• Humans
• Consensus
• Fiducial Markers
• Four-Dimensional Computed Tomography
• Immobilization/methods
• Movement
• Organ Motion
• Organs at Risk/diagnostic imaging
• Organs at Risk/radiation effects
• Pancreatic Neoplasms/radiotherapy
• Pancreatic Neoplasms/diagnostic imaging
• Proton Therapy/methods
• Proton Therapy/adverse effects
• Proton Therapy/standards
• Radiation Injuries/prevention & control
• Radiotherapy Dosage
• Radiotherapy Planning, Computer-Assisted/methods
• Radiotherapy, Image-Guided/methods
• Respiration
• Stomach/diagnostic imaging

• 4D dynamic dose
• 4D robust optimization
• Intensity modulated Proton Therapy
• Pancreatic cancer

• Humans
• Pancreatic Neoplasms/radiotherapy
• Proton Therapy/methods
• Radiotherapy Planning, Computer-Assisted/methods
• Radiotherapy, Intensity-Modulated/methods
• Respiration
• Retrospective Studies
• Four-Dimensional Computed Tomography/methods
• Radiotherapy Dosage
• Male
• Female
• Organs at Risk/radiation effects

• 12105160 National Natural Science Foundation of China
• 82072094 National Natural Science Foundation of China
• ZR2021QA099 Natural Science Foundation of Shandong Province
• ZR2019LZL017 Natural Science Foundation of Shandong Province
• ts201712098 Taishan Scholar Project of Shandong Province
• 2022B03019-5 Xinjiang Uygur Autonomous Region key research and development project
• 2021HZ81 Tumor precision radiotherapy peak plan

• Humans
• Proton Therapy
• Protons
• Radiometry
• Radiotherapy Dosage

• chemoradiotherapy
• cost-effectiveness
• incremental cost-effectiveness ratio
• locally advanced pancreatic cancer
• particle radiotherapy
• proton beam therapy
• quality-adjusted life year
• radiotherapy

• Humans
• Proton Therapy
• Cost-Benefit Analysis
• Japan
• Pancreatic Neoplasms/radiotherapy

• 19H03596 Ministry of Education, Culture, Sports, Science and Technology
• Ministry of Education, Culture, Sports, Science and Technology

• VMAT
• carbon-ion beam
• dose distribution
• proton beam
• radiotherapy
• treatment planning

• Humans
• Protons
• Rectum
• Radiotherapy, Intensity-Modulated/methods
• Radiotherapy Planning, Computer-Assisted/methods
• Radiotherapy Dosage
• Neoplasm Recurrence, Local/radiotherapy
• Rectal Neoplasms/radiotherapy
• Chronic Disease

• QST President's Strategic Fund Advanced Study Laboratory

• dose escalation
• pancreatic cancer
• proton beam therapy
• stereotactic body radiotherapy

• double scattering proton therapy
• intensity modulated proton therapy
• pancreatic cancer
• pencil beam scanning
• proton radiation therapy
• toxicity

• P30 CA008748 NCI NIH HHS

• Hodgkin
• Protons
• Radiation
• Secondary malignancy
• Toxicity

Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy (GPT) for non-metastatic, locally advanced pancreatic cancer (LAPC) remain unclear. This study aimed to determine the factors associated with long-term survival in GPT for non-metastatic LAPC.

The medical records of 123 patients with LAPC treated with GPT between February 2009 and December 2019 at Hyogo Ion Beam Medical Center were retrospectively reviewed to assess the factors associated with long-term survival outcomes.

The median overall survival of the total cohort treated with GPT was 18.7 months. The 1- and 2-year overall, local progression-free, and progression-free survival rates were 70.4% and 35.7%, 78.2% and 59.0%, and 38.6% and 20.8%, respectively. Multivariate analysis revealed that LAPCs at the pancreatic body-tail and those without anterior peripancreatic invasion were independently associated with longer overall survival (P = 0.040 and P = 0.015, respectively). The median overall survival of patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion were 24.1 and 28.1 months, respectively. LAPCs at the pancreatic body-tail had a higher volume ratio irradiated over 60 Gy equivalents at gross tumor volume than those at the pancreatic head (P < 0.001). LAPCs with anterior peripancreatic invasion had more peritoneal recurrence within 6 months after GTP than those without anterior peripancreatic invasion (P = 0.039).

