Fractionated Proton Radiation Research Articles

Treatment of Uveal Melanoma With Radioactive Iodine 125 Implant Compared With Proton Beam Radiotherapy.

ObjectiveTo review the current state of radiation therapy for uveal melanoma and compare particle radiation and brachytherapy.Patients and MethodsThe medical records of 156 patients treated for uveal melanoma between May 30, 2012, and March 16, 2020, were retrospectively reviewed. Treatments consisted of either radioactive iodine 125 implant (RAI) or fractionated proton radiation (proton beam therapy [PBT]). Baseline characteristics were compared using a Wilcoxon rank sum test or χ2 test. Outcomes were compared using Cox proportional hazards regression models or logistic regression models.ResultsThe median length of follow-up after treatment was 2.7 years (range, 0.5 to 9.0 years). Patients who underwent treatment with RAI were older (median age, 67 vs 59 years; P<.001) and had a lower tumor classification (American Joint Commission on Cancer; P=.001) compared with those who underwent PBT. There was no significant difference between RAI and PBT in the outcomes of liver metastases, death, enucleation, tearing, vision loss, retinal detachment, tumor thickness, conjunctivitis, optic neuropathy, iris neovascularization, or neovascular glaucoma (all P>.05). Patients who underwent RAI treatment had significantly higher risk of diplopia (P<.001), cataract progression (P<.001), and maculopathy (P=.03) compared with those who received PBT. Patients who underwent RAI were at higher risk of eyelash loss (P=.006) compared with the PBT group.ConclusionTreatment with PBT and RAI has similar efficacy; however, there are differences in the adverse outcomes associated with these 2 modalities.

Fractionated and Acute Proton Radiation Show Differential Intestinal Tumorigenesis and DNA Damage and Repair Pathway Response in ApcMin/+ Mice

Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic workers have established radiation as a risk factor for colorectal cancer (CRC), we have yet to determine the risk of CRC posed by proton radiation owing to a lack of sufficient human or animal data. The purpose of the current study was to quantitatively and qualitatively characterize differential effects of acute and fractionated high-energy protons on colorectal carcinogenesis. We used ApcMin/+ mice, a well-studied CRC model, to examine acute versus fractionated proton radiation-induced differences in intestinal tumorigenesis and associated signaling pathways. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy × 4). Intestinal tumor number and grade were scored 100 to 110 days after irradiation, and tumor and tumor-adjacent normal tissues were harvested to assess proliferative β-catenin/Akt pathways and DNA damage response and repair pathways relevant to colorectal carcinogenesis. Significantly higher intestinal tumor number and grade, along with decreased differentiation, were observed after acute radiation relative to fractionated radiation. Acute protons induced upregulation of β-catenin and Akt pathways with increased proliferative marker phospho-histone H3. Increased DNA damage along with decreased DNA repair factors involved in mismatch repair and nonhomologous end joining were also observed after exposure to acute protons. We show increased γH2AX, 53BP1, and 8-oxo-dG, suggesting that increased ongoing DNA damage along with decreased DNA repair factors and increased proliferative responses could be triggering a higher number of intestinal tumors after acute relative to fractionated proton exposures in ApcMin/+ mice. Taken together, our data suggest greater carcinogenic potential of acute relative to fractionated proton radiation.

Abstract 4158: Differential intestinal tumorigenesis and DNA repair response in APCMin/+ mice after acute and fractionated proton radiation

