Pulse reduced dose rate intensity modulated proton therapy for re-irradiation of central nervous system malignancies

Abstract

A method for retreatment of a tumor includes the step of providing therapy pulses to the tumor according to a pulse reduced dose rate (PRDR) therapy pattern. The therapy pulse is a PRDR intensity modulated proton therapy (IMPT) pulse, including a proton pulse provided to the tumor. Also disclosed is a system for retreatment of a tumor, the system comprising: a first beamlet emitter for providing a first plurality of intensity modulated proton therapy (IMPT) pulses according to a pulse reduced dose rate (PRDR) therapy pattern; and a second beamlet emitter for providing a second plurality of intensity modulated proton therapy (IMPT) pulses according to the PRNR therapy pattern. The system also includes a controller configured to cause the first plurality of IMPT pulses and the second plurality of IMPT pulses to be provided to the tumor in a pulse sequence with a time gap between delivery of the pulses.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 484,082, filed on February 9, 2023, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates generally to methods and systems for treating central nervous system (CNS) tumors, and particularly to systems and methods for providing pulsed proton therapy for irradiating and / or re-irradiating intracranial tumors. Background Art

[0004] Recurrent high-grade intracranial malignancies carry a dismal prognosis and lack consistent management guidelines. In particular, high-grade intracranial malignancies, such as glioblastoma, the most common malignant brain tumor in adults, have a high recurrence rate and a poor prognosis. Salvage strategies such as surgery, reirradiation (reRT), systemic therapy, and tumor treating fields (TTFields) have not demonstrated a significant overall survival advantage in the recurrent setting. See Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncology .2022;24(Supplement_5):v1-v and Grossman SA, Ye X, Piantadosi S, et al. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin.Cancer Res. 2010;16(8):2443-2449.

[0005] In particular, re-irradiation is rarely used due to concerns about irreversible treatment-related toxicities. Pulsed reduced dose rate radiotherapy (PRDR) is a re-irradiation technique delivered by photons that aims to reduce toxicity while enhancing tumor control by exploiting dose rate effects and low-dose superradiosensitivity in tumors. PRDR also aims to promote sublethal damage repair in normal tissues. For example, PRDR photon therapy has been used for retreatment of CNS malignancies to overcome dose constraints and reduce side effects associated with re-irradiation. A typical photon PRDR workflow can include delivering a series of approximately 10 (dose) pulses of 0.2 Gy / pulse (2 Gy / fx) with an interval of 3 minutes between pulses. This series of photon pulses produces an average effective therapeutic dose rate of approximately 7 cGy / minute in a single fractionated treatment.

[0006] However, additional treatment options are needed for intracranial malignancies to control or reduce toxicity while improving patient response rates and overall survival. The disclosed treatment methods and medical systems are intended to address such problems that may arise using current treatment methods. Summary of the Invention

[0007] According to one aspect of the present disclosure, a method for tumor retreatment includes the step of providing therapy pulses to the tumor according to a pulsed reduced dose rate (PRDR) therapy mode. The therapy pulses are PRDR intensity modulated proton therapy (IMPT) pulses including proton pulses provided to the tumor.

[0008] According to another aspect of the present disclosure, a system for tumor retreatment includes: a first beamlet emitter for providing a first plurality of intensity modulated proton therapy (IMPT) pulses according to a pulsed reduced dose rate (PRDR) therapy mode; and a second beamlet emitter for providing a second plurality of intensity modulated proton therapy (IMPT) pulses according to the PRDR therapy mode. The system also includes a controller electrically connected to the first beamlet emitter and the second beamlet emitter. The controller is configured to cause the first plurality of IMPT pulses and the second plurality of IMPT pulses to be sequentially provided to the tumor, with a time gap between the delivery of one or more of the first plurality of pulses and the delivery of one or more of the second plurality of pulses.

[0009] Non-limiting examples of the present invention will now be described in the following numbered clauses:

[0010] Item 1: A method for retreatment of a tumor, comprising: providing therapy pulses to the tumor according to a pulsed reduced dose rate (PRDR) therapy mode, wherein the therapy pulses are PRDR intensity modulated proton therapy (IMPT) pulses comprising proton pulses provided to the tumor.

[0011] Clause 2: The method of Clause 1, wherein the tumor was previously treated by administering pulsed reduced dose rate (PRDR) photon therapy pulses to the tumor.

[0012] Item 3: The method of Item 2, wherein the PRDR photon therapy pulses are approximately 0.2 Gy / pulse (2 Gy / fx), and the interval between PRDR photon therapy pulses is at least 3 minutes.

[0013] Clause 4: The method of any of clauses 1-3, wherein the PRDR-IMPT pulses have an average effective treatment dose rate of about 7 cGy / minute in one fractionated treatment.

[0014] Clause 5: The method of any of clauses 1-4, wherein there is a time gap of about 4 minutes to about 5 minutes between PRDR-IMPT pulses.