GPT is a promising treatment option for patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion.

• Chemoradiotherapy
• Gemcitabine
• Long-term survival outcome
• Pancreatic cancer
• Prognostic factor
• Proton radiotherapy
• Retrospective study

• R37 CA229417 NCI NIH HHS

To investigate the potential clinical benefits of using stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) technique for locally advanced pancreatic cancer (LAPC) among different treatment modalities and planning strategies, including photon and proton.

A total of 19 patients were retrospectively selected in this study: 13 cases with the tumor located in the head of the pancreas and 6 cases with the tumor in the body of the pancreas. SBRT-SIB plans were generated using volumetric modulated arc therapy (VMAT), two-field Intensity Modulated Proton Therapy (IMPT), and three-field IMPT. The IMPT used the robust optimization parameters of ± 3.5% range and 5-mm setup uncertainties. Root-mean-square deviation dose (RMSD) volume histograms were used to evaluate the target coverage robustness quantitatively. Dosimetric metrics based on the dose-volume histogram (DVH), homogeneity index (HI), and normal tissue complication probability (NTCP) were analyzed to evaluate the potential clinical benefits among different planning groups.

With a similar CTV and SIB coverage, two-field IMPT provided a lower maximum dose for the stomach (median: 18.6GyE, p<0.05) and duodenum (median: 32.62GyE, p<0.05) when the target was located in the head of the pancreas compared to VMAT and three-field IMPT. The risks of gastric bleed (3.42%) and grade ≥ 3 GI toxicity (4.55%) were also decreased. However, for the target in the body of the pancreas, VMAT showed a lower maximum dose for the stomach (median 30.93GyE, p<0.05) and toxicity of gastric bleed (median: 8.67%, p<0.05) compared to two-field IMPT and three-field IMPT, while other maximum doses and NTCPs were similar. The RMSD volume histogram (RVH) analysis shows that three-field IMPT provided better robustness for targets but not for OARs. Instead, three-field IMPT increased the Dmean of organs such as the stomach, duodenum, and intestine.

The results indicated that the tumor locations could play a critical role in determining clinical benefits among different treatment modalities. Two-field IMPT could be a better option for LAPC patients whose tumors are located in the head of the pancreas. It provides lower severe toxicity for the stomach and duodenum. Nevertheless, VMAT is preferred for the body with better protection for the possibility of gastric bleed.

• intensity modulated proton therapy (IMPT)
• normal tissue complication probability (NTCP)
• pancreatic cancer
• simultaneous integrated boost (SIB)
• stereotactic body radiation therapy (SBRT)
• volumetric modulated arc therapy (VMAT)

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

•

Robustly optimized proton plans (rMFO-IMPT) with simultaneously integrated boost (SIB) were clinically applicable.

To compare the dosimetric results of an in-silico study among intensity-modulated photon (IMRT) and robustly optimized intensity-modulated proton (IMPT) treatment techniques using a dose-escalated simultaneously integrated boost (SIB) approach in locally recurrent or advanced pancreatic cancer patients.

For each of 15 locally advanced pancreatic cancer patients, a volumetric-modulated arc therapy (VMAT), a Tomotherapy (TOMO), and an IMPT treatment plan was optimized on free-breathing treatment planning computed tomography (CT) images. For the photon treatment plans, doses of 66 Gy and 51 Gy, both as SIB in 30 fractions, were prescribed to the gross tumor volume (GTV) and to the planning target volume (PTV), respectively. For the proton plans, a dose prescription of 66 Gy(RBE) to the GTV and of 51 Gy(RBE) to the clinical target volume (CTV) was planned. For each SIB-treatment plan, doses to the targets and OARs were evaluated and statistically compared.

All treatment techniques reached the prescribed doses to the GTV and CTV or PTV. The stomach and the bowel, in particular the duodenum and the small bowel, were found to be frequently exposed to doses exceeding 50 Gy, irrespective of the treatment technique. For doses below 50 Gy, the IMPT technique was statistically significant superior to both IMRT techniques regarding decreasing dose to the OARs, e.g. volume of the bowel receiving 15 Gy (V_15Gy) was reduced for IMPT compared to VMAT (p = 0.003) and TOMO (p < 0.001).

