Carbon ion radiotherapy as definitive treatment in locally recurrent pancreatic cancer

Abstract Purpose Data on management of locally recurrent pancreatic cancer (LRPC) after primary resection are limited. Recently, surprisingly high overall survival rates were reported after irradiation with carbon ions. Here, we report on our clinical experience using carbon ion radiotherapy as definitive treatment in LRPC at the Heidelberg Ion-Beam Therapy Center (HIT). Methods Between 2015 and 2019, we treated 13 patients with LRPC with carbon ions with a median total dose of 48 Gy (RBE) in 12 fractions using an active raster-scanning technique at a rotating gantry. No concomitant chemotherapy was administered. Overall survival, local control, and toxicity rates were evaluated 18 months after the last patient finished radiotherapy. Results With a median follow-up time of 9.5 months, one patient is still alive (8%). Median OS was 12.7 months. Ten patients (77%) developed distant metastases. Additionally, one local recurrence (8%) and two regional tumor recurrences (15%) were observed. The estimated 1‑year local control and locoregional control rates were 87.5% and 75%, respectively. During radiotherapy, we registered one gastrointestinal bleeding CTCAE grade III (8%) due to gastritis. The bleeding was sufficiently managed with conservative therapy. No further higher-grade acute or late toxicities were observed. Conclusion We demonstrate high local control rates in a rare cohort of LRPC patients treated with carbon ion radiotherapy. The observed median overall survival rate was not improved compared to historical in-house data using photon radiotherapy. This is likely due to a high rate of distant tumor progression, highlighting the necessity of additional chemotherapy.

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Carbon ion radiotherapy as definitive treatment in non-metastasized pancreatic cancer: study protocol of the prospective phase II PACK-study

BMC Cancer ◽

10.1186/s12885-020-07434-8 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Jakob Liermann ◽

Patrick Naumann ◽

Adriane Hommertgen ◽

Moritz Pohl ◽

Meinhard Kieser ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Phase Ii ◽

Ion Beam ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Carbon Ion Radiotherapy ◽

Definitive Treatment ◽

Tumor Control ◽

Carbon Ion

Abstract Background Radiotherapy is known to improve local tumor control in locally advanced pancreatic cancer (LAPC), although there is a lack of convincing data on a potential overall survival benefit of chemoradiotherapy over chemotherapy alone. To improve efficacy of radiotherapy, new approaches need to be evolved. Carbon ion radiotherapy is supposed to be more effective than photon radiotherapy due to a higher relative biological effectiveness (RBE) and due to a steep dose-gradient making dose delivery highly conformal. Methods The present Phase II PACK-study investigates carbon ion radiotherapy as definitive treatment in LAPC as well as in locally recurrent pancreatic cancer. A total irradiation dose of 48 Gy (RBE) will be delivered in twelve fractions. Concurrent chemotherapy is accepted, if indicated. The primary endpoint is the overall survival rate after 12 months. Secondary endpoints are progression free survival, safety, quality of life and impact on tumor markers CA 19–9 and CEA. A total of twenty-five patients are planned for recruitment over 2 years. Discussion Recently, Japanese researches could show promising results in a Phase I/II-study evaluating chemoradiotherapy of carbon ion radiotherapy and gemcitabine in LAPC. The present prospective PACK-study investigates the efficacy of carbon ion radiotherapy in pancreatic cancer at Heidelberg Ion Beam Therapy Center (HIT) in Germany. Trial registration The trial is registered at ClinicalTrials.gov: NCT04194268 (Retrospectively registered on December, 11th 2019).

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Effectiveness of Carbon Ion Radiation in Locally Advanced Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.708884 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jakob Liermann ◽

Patrick Naumann ◽

Fabian Weykamp ◽

Philipp Hoegen ◽

Juergen Debus ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Local Control ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