[0015] Clause 6: The method of any of clauses 1-5, wherein the PRDR-IMPT pulses are provided to redraw a treatment field previously treated by a PRDR photon therapy pulse.

[0016] Clause 7: The method of any one of clauses 1-6, wherein the tumor comprises a central nervous system (CNS) tumor and / or an intracranial tumor.

[0017] Clause 8: The method of any of Clauses 1-7, wherein a pulsed reduced dose rate (PRDR) therapy mode comprises delivering a dose of about 50 GyRBE to about 75 GyRBE in about 20 to about 40 fractions.

[0018] Clause 9: The method of Clause 8, wherein the fractions are delivered to the patient over a period of about 20 minutes to about 50 minutes.

[0019] Clause 10: The method of any of clauses 1-9, wherein up to about 70% of the total dose of the proton therapy pulses delivered to the tumor is controlled by each beam of the ion beam applicator, and the remaining at least 30% of the total dose is modulated for organ at risk (OAR) protection.

[0020] Clause 11: The method of any of clauses 1-10, wherein the therapy pulses are provided according to one or more of the following therapies: stereotactic radiosurgery (SRS), fractionated SRS, hypofractionation, fractionated proton therapy, or particle therapy.

[0021] Clause 12: The method of any of clauses 1-11, wherein providing therapy pulses comprises directing a radiation beam to at least one of the following regions of the patient's body: the brain, the brainstem, the optic chiasm, the ipsilateral and / or contralateral optic nerves, the ipsilateral and / or contralateral cochlea, or the ipsilateral and / or contralateral hippocampus.

[0022] Clause 13: The method of any one of Clauses 1-12, further comprising administering to the patient an effective amount of at least one of bevacizumab and ivosidenib to treat the tumor.

[0023] Item 14: A system for retreatment of a tumor, comprising: a first beamlet emitter for providing a first plurality of intensity modulated proton therapy (IMPT) pulses according to a pulsed reduced dose rate (PRDR) therapy mode; a second beamlet emitter for providing a second plurality of intensity modulated proton therapy (IMPT) pulses according to the PRDR therapy mode; and a controller electrically connected to the first beamlet emitter and the second beamlet emitter, wherein the controller is configured to cause the first plurality of IMPT pulses and the second plurality of IMPT pulses to be provided to the tumor in sequence with a time gap between delivery of one or more of the first plurality of IMPT pulses and one or more of the second plurality of IMPT pulses.

[0024] Clause 15: The system of clause 14, wherein the controller is configured to cause the first beamlet emitter and the second beamlet emitter to provide PRDR-IMPT pulses having an average effective treatment dose rate of approximately 7 cGy / minute in one fractionated treatment.

[0025] Clause 16: The system of Clause 14 or Clause 15, wherein the time interval between delivery of one or more of the first plurality of IMPT pulses and one or more of the second plurality of IMPT pulses is about 4 minutes to about 5 minutes.

[0026] Clause 17: The system of any of clauses 14-16, wherein the tumor is a central nervous system (CNS) tumor and / or an intracranial tumor.

[0027] Clause 18: A system as described in any of clauses 14 to 17, wherein up to about 70% of the total dose provided by the first beamlet emitter and the second beamlet emitter is controlled by the beamlet emitters, and the remaining at least 30% of the total dose is modulated for protection of organs at risk (OARs).

[0028] Clause 19: The system of any of clauses 14-18, wherein the controller is configured to cause the first beamlet emitter and the second beamlet emitter to deliver the first plurality of IMPT pulses and the second plurality of IMPT pulses over a time period of about 20 minutes to about 50 minutes to provide a total dose of IMPT pulses to the tumor.

[0029] Clause 20: A system as described in any of clauses 14-19, wherein the controller is configured to cause the first beamlet emitter and the second beamlet emitter to deliver a pulsed reduced dose rate (PRDR) therapy mode, which includes delivering a total dose of about 50 GyRBE to about 75 GyRBE in about 20 to about 40 fractions. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] These and other features and characteristics of the present disclosure, as well as the methods of operation and functions of the related structural elements and the combination and manufacturing economy of the various parts, will become more apparent after reference to the accompanying drawings and in conjunction with the following description and appended claims, all of which form a part of this specification, wherein like reference numerals indicate corresponding parts in the various figures. However, it is to be expressly understood that the drawings are for illustration and description purposes only and are not intended to be limiting of the present invention.

[0031] Figure 1A is a schematic diagram of a PRDR-IMPT delivery strategy according to one aspect of the present disclosure;

[0032] Figure 1B is another schematic diagram of a PRDR-IMPT delivery strategy according to one aspect of the present disclosure;

[0033] Figure 2 It is a medical image that provides isodose comparison between PRDR-IMRT and IMPT plans;

[0034] Figure 3 Line graph showing dose volume histogram (DVH) comparison between PRDR-IMRT and PRDR-IMPT plans for a sample subject;

[0035] Figures 4A-4D Line graphs comparing PRDR photon and PRDR-IMPT plans according