Abstract Ionizing radiation (IR) exposure is a risk factor for colorectal cancer (CRC) development. With increasing interest in exploring outer space, astronauts on prolonged space missions such as a mission to Mars are expected to receive IR doses that could heighten the risk of CRC. It is estimated that about 90% of the IR in outer space is energetic protons, and the radiation dose during solar particle events (SPEs) could reach up to 2 Gy behind shielding. However, the risk of CRC after energetic proton radiation is not yet fully defined due to lack of human or animal model data. The purpose of the current study was to quantitatively and qualitatively compare and characterize differences in intestinal tumorigenesis between acute and fractionated proton irradiation in APCMin/+ mice, a well-established mouse model for human CRC. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy x 4). Since proton dose to astronauts are variable based on space environment, in this initial study we chose a high single dose and a lower daily dose pattern to assess intestinal tumorigenesis. Intestinal tumor frequency and grade were noted, and tumor samples were collected from irradiated and control mice euthanized 100 to 110 days after radiation exposure. Molecular analysis was focused on DNA damage and repair, and cellular proliferative signaling pathways relevant to CRC using immunoblots, immunohistochemistry, and qPCR. Relative to control and fractionated-protons, there was significantly higher intestinal tumor frequency and grade after acute (single dose) proton irradiation. Decreased cellular differentiation and increased oxidative damage to DNA was observed after acute proton radiation. At the molecular level, our data showed increased DNA double strand breaks associated with decreased levels of DNA repair proteins, and upregulation of proliferative β-catenin and Akt signaling after acute proton exposure. Since increased DNA damage was not associated with concomitant increased apoptosis, our data suggest continued proliferation of cells bearing sub-lethal damage to promote tumorigenesis. In the fractionated proton group, tumor frequency and grade as well as molecular changes were comparable to sham-irradiated control group. When considered along with decreased tumor frequency and upregulation of DNA repair pathways after fractionation, our data are suggestive of marked differences in carcinogenic effects of acute vs. fractionated proton radiation. In summary, our data suggest that acute exposure to proton radiation is associated with higher risk of intestinal tumorigenesis in APCMin/+ mice with implications for gastrointestinal cancer risk in astronauts undertaking long duration space missions and in patients undergoing proton radiotherapy. Citation Format: Kamal Datta, Shubhankar Suman, Santosh Kumar, Albert J. Fornace. Differential intestinal tumorigenesis and DNA repair response in APCMin/+ mice after acute and fractionated proton radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4158.

Abstract A25: Intestinal tumorigenesis in APCMin/+ mice was higher after acute relative to fractionated proton radiation: Implications for space radiation-induced colorectal carcinogenesis

Abstract Ionizing radiation (IR) is a risk factor for colorectal cancer (CRC) based on epidemiologic studies. With increasing interest in exploring outer space, astronauts on prolonged space missions such as a mission to Mars will be exposed to IR doses that are expected to heighten the risk of CRC. Sources of space radiation beyond Earth's magnetosphere are galactic cosmic radiation (GCR) and solar particle event (SPE) and about 90% of the IR in outer space is energetic protons, which are more damaging than photon radiations such as γ-rays. While astronauts on deep-space missions are estimated to receive ~250 μGy/day of proton, radiation dose during SPE could reach up to ~2 Gy behind shielding. However, the risk of CRC after energetic proton radiation is not yet fully defined due to lack of human or animal model data. Limitations in obtaining adequate human data mandate that in vivo mechanistic data for CRC risk estimates be obtained using animal models and surrogate biologic and molecular end points relevant to human disease process. The purpose of the current study was to quantitatively and qualitatively compare and characterize differences in intestinal tumorigenesis between acute and fractionated proton irradiation in APCMin/+ mice, a well-established mouse model for human CRC. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy x 4). Since proton dose to astronauts is variable based on space environment, in this initial study we chose a high single dose and a low daily dose pattern to assess intestinal tumorigenesis. Intestinal tumor frequency and grade were noted, and tumor and normal tissue samples were collected from irradiated and control mice euthanized 100 to 110 days after radiation exposure. Molecular analysis was focused on DNA damage, genomic instability, specific epigenetic changes and mutation analysis, and cellular proliferative signaling pathways relevant to CRC using immunoblots, immunohistochemistry, and PCR. Relative to control and fractionated protons, there was significantly higher intestinal tumor frequency and grade after acute proton irradiation. At the molecular level our data showed increased DNA damage and DNA double-strand breaks, decreased genomic stability, and upregulation of proliferative β-catenin and Akt signaling after acute proton exposure. Since increased DNA damage was not associated with concomitant increased apoptosis and there was increased microsatellite instability, our data are suggestive of continued proliferation of cells bearing sublethal damages. Mutational analysis showed significantly more tumors had higher overall mutation frequency and increased p53 hot spot mutations after acute relative to fractionated proton exposure. In fractionated proton groups, tumor frequency and grade as well as molecular changes were statistically comparable to control groups. When considered along with higher mutational frequency and altered promoter methylation of key CRC-related genes in tumor adjacent normal tissues, our data are suggestive of marked differences in carcinogenesis of acute vs. fractionated proton radiation with higher tumorigenic effects associated with acute exposures. Citation Format: Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Jr., Kamal Datta. Intestinal tumorigenesis in APCMin/+ mice was higher after acute relative to fractionated proton radiation: Implications for space radiation-induced colorectal carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A25.

