxicity and preliminary outcome.

BACKGROUND: To report our early experience with carbon ion irradiation in the treatment of gross residual or unresectable malignant peripheral nerve sheath tumors (MPNST). METHODS: We retrospectively analysed 11 patients (pts) with MPNST, who have been treated with carbon ion irradiation (C12) at our institution between 2010 and 2013. All pts had measurable gross disease at the initiation of radiation treatment. Median age was 47 years (29-79). Tumors were mainly located in the pelvic/sacral (5 pts) and sinunasal/orbital region (5 pts). 5 pts presented already in recurrent situation, 3 pts had been previously irradiated, and in 3 pts MPNST were neurofibromatosis type 1 (NF1) associated. Median cumulative dose was 60 GyE. Treatment was carried out either as a combination of IMRT plus C12 boost (4 pts) or C12 only (7 pts). RESULTS: Median follow-up was 17 months (3-31 months). We observed 3 local progressions, translating into estimated 1- and 2-year local control rates of 65%. One patient developed distant failure, resulting in estimated 1- and 2-year PFS rates of 56%. Two patients have died, therefore the estimated 1- and 2-year OS rates are 75%. Acute radiation related toxicities were generally mild, no grade 3 side effects were observed. Severe late toxicity (grade 3) was scored in 2 patients (trismus, wound healing delays). CONCLUSION: Carbon ion irradiation yields very promising short term local control and overall survival rates with low morbidity in patients suffering from gross residual or unresectable malignant peripheral nerve sheath tumors and should be further investigated in a prospective trial.

Feasibility of carbon ion radiotherapy for locally advanced sinonasal adenocarcinoma.

BACKGROUND AND PURPOSE: To evaluate the safety and efficacy of carbon ion radiotherapy (CIRT) for locally advanced sinonasal adenocarcinoma. MATERIAL AND METHODS: Twenty-two patients with sinonasal adenocarcinoma were treated with CIRT. CIRT was the primary treatment for 16 patients. Four patients received CIRT for local recurrence after surgery and two for residual tumour after surgery or chemotherapy. At the start of CIRT, 1 patient had T-classification (T) 2 disease, 2 had T3 disease, 5 had T4a disease, and 14 had T4b disease. Fourteen patients were treated with 57.6 Gy equivalent (GyE)/16 fractions, and 8, with 64.0 GyE/16 fractions. RESULTS: The median follow-up period was 43 months for all patients. The 3-year local control and loco-regional control rates for all patients were 76.9% (95% confidence interval [CI]=56.7-97.1%) and 61.3% (95% CI=38.5-84.1%), respectively. The 3-year overall survival and disease-specific survival rates were 59.1% (95% CI=38.6-79.6%) and 65.6% (95% CI=44.9-86.3%), respectively. Acute reactions of grade 3 of the skin and mucosa were observed in 2 and 4 patients, respectively. Late reactions included lateral visual loss (5 patients), mucosal ulceration (1 patient), and brain necrosis with clinical symptoms (1 patient). In the 5 patients who developed visual loss, the optic nerve was close to the tumour. CONCLUSIONS: CIRT was effective and generally safe for locally advanced sinonasal adenocarcinoma.