Carbon Ion Radiotherapy ◽

Free Survival ◽

Carbon Ion

PurposeEffective treatment strategies for unresectable locally advanced pancreatic cancer (LAPC) patients are eagerly warranted. Recently, convincing oncological outcomes were demonstrated by carbon ion radiotherapy. Nevertheless, there is a lack of evidence for this modern radiation technique due to the limited number of carbon ion facilities worldwide. Here, we analyze feasibility and efficacy of carbon ion radiotherapy in the management of LAPC at Heidelberg Ion Beam Therapy Center (HIT).MethodsBetween 2015 and 2020, 21 LAPC patients were irradiated with carbon ions with a total dose of 48 Gy (RBE) in single doses of 4 Gy (RBE). Three patients (14%) were treated with concomitant chemotherapy with gemcitabine 300 mg/m2 body surface weekly. Toxicity rates were extracted from the charts. Overall survival, progression free survival, local control, and locoregional control were evaluated using Kaplan–Meier estimates.ResultsOne patient developed ascites CTCAE grade III during radiotherapy, which was related to a later histologically confirmed metachronous peritoneal carcinomatosis. No further higher-graded toxicity could be observed. The most common symptoms were nausea and abdominal pain. After a median estimated follow-up time of 19.1 months, the median progression free survival was 3.7 months, and the median overall survival was 11.9 months. The estimated 1-year local control and locoregional control rates were 89 and 84%, respectively.ConclusionCarbon ion radiotherapy of LAPC patients is safely feasible. Local tumor control rates were high. Nevertheless, compared to historical data, an overall survival improvement could not be observed. This could be explained by the poor prognosis of the selected underlying patients that mostly did not respond to prior chemotherapy as well as the early and frequent emergence of distant metastases that demonstrate the necessity of additional chemotherapy in further studies.

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Definitive radiotherapy for patients with isolated local recurrence of primary resected pancreatic cancer: A retrospective analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.366 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 366-366

Author(s):

Akira Nakamura ◽

Keiko Shibuya ◽

Kyoichi Takaori ◽

Yoshiya Kawaguchi ◽

Michio Yoshimura ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Local Recurrence ◽

Local Control ◽

Local Control Rate ◽

Definitive Radiotherapy ◽

Recurrent Pancreatic Cancer ◽

Locally Recurrent ◽

Grade 3 ◽

Isolated Local Recurrence

366 Background: Only surgical resection can provide a chance of long-term survival for patients with pancreatic cancer, but loco-regional recurrence has been a major challenge which inevitably results in poor prognosis and loss of patients’ quality of life. Curative reoperation is seldom attainable but has been suggested to have benefits on overall survival. We hypothesized that definitive radiotherapy could offer a good control for the unresectable local recurrence and improve survival. The primary objective of this retrospective analysis is to evaluate the efficacy and tolerability of definitive radiotherapy for patients with isolated locally-recurrent pancreatic cancer. Methods: A total of 26 patients, who developed local recurrence of primarily resected pancreatic cancer and received radiotherapy between 2000 and 2011, were retrospectively analyzed. The isolated local recurrence was diagnosed with the radiological images (CT/MRI/PET) and tumor marker relapse. The overall survival (OS) and local control rate (LC) were calculated from the start day of radiotherapy and estimated by Kaplan-Meier method. The responses in tumor size and tumor markers were evaluated. The treatment-related toxicity was assessed according to CTC-AE (ver. 4.0). Results: The median total dose of radiotherapy was 50.4 Gy (range, 39.6–54 Gy). Concurrent chemotherapy consisted of gemcitabine (62%), S-1 (19%), and 5-fluorouracil (4%). At a median follow-up time of 13 months, the 1-year OS and median survival were 75% and 21.6 months, respectively. The 1-year local control rate was 59%. Objective radiological response was not seen. The tumor marker reduction and ≥ 50% reduction were observed in 65% and 12%. Grade≥3 hematological toxicity was seen in 62%. Grade ≥ 3 of acute gastrointestinal toxicity was not observed. At a late phase, Grade 3 ileus observed in one, and Grade 3 gastric bleeding ulcer was seen in one patient. Conclusions: Definitive radiotherapy resulted in encouraging local control and overall survival for patients with isolated locally-recurrent pancreatic cancer. This treatment strategy should be further evaluated prospectively.

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Accelerated Hypofractionated Active Raster-Scanned Carbon Ion Radiotherapy (CIRT) for Laryngeal Malignancies: Feasibility and Safety

Cancers ◽

10.3390/cancers10100388 ◽

2018 ◽

Vol 10 (10) ◽

pp. 388 ◽

Cited By ~ 1

Author(s):

Sati Akbaba ◽

Kristin Lang ◽

Thomas Held ◽

Olcay Bulut ◽

Matthias Mattke ◽

...