Fractionated Proton Radiation Therapy for Optic Nerve Sheath Meningiomas

To evaluate the safety and efficacy of fractionated proton radiation therapy for patients with optic nerve sheath meningiomas. Between 1992 and 2007, 13 evaluable patients with a total of 14 lesions were treated at our institution with fractionated proton therapy for optic nerve sheath meningiomas. Two patients had a biopsy prior to radiation therapy for histologic verification; 2 other patients had prior surgical resection of the tumor. Four eyes were blind as a result of the tumor, and 1 was blind as a result of surgery; 9 eyes had some vision at the time of radiation. The median dose for patients with vision was 54 Gy; if the eye was blind the median dose was 56.7 Gy. Mean and median follow-up periods were 12.7 and 13.9 years, respectively. Complete local control was achieved in all patients. Vision was preserved or improved in 8 of the 9 patients that had pre-treatment vision (89%). The one patient with worsened vision after treatment had very poor vision prior to radiation. Two patients had toxicity related to radiation treatment: one patient developed pituitary dysfunction, and another who had tumor that was extending into the globe, developed macular edema and retinopathy. Fractionated proton radiation therapy for optic nerve sheath meningioma achieves excellent control with minimal toxicity. Vision preservation is excellent with this modality, and is an effective treatment option for patients with optic nerve sheath meningioma.

Radiation Tolerance of the Optic Pathway After Fractionated Proton Radiation Therapy

Radiation Tolerance of the Optic Pathway After Fractionated Proton Radiation Therapy

Radiation Tolerance of the Optic Pathway After Fractionated Proton Radiation Therapy

Radiation Tolerance of the Optic Pathway After Fractionated Proton Radiation Therapy

A Comparison of Critical Structure Dose and Toxicity Risks in Patients with Low Grade Gliomas Treated with IMRT versus Proton Radiation Therapy

Proton therapy offers dosimetric advantage of decreased dose to non-target tissues. This study explored the potential benefits of proton radiation therapy versus photon based intensity modulated radiation therapy (IMRT) for patients with low grade gliomas (LGG) through dosimetric comparison and biological modeling of potential radiation-induced toxicities. Eleven patients were treated with fractionated proton radiation therapy on a prospective protocol assessing for feasibility and treatment toxicity of proton radiation therapy in patients with LGG. IMRT treatment plans were created for each patient using the same CT planning data set and defined structures. The prescription dose to clinical target volume (CTV) was 54 Gy(RBE). The toxicity risk of IMRT and protons was estimated based upon equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) modeling. The risk of secondary tumors for each modality was estimated. Proton EUD for most immediate normal tissue structures was between 10-20 Gy lower than the EUD delivered by IMRT. However, the difference in NTCP was negligible for both modalities. The mean excess risk of proton radiation-induced second tumor in the brain per 10,000 cases per year is 47 (range 11-83), while the mean risk for IMRT is 106 (range 70-134). The mean ratio of excess risk IMRT/protons is 2.2 (range 1.6-6.5), demonstrating that the risk of secondary tumors is consistently higher for IMRT. Proton therapy effectively reduces the dose to surrounding normal tissues in LGG patients. IMRT has a twofold higher risk of secondary intracranial tumors as compared to proton therapy. In most cases, NTCP is negligible for both modalities. The benefit of proton therapy over IMRT may be more substantial in patients with tumors in proximity to critical structures.