With all photon and proton techniques investigated, the radiation dose to gastrointestinal OARs remained critical when treating patients with unresectable locally recurrent or advanced pancreatic cancer using a dose-escalated SIB approach.

• Dose escalation
• Intensity-modulated proton therapy
• Intensity-modulated radiation therapy
• Pancreatic cancer
• Robust optimization
• Simultaneously integrated boost

• heavy-particle radiotherapy
• neoadjuvant therapy
• pancreatic cancer
• radiotherapy
• stereotactic radiotherapy

The purpose of this study was to determine the potential of escalated dose radiation (EDR) robust intensity-modulated proton radiotherapy (ro-IMPT) in reducing GI toxicity risk in locally advanced unresectable pancreatic cancer (LAUPC) of the head in term of normal tissue complication probability (NTCP) predictive model.

For 9 patients, intensity-modulated radiotherapy (IMRT) was compared with ro-IMPT. For all plans, the prescription dose was 59.4GyE (Gray equivalent) in 33 fractions with an equivalent organ at risk (OAR) constraints. Physical dose distribution was evaluated. GI toxicity risk for different endpoints was estimated using published NTCP Lyman Kutcher Burman (LKB) models for stomach, duodenum, small bowel, and combine stomach and duodenum (Stoduo). A Wilcoxon signed-rank test was used for dosimetry parameters and NTCP values comparison.

The dosimetric results have shown that, with similar target coverage, ro-IMPT achieves a significant dose-volume reduction in the stomach, small bowel, and stoduo in low to high dose range in comparison to IMRT. NTCP evaluation for the endpoint gastric bleeding of stomach (10.55% vs. 13.97%, P = 0.007), duodenum (1.87% vs. 5.02%, P = 0.004), and stoduo (5.67% vs. 7.81%, P = 0.008) suggest reduced toxicity by ro-IMPT compared to IMRT. ∆NTCP _{IMRT – ro-IMPT} (using parameter from Pan et al. for gastric bleed) of ≥5 to < 10% was seen in 3 patients (33%) for stomach and 2 patients (22%) for stoduo. An overall GI toxicity relative risk (NTCP_ro-IMPT/NTCP_IMRT) reduction was noted (0.16–0.81) for all GI-OARs except for duodenum (> 1) with endpoint grade ≥ 3 GI toxicity (using parameters from Holyoake et al.).

With similar target coverage and better conformity, ro-IMPT has the potential to substantially reduce the risk of GI toxicity compared to IMRT in EDR of LAUPC of the head. This result needs to be further evaluated in future clinical studies.

• Intensity-modulated proton therapy
• Intensity-modulated radiotherapy
• Normal tissue complication probability
• Pancreatic cancer

• Dose escalation
• Locally advanced pancreatic cancer
• Phase I
• Proton and carbon ion radiation therapy

• Protons
• cancer
• gastrointestinal (GI)
• radiation
• reirradiation

• Radiotherapy
• outcomes
• pancreas cancer
• pancreatic cancer
• particle therapy
• proton therapy

• dosimetry
• intensity modulated radiation therapy (IMRT)
• normal tissue complication probability (NTCP)
• pancreatic cancer
• proton beam therapy (PBT)
• volumetric modulated arc therapy (VMAT)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive tumors, with a low rate of survival, likely due to the tendency of the tumor for early local and distant spread. Pancreatic cancer accounts for about 3% of all cancers in the US and about 7% of all cancer deaths. Surgical resection still represents the best curative treatment for PDAC, although only 10–20% of patients are upfront resectable at diagnosis, 50% has metastatic disease and 35% locally advanced cancer. The 5-year overall survival (OS) after curative resection is limited to 20%. Moreover among patients who undergo surgery, 30% develop early recurrence while most of them will eventually relapse. The risk of early failure after surgery could be associated with inadequate preoperative radiological staging, lack of radical surgery and differences in tumor aggressiveness. In recent years, more accurate patient categorization due to sophisticated imaging tools and techniques increase the survival rate while neoadjuvant treatment can help surgeons select patients who will benefit most from surgery. Neoadjuvant therapy includes chemotherapy alone, chemoradiotherapy, chemotherapy with chemoradiation and targeted therapies. The aim of this review is to present the available data concerning the management of patients with borderline PDAC.