Keyword(s):

Local Control ◽

Lung Metastases ◽

Ion Beam ◽

Progression Free Survival ◽

Carbon Ion Radiotherapy ◽

Carbon Ions ◽

Carbon Ion ◽

Swallowing Problems ◽

Grade 3

(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC; n = 8; 53.3%) or chondrosarcoma (CS; n = 7; 46.7%) who underwent radiotherapy with carbon ions (C12) at the Heidelberg Ion Beam Therapy Center (HIT) between 2013 and 2018 were identified retrospectively and analyzed for local control (LC), overall survival (OS), and distant progression-free survival using the Kaplan–Meier method. CIRT was applied either alone (n = 7, 46.7%) or in combination with intensity modulated radiotherapy (IMRT) (n = 8, 53.3%). The toxicity was assessed according to the Common Toxicity Terminology Criteria for Adverse Events (CTCAE) v4.03. (3). Results: the median follow-up was 24 months (range 5–61 months). Overall, the therapy was tolerated very well. No grade >3 acute and chronic toxicity could be identified. The most reported acute grade 3 side effects were acute dysphagia (n = 2; 13%) and acute odynophagia (n = 3; 20%), making supportive nutrition via gastric tube (n = 2; 13.3%) and via high caloric drinks (n = 1; 6.7%) necessary due to swallowing problems (n = 4; 27%). Overall, chronic grade 3 toxicity in the form of chronic hoarseness occurred in 7% of the patients (n = 1; 7%). At the last follow-up, all the patients were alive. No local or locoregional recurrence could be identified. Only one patient with laryngeal ACC developed lung metastases three years after the first diagnosis. (4) Conclusions: the accelerated hypofractionated active raster-scanned carbon ion radiotherapy for radioresistant laryngeal malignancies is feasible in practice with excellent local control rates and moderate acute and late toxicity. Further follow-ups are necessary to evaluate the long-term clinical outcome.

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Carbon Ion Radiotherapy for Oligo-Recurrence in the Lung

Pulmonary Medicine ◽

10.1155/2013/219746 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Naoyoshi Yamamoto ◽

Mio Nakajima ◽

Hirohiko Tsujii ◽

Tadashi Kamada

Keyword(s):

Colorectal Cancer ◽

Lung Cancer ◽

Overall Survival ◽

Survival Rate ◽

Local Control ◽

Local Control Rate ◽

Carbon Ion Radiotherapy ◽

Overall Survival Rate ◽

Carbon Ion ◽

Metastatic Lung

The clinical results after carbon ion radiotherapy for the metastatic lung tumors believed to be in the state of oligo-recurrence were evaluated. One hundred and sixteen lesions in 91 patients with lung cancer metastasis were treated with carbon ion radiotherapy at our institute from April 1997 to February 2011. Regarding the prescribed dose, total dose ranged between 40 gray equivalents (GyE) and 80 GyE, and fraction size ranged from 1 to 16 fractions. After a median followup period of 2.3 years (range, 0.3–13.1 years), the statistical overall survival rate and local control rate were 71.2% and 91.9% at 2 years after treatment, respectively. Treatment-related side effects were not a clinical problem. When classified by the primary organ, there were 49 cases of lung cancer, 20 cases of colorectal cancer, and 22 cases of others. The overall survival rate and local control rate for lung metastasis cases from lung cancer at 2 years after treatment were 81.5% and 92.4%, respectively, and 65.0% and 92.0% regarding lung metastasis from colorectal cancer. Carbon ion beam therapy for the metastatic lung tumors is a safe therapy, and the therapeutic effect is comparable to the outcome obtained from reported surgical resections.

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Adenoid cystic Carcinoma and Carbon ion Only irradiation (ACCO): Study protocol for a prospective, open, randomized, two-armed, phase II study

BMC Cancer ◽

10.1186/s12885-021-08473-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kristin Lang ◽

Sebastian Adeberg ◽

Semi Harrabi ◽

Thomas Held ◽

Meinhard Kieser ◽

...

Keyword(s):

Adenoid Cystic Carcinoma ◽

Head And Neck ◽

Phase Ii ◽

Local Control ◽

Carbon Ion Radiotherapy ◽

Carbon Ions ◽

Node Negative ◽

Carbon Ion ◽

Adenoid Cystic ◽

High Let

Abstract Background Adenoid cystic carcinoma is a rare form of head and neck cancer with a slow, but aggressive growth pattern which remains a challenge for local tumor control. Based on phase II data, radiation treatment using partially high LET radiation results in a prolonged PFS and OS. There is a paucity of randomized clinical data examining the role of the use of high LET radiation only. Therefore, the purpose of this prospective clinical trial is to analyze local control rates in patients with node negative ACC treated with carbon ion radiotherapy alone compared to a combined modality approach. Methods This trial is conducted as a prospective, open-label, phase II, two-armed, investigator-initiated study comparing the local control rates in node negative ACCs of the head and neck treated either with sole carbon ion radiotherapy or a combination of carbon ions and photons. Secondary outcomes investigated are progression-free survival, overall survival, acute and late toxicity, and quality of life. A total of 314 patients will be randomly assigned to C12 treatment alone or bimodal treatment: Patients in the experimental group will receive a dose of 51 Gy (RBE) in 17 fractions and a boost of 15 Gy (RBE) in 5 fractions. Patients in the control group will receive 25 fractions photon IMRT 50Gy and a boost using 8 × 3 Gy (RBE) carbon ions. Local control will be assessed in regular follow up examinations until 5 years after the completion of treatment. Discussion The present trial aims to evaluate local control rates to compare sole carbon ion radiotherapy to bimodal radiotherapy with carbon ions and photons in patients with node negative ACCs of the head and neck region. Local control is selected as the primary endpoint due to its major clinical relevance because of slow but aggressive growth patterns. Trial registration The study was prospectively registered on 2nd January 2020: ClinicalTrials.gov, NCT04214366. “Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation (ACCO)”. Study status Under recruitment, participant recruitment is not completed. Start of recruitment was January 2020. There are no results been published or submitted to any journal.

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Long-term outcomes after carbon-ion radiotherapy for oral mucosal malignant melanoma

Journal of Radiation Research ◽

10.1093/jrr/rrw117 ◽

2016 ◽

Vol 58 (4) ◽

pp. 517-522 ◽

Cited By ~ 8

Author(s):

Kensuke Naganawa ◽

Masashi Koto ◽

Ryo Takagi ◽

Azusa Hasegawa ◽

Hiroaki Ikawa ◽

...

Keyword(s):

Overall Survival ◽

Malignant Melanoma ◽

Local Control ◽

Significant Risk ◽

Carbon Ion Radiotherapy ◽

Significant Prognostic Factor ◽

Effective Treatment Option ◽

Carbon Ion ◽

Mucosal Malignant Melanoma

Abstract Oral mucosal malignant melanoma (OMM) is extremely rare and has a poor prognosis. Owing to its rarity, it has not yet been possible to establish an optimal treatment modality. The objective of this study was to evaluate the long-term efficacy of carbon-ion radiotherapy (C-ion RT) for OMM. Between 1997 and 2013, 19 patients with OMM were treated with C-ion RT alone. Patient ages ranged from 44 to 84 years (median, 69 years). Nine men and 10 women were included. OMMs were restaged in accordance with the seventh edition of the tumour/node/metastasis (TNM) Staging System of the International Union Against Cancer. Before treatment, 14 patients had T3 disease and 5 had T4a disease. Three patients were classified as having N1 disease. All patients were classified as having M0. The hard palate was the most frequently involved oral subsite. All patients were treated with 57.6 Gy (relative biological effectiveness) in 16 fractions. The median follow-up period was 61 months (range, 8–190 months). The 5-year local control, overall survival and progression-free survival rates were 89.5%, 57.4% and 51.6%, respectively. For local control and overall survival, T classification was found to be a significant prognostic factor. Grade 2 and 3 osteoradionecrosis was observed in three and four patients, respectively. The presence of teeth within the planning target volume was a significant risk factor for developing osteoradionecrosis. C-ion RT was an effective treatment option with acceptable toxicity for OMM.

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Intensity Modulated Radiotherapy with Carbon Ion Radiotherapy Boost for Acinic Cell Carcinoma of the Salivary Glands

Cancers ◽

10.3390/cancers13010124 ◽

2021 ◽

Vol 13 (1) ◽

pp. 124

Author(s):

Maximilian P. Schmid ◽

Thomas Held ◽

Kristin Lang ◽

Klaus Herfarth ◽

Juliane Hörner-Rieber ◽

...

Keyword(s):

Cell Carcinoma ◽

Salivary Glands ◽

Ion Beam ◽

Intensity Modulated Radiotherapy ◽

Acinic Cell Carcinoma ◽

Carbon Ion Radiotherapy ◽

Definitive Treatment ◽

Carbon Ion ◽

Intensity Modulated ◽

Acinic Cell

Aim: to report clinical outcome in patients with acinic cell carcinoma of the salivary glands treated with intensity-modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) boost. Materials and Methods: all patients with acinic cell carcinoma of the salivary glands treated at the Heidelberg Ion-Beam Therapy Center were considered for this retrospective analysis. All patients received a CIRT boost with 18–24 Gy radiobiologic effectiveness (RBE)-weighted dose in 3 Gy RBE-weighted dose per fraction followed by IMRT, with 50–54 Gy in 2 Gy per fraction. Disease outcome was evaluated for local (LR), nodal (NR), distant recurrence (DR), and disease-free (DFS) and overall survival (OS). Morbidity was scored based on Common Terminology Criteria for Adverse Events (CTCAE) version 5. Descriptive statistics and the Kaplan-Meier method were used for analysis. Results: fifteen patients were available for analysis. Median follow-up after radiotherapy was 43 months. Six patients were treated for primary disease and nine for recurrent disease. Eight patients were treated with radiotherapy for macroscopic disease. Disease recurrence was observed in four patients: 1 LR, 2 NR, and 2 DR; 5-year local control, DFS, and OS were 80%, 52%, and 80%, respectively. No radiotherapy-related G3-5 morbidity was observed. Conclusion: In acinic cell carcinoma, IMRT with carbon ion radiotherapy boost leads to excellent results after R1-resection and is a promising treatment modality for definitive treatment in inoperable patients.

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Efficacy and feasibility of re-irradiation using carbon ions for pancreatic cancer that recurs after carbon-ion radiotherapy

Clinical and Translational Radiation Oncology ◽

10.1016/j.ctro.2020.10.007 ◽

2021 ◽

Vol 26 ◽

pp. 24-29

Author(s):

Yasuhito Hagiwara ◽

Shigeru Yamada ◽

Yuka Isozaki ◽

Hirotoshi Takiyama ◽

Makoto Shinoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Carbon Ion Radiotherapy ◽

Carbon Ions ◽

Carbon Ion

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Radiomics and Dosiomics for Predicting Local Control after Carbon-Ion Radiotherapy in Skull-Base Chordoma

Cancers ◽

10.3390/cancers13020339 ◽

2021 ◽

Vol 13 (2) ◽

pp. 339

Author(s):

Giulia Buizza ◽

Chiara Paganelli ◽

Emma D’Ippolito ◽

Giulia Fontana ◽

Silvia Molinelli ◽

...

Keyword(s):

Prognostic Factors ◽

Skull Base ◽

Local Control ◽

Tumour Progression ◽

Risk Groups ◽

Carbon Ion Radiotherapy ◽

Survival Models ◽

Carbon Ion ◽

Combined Models ◽

Skull Base Chordoma

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 patients underwent MR and CT imaging, from which tumour contours and dose maps were obtained. MRI and CT-based radiomic, and dosiomic features were selected and fed to two survival models, singularly or by combining them with clinical factors. Adverse LC was given by in-field recurrence or tumour progression. The dataset was split in development and test sets and the models’ performance evaluated using the concordance index (C-index). Patients were then assigned a low- or high-risk score. Survival curves were estimated, and risk groups compared through log-rank tests (after Bonferroni correction α = 0.0083). The best performing models were built on features describing tumour shape and dosiomic heterogeneity (median/interquartile range validation C-index: 0.80/024 and 0.79/0.26), followed by combined (0.73/0.30 and 0.75/0.27) and CT-based models (0.77/0.24 and 0.64/0.28). Dosiomic and combined models could consistently stratify patients in two significantly different groups. Dosiomic and multi-parametric radiomic features showed to be promising prognostic factors for LC in SBC treated with CIRT.

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