Protons and Parachutes

Protons and Parachutes

Proton Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base

Most patients with conventional radiotherapy after surgery die with local disease progression. The superior local tumor control and overall survival achieved with fractionated proton RT can be attributed to improved dose localization characteristics of protons, resulting in higher doses delivered. Patients with base of skull neoplasms are increasingly considered for stereotactic radiosurgery. Recently, Muthukumar et al reported for the University of Pittsburgh group on cobalt-60 Gamma Knife (Elekta Instruments, Atlanta, GA) therapy for 15 patients with chordomas or chondrosarcomas of the base of the skull. With tumor volumes ranging between 0.98 and 10.3 mL (mean, 4.6 mL), doses to the tumor margin varying from 12 to 20 Gy (median, 18 Gy) were delivered. Two patients were treated without histologic tumor confirmation. After a median follow-up time of 40 months, 2 patients had died of disease, 2 patients had succumbed to intercurrent disease, and 1 patient surviving at the time of analysis had developed tumor progression. Neither actuarial local control nor actuarial survival data were presented. In the LLUMC series, most tumors exceeded sizes reportedly suitable for radiosurgery or were of a highly irregular configuration. Nevertheless, in 11 patients, tumors less than 15 mL in size remained locally controlled as did tumors sized between 15 and 25 mL in 11 additional patients; these patients were thus potential candidates for stereotactic radiosurgery. At present, too few reports on radiosurgery contain sufficient patient numbers and statistical analyses to permit one to draw conclusions about the feasibility of radiosurgery for chordomas and chondrosarcomas of the base of the skull. A principal difference between proton RT and radiosurgery as currently practiced in most centers concerns target definition. In proton RT, the GTV is treated. In addition, a clinical volume is defined, which is distinctly different from the GTV in size and shape, to include the operative site and other areas of microscopic risk. In many instances, only the GTV is targeted in radiosurgery. Although it is certainly appropriate to explore the role that radiosurgical techniques may have in treating these tumors, results should be evaluated against the excellent outcome that can be achieved with fractionated proton RT, particularly in patients with tumors small enough and of favorable configuration and location to make them candidates for radiosurgery. The present problem of particle therapy is its limited availability. In the United States, only two proton centers can currently provide treatment for base of skull lesions. The HCL is soon to be replaced by a hospital-based facility at the MGH. Several other proton centers in the United States are currently under active consideration. Proton RT is an evolutionary process. Recent developments in proton RT include intensity modulated therapy and improvements in beam delivery systems, namely, the introduction of active beam scanning. These should further increase the degree of dose conformity. In addition, other heavy particles are also being investigated so as to combine the physical advantages of protons with the differential increased biologic effectiveness of particles in tumor as compared to normal tissues. A report from the Heavy Ion Research Facility in Darmstadt, Germany, has not revealed any increased acute toxicities in the first 13 patients with skull base chordomas or chondrosarcomas treated using carbon ions. Several important factors have emerged from recently published results: Patients with low-grade chondrosarcomas and male patients with chordomas have an excellent chance of durable tumor control and long-term survival after proton RT. Severe complications are within the acceptable range considering the high doses delivered and given the major morbidity associated with uncontrollable tumor growth in such patients. Female patients with chordomas experience increased early and late failures

131 Proton radiation therapy for chordomas and chondrosarcomas of the skull base

Object. Local tumor control, patient survival, and treatment failure outcomes were analyzed to assess treatment efficacy in 58 patients in whom fractionated proton radiation therapy (RT) was administered for skull base chordomas and chondrosarcomas. Methods. Between March 1992 and January 1998, a total of 58 patients who could be evaluated were treated for skull base tumors, 33 for chordoma and 25 for chondrosarcoma. Following various surgical procedures, residual tumor was detected in 91% of patients; 59% demonstrated brainstem involvement. Target dosages ranged from 64.8 and 79.2 (mean 70.7) Co Gy equivalent. The range of follow up was 7 to 75 months (mean 33 months). In 10 patients (17%) the treatment failed locally, resulting in local control rates of 92% (23 of 25 patients) for chondrosarcomas and 76% (25 of 33 patients) for chordomas. Tumor volume and brainstem involvement influenced control rates. All tumors with volumes of 25 ml or less remained locally controlled, compared with 56% of tumors larg...

Successful treatment of esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy and proton radiation. Results in 9 cases.

