Histopathologic and MR Imaging Appearance of Spontaneous and Radiation-Induced Necrosis in Uveal Melanomas: Initial Results

Necrosis in uveal melanomas can be spontaneous or induced by radiotherapy. The purpose of our study was to compare the histopathologic and MRI findings of radiation-induced necrosis of a group of proton beam-irradiated uveal melanomas with those of spontaneous necrosis of a control group of patients undergoing primary enucleation. 11 uveal melanomas who had undergone proton beam radiotherapy, MRI and secondary enucleation, and a control group of 15 untreated uveal melanomas who had undergone MRI and primary enucleation were retrospectively identified. Within the irradiated and nonirradiated group, 7 and 6 eyes with histological evidence of necrosis respectively, were furtherly selected for the final analysis; the appearance of necrosis was assessed at histopathologic examination and MRI. Irradiated melanomas showed a higher degree of necrosis as compared with nonirradiated tumors. Irradiated and nonirradiated lesions differed based on the appearance and distribution of necrosis. Irradiated tumors showed large necrotic foci, sharply demarcated from the viable neoplastic tissue; nonirradiated tumors demonstrated small, distinct foci of necrosis. Radiation-induced necrosis, more pigmented than surrounding viable tumor, displayed high signal intensity on T1-weighted and low signal intensity on T2-weighted images. The hemorrhagic/coagulative necrosis, more prevalent in nonirradiated tumors (4 out of 6 vs. 1 out of 7 cases), appeared hyperintense on T2-weighted and hypointense on T1-weighted images. Our study boosts the capability to recognize radiation-induced alterations in uveal melanomas at MRI and may improve the accuracy of radiologists in the evaluation of follow-up MR examination after radiotherapy.

New Perspectives for Eye-Sparing Treatment Strategies in Primary Uveal Melanoma

Uveal melanoma is the most common intraocular malignancy and arises from melanocytes in the choroid, ciliary body, or iris. The current eye-sparing treatment options include surgical treatment, plaque brachytherapy, proton beam radiotherapy, stereotactic photon radiotherapy, or photodynamic therapy. However, the efficacy of these methods is still unsatisfactory. This article reviews several possible new treatment options and their potential advantages in treating localized uveal melanoma. These methods may be based on the physical destruction of the cancerous cells by applying ultrasounds. Two examples of such an approach are High-Intensity Focused Ultrasound (HIFU)—a promising technology of thermal destruction of solid tumors located deep under the skin and sonodynamic therapy (SDT) that induces reactive oxygen species. Another approach may be based on improving the penetration of anti-cancer agents into UM cells. The most promising technologies from this group are based on enhancing drug delivery by applying electric current. One such approach is called transcorneal iontophoresis and has already been shown to increase the local concentration of several different therapeutics. Another technique, electrically enhanced chemotherapy, may promote drug delivery from the intercellular space to cells. Finally, new advanced nanoparticles are developed to combine diagnostic imaging and therapy (i.e., theranostics). However, these methods are mostly at an early stage of development. More advanced and targeted preclinical studies and clinical trials would be needed to introduce some of these techniques to routine clinical practice.

Glioblastoma radiotherapy using Intensity modulated Radiotherapy (IMRT) or proton Radiotherapy—GRIPS Trial (Glioblastoma Radiotherapy via IMRT or Proton BeamS): a study protocol for a multicenter, prospective, open-label, randomized, two-arm, phase III study

Background Radiation therapy is an integral part of the multimodal primary therapy of glioblastomas. As the overall prognosis in this tumor entity remains unfavorable, current research is focused on additional drug therapies, which are often accompanied by increases in toxicity. By using proton beams instead of photon beams, it is possible to protect large parts of the brain which are not affected by the tumor more effectively. An initial retrospective matched-pair analysis showed that this theoretical physical benefit is also clinically associated with a reduction in toxicity during therapy and in the first few months thereafter. Methods/design The GRIPS trial is a multicenter, prospective, open-label, randomized, two-arm, phase III study using either intensity modulated photon radiation techniques (standard arm) or proton beam radiotherapy (experimental arm). Additionally, patients are stratified according to "fractionation scheme" (normofractionated/hypofractionated), "subventricular zone involvement" (yes/no) and concurrent chemotherapy (yes/no) and the planned case number is 326 patients. Radiation therapy is performed with a dose of 30 × 2 Gy(RBE) or 33 × 1.8 Gy(RBE), or for patients treated according to the hypofractionation protocol with 15 × 2.67 Gy(RBE). A possible administration of additional chemotherapy (concurrent or adjuvant) or tumor treating fields is applied in dosage and frequency according to the therapy standard outside of this study. The primary endpoint is the cumulative rate of toxicity CTC grade 2 and higher in the first 4 months. Secondary endpoints include overall survival, progression-free survival, quality of life, and neurocognition. Discussion Aim of the GRIPS study is to prospectively assess whether the theoretical physical advantage of proton beam radiotherapy will translate into a clinical reduction of toxicity during and in the first months after therapy. Trial registration ClinicalTrials (NCT): NCT04752280.