• Borderline resectable
• Chemoradiation
• Chemotherapy
• Pancreatic adenocarcinoma

• MR-guided radiotherapy
• Online adaptive radiotherapy
• Pancreatic cancer

• Humans
• Magnetic Resonance Imaging/methods
• Organs at Risk/radiation effects
• Pancreatic Neoplasms/diagnostic imaging
• Pancreatic Neoplasms/radiotherapy
• Prognosis
• Radiotherapy, Image-Guided/methods

• Chemotherapy
• Pancreatic cancer
• Proton beam therapy
• Radiotherapy

• Dose escalation
• Intensity modulated proton therapy
• Pancreatic cancer
• Simultaneous integrated boost

• Liver
• cholangiocarcinoma
• esophageal
• esophagus
• gastric
• gastrointestinal cancers (GI cancers)
• pancreas
• pancreatic
• proton beam therapy (PBT)

• Stereotactic body radiotherapy (SBRT)
• carbon ions
• intensity modulated radiation therapy (IMRT)
• pancreatic cancer
• protons

• Pancreas
• dosimetry
• pancreatic cancer
• passive scattering (PS)
• pencil beam scanning (PBS)
• proton beam therapy

• carbon
• pancreatic cancer
• proton
• radiotherapy
• stereotactic

• Proton
• pancreatic cancer
• reirradiation
• survival
• toxicity

• Adjuvant
• Chemoradiation
• Neoadjuvant
• Pancreas cancer
• Pancreatic cancer
• Proton therapy
• Radiation therapy
• Stereotactic body radiotherapy

• Duodenum
• Pancreatic cancer
• Stereotactic body radiotherapy
• Toxicity

• Cardiac toxicity
• Proton therapy
• Thymic carcinoma
• Thymoma

• Intensity-modulated radiation therapy
• Pancreatic cancer
• Proton plan robustness
• Spot-scanned proton therapy
• Stereotactic body proton therapy
• Stereotactic body radiation therapy

• Cancer
• Particle therapy
• Proton beam therapy
• Radiotherapy

Pancreatic cancer is the fourth most common cause of cancer death in the United States. Surgery remains the only curative option; however only 20% of the patients have resectable disease at the time of initial presentation. The definition of borderline resectable pancreatic cancer is not uniform but generally denotes to regional vessel involvement that makes it unlikely to have negative surgical margins. The accurate staging of pancreatic cancer requires triple phase computed tomography or magnetic resonance imaging of the pancreas. Management of patients with borderline resectable pancreatic cancer remains unclear. The data for treatment of these patients is primarily derived from retrospective single institution experience. The prospective trials have been plagued by small numbers and poor accrual. Neoadjuvant therapy is recommended and typically consists of chemotherapy and radiation therapy. The chemotherapeutic regimens continue to evolve along with type and dose of radiation therapy. Gemcitabine or 5-fluorouracil based chemotherapeutic combinations are administered. The type and dose of radiation vary among different institutions. With neoadjuvant treatment, approximately 50% of the patients are able to undergo surgical resections with negative margins obtained in greater than 80% of the patients. Newer trials are attempting to standardize the definition of borderline resectable pancreatic cancer and treatment regimens. In this review, we outline the definition, imaging requirements and management of patients with borderline resectable pancreatic cancer.

• Pancreatic cancer
• Surgery
• Chemotherapy
• Radiation
• Borderline

Radiotherapy is commonly offered to patients with pancreatic malignancies although its ultimate utility is compromised since the pancreas is surrounded by exquisitely radiosensitive normal tissues, such as the duodenum, stomach, jejunum, liver, and kidneys. Proton radiotherapy can be used to create dose distributions that conform to tumor targets with significant normal tissue sparing. Because of this, protons appear to represent a superior modality for radiotherapy delivery to patients with unresectable tumors and those receiving postoperative radiotherapy. A particularly exciting opportunity for protons also exists for patients with resectable and marginally resectable disease. In this paper, we review the current literature on proton therapy for pancreatic cancer and discuss scenarios wherein the improvement in the therapeutic index with protons may have the potential to change the management paradigm for this malignancy.

• Proton therapy
• Pancreatic cancer
• Review