To study the efficacy of a newly designed treatment strategy for esthesioneuroblastoma and neuroendocrine carcinoma of the paranasal sinuses. Nonrandomized prospective study of a case series in a tertiary referral center. Nine consecutive patients with newly diagnosed esthesioneuroblastoma or neuroendocrine carcinoma of the paranasal sinuses from June 1992 to October 1995 underwent this treatment protocol. After histological diagnosis and detailed imaging, 2 cycles of cisplatin and etoposide chemotherapy were instituted. Chemotherapy responders were treated with combined photon and stereotaxic fractionated proton radiation therapy totaling approximately 68 Gy to the primary site, whereas poor responders were treated with surgical resection followed by postoperative radiation. In both cases, therapy was then concluded with 2 additional cycles of cisplatin and etoposide chemotherapy. Response to therapy, survival, disease-free survival, and complications of therapy were examined. Nine patients with a median Dulguerov T stage of T3 (range, T2 to T4) completed the treatment protocol, with mean follow-up after diagnosis of 20.5 months. Eight of 9 patients exhibited a dramatic response to therapy with remission of their tumor, and resection was not required. One patient failed to respond to induction chemotherapy and received surgical therapy to be followed by postoperative radiotherapy. There have been no recurrences (mean disease-free interval of 14.0 months). Complications were limited and generally transient. The use of combined cisplatin and etoposide chemotherapy with proton radiation has demonstrated initial success in treatment of these tumors. Dramatic response from chemotherapy is possible even in bulky or unresectable disease. This protocol has an acceptable complication rate and conveys less morbidity than craniofacial resection and conventional radiotherapy. Further follow-up will be required to determine the long-term success rate of this therapeutic protocol.

Clival Chordoma in Childhood: A Report of Two Cases

Clival Chordoma in Childhood: A Report of Two Cases

Fractionated Proton Radiation Therapy of Cranial and Intracranial Tumors

Since 1973 fractionated proton radiation therapy has been used in the treatment of malignant disease. Protons have favorable physical characteristics that yield dose distributions superior to those of photons in certain clinical situations. As of December 31, 1987, 1,678 patients had been treated. Of these, 110 had chordomas or low-grade chondrosarcomas of the base of skull. The first 68 patients have a minimum follow-up of 17 months. The median dose was 69 Cobalt Gray Equivalent (CGE). (CGE is the dose in proton Gray multiplied by 1.1, which is the relative biological effectiveness for protons relative to 60Cobalt.) The actuarial 5-year local control rate is 82%, and the disease-free survival rate is 76%. Thirteen patients with meningiomas have been treated, following subtotal resection. The median dose was 59.4 CGE. With a median follow-up of 26 months, no patient has had tumor progression. In addition, nine patients with gliomas and 12 with craniopharyngiomas have been treated.

Considerations in fractionated proton radiation therapy: clinical potential and results

Protons have a finite range in tissue and can provide a better concentration of radiation dose in the tumor than conventional X-rays in certain situations. The development of optimized treatment plans for X-rays and protons followed by a comparative evaluation is one method of selecting tumor sites best suited for proton treatment. The preliminary results of comparative treatment planning for base of skull tumors and carcinoma of the prostate are discussed. These comparisons suggest a clinical gain for proton treatment of tumors in these locations. The clinical experience with fractionated proton treatment of several tumor sites is also discussed. The results of high dose proton treatment of chordomas and low grade chondrosarcomas of the base of skull is particularly promising: an actuarial 5-year local control of 78% has been obtained in 50 patients followed for a minimum of 22 months.

Fractionated proton radiation therapy of chordoma and low-grade chondrosarcoma of the base of the skull

Sixty-eight patients with chordoma or low-grade chondrosarcoma at the base of the skull received fractionated high-dose postoperative radiation delivered with a 160-MeV proton beam. Protons have favorable physical characteristics which allow the delivery of high doses of radiation to these critically located tumors. The methods employed for these treatments are described. These patients have been followed for at least 17 months and for a median of 34 months. The median tumor dose was 69 CGE (cobalt Gy equivalent): CGE is the dose in proton Gy multiplied by 1.1, which is the relative biological effectiveness for protons compared to cobalt-60. The daily dose was 1.8 to 2.1 CGE. For this group the 5-year actuarial local control rate is 82% and disease-free survival rate is 76%. The incidence of treatment-related morbidity has been acceptable.