Effectiveness and Toxicity of Fractionated Proton Beam Radiotherapy for Cranial Nerve Schwannoma Unsuitable for Stereotactic Radiosurgery

PurposeIn this benign tumor entity, preservation of cranial nerve function is of special importance. Due to its advantageous physical properties, proton beam radiotherapy (PRT) is a promising approach that spares healthy tissue. Could PRT go along with satisfactory preservation rates for cranial nerve function without compromising tumor control in patients with cranial nerve schwannoma unsuitable for stereotactic radiosurgery?MethodsWe analyzed 45 patients with cranial nerve schwannomas who underwent PRT between 2012 and 2020 at our institution. Response assessment was performed by MRI according to RECIST 1.1, and toxicity was graded following CTCAE 5.0.ResultsThe most common schwannoma origin was the vestibulocochlear nerve with 82.2%, followed by the trigeminal nerve with 8.9% and the glossopharyngeal nerve as well as the vagal nerve, both with each 4.4%. At radiotherapy start, 58% of cranial nerve schwannomas were progressive and 95.6% were symptomatic. Patients were treated with a median total dose of 54 Gy RBE in 1.8 Gy RBE per fraction. MRI during the median follow-up period of 42 months (IQR 26–61) revealed stable disease in 93.3% of the patients and partial regression in 6.7%. There was no case of progressive disease. New or worsening cranial nerve dysfunction was found in 20.0% of all patients, but always graded as CTCAE °I-II. In seven cases (16%), radiation-induced contrast enhancements (RICE) were detected after a median time of 14 months (range 2–26 months). RICE were asymptomatic (71%) or transient symptomatic (CTCAE °II; 29%). No CTCAE °III/IV toxicities were observed. Lesions regressed during the follow-up period in three of the seven cases, and no lesion progressed during the follow-up period.ConclusionThese data demonstrate excellent effectiveness with 100% local control in a median follow-up period of 3.6 years with a promising cranial nerve functional protection rate of 80%. RICE occurred in 16% of the patients after PRT and were not or only mildly symptomatic.

Glioblastoma Radiotherapy Using Intensity Modulated Radiotherapy (IMRT) or Proton Radiation - GRIPS Trial (Glioblastoma Radiotherapy via IMRT or Proton BeamS): A Study Protocol for a Multicenter, Prospective, Open-label, Randomized, Two-arm, Phase III Study.

Background:Radiation therapy is an integral part of the multimodal primary therapy of glioblastomas. As the overall prognosis in this tumor entity remains unfavorable, current research is focused on additional drug therapies, which are often accompanied by increases in toxicity. By using proton beams instead of photon beams, it is possible to protect large parts of the brain which are not affected by the tumor more effectively. An initial retrospective matched-pair analysis showed that this theoretical physical benefit is also clinically associated with a reduction in toxicity during therapy and in the first few months thereafter. Methods/design:The GRIPS trial is a multicenter, prospective, open-label, randomized, two-arm, phase III study using either intensity modulated photon radiation techniques (standard arm) or proton beam radiotherapy (experimental arm). Additionally, patients are stratified according to "fractionation scheme" (normofractionated/hypofractionated), "subventricular zone involvement" (yes/no) and synchronous chemotherapy (yes/no) and the planned case number is 326 patients.Radiation therapy is performed with a dose of 30 x 2 Gy(RBE) or 33 x 1.8 Gy(RBE), or for patients treated according to the hypofractionation protocol with 15 x 2.67 Gy(RBE). A possible administration of additional chemotherapy (synchronous or adjuvant) or tumor treating fields is applied in dosage and frequency according to the therapy standard outside of this study. The primary endpoint is the cumulative rate of toxicity CTC grade 2 and higher in the first 4 months. Secondary endpoints include overall survival, progression-free survival, quality of life, and neurocognition. Discussion: Aim of the GRIPS study is to prospectively assess whether the theoretical physical advantage of proton beam radiotherapy will translate into a clinical reduction of toxicity during and in the first months after therapy.Trial registration:ClinicalTrials (NCT): NCT04752280

Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire, Challenges and Limitations

Around 50% of cancer patients will require radiotherapy (RT) and 10–15% of these patients could be eligible for proton beam radiotherapy (PBT). Dosimetric advantages are undeniable, mainly in pediatric and reirradiation scenarios. Though, PBT facilities are scarce worldwide and the IAEA has reported 116 functional particle facilities, of which 98 are PBT, virtually absent in low- and middle-income countries (LMIC). The Latin America and Caribbean region represent a unique opportunity for a PBT center, as there are currently no functional facilities and current RT needs are significant. The challenges can be summarized as high initial investment and maintenance, geographic coverage, required baseline technology and certification, over-optimistic workload, unclear rates and reimbursement, unmet business plan and revenue expectations, and lack of trained human resources. Investment costs for a PBT facility are estimated to be at around 140 million euros; therefore, this seems unsuitable for LMIC. Mexico’s geographical advantage, GDP, baseline technologies and high demand for RT makes it an ideal candidate. Nevertheless, a PBT center would account for a third of Mexico’s annual health expenditure for 2020. Enormous efforts must be made by both the private sector and governmental authorities to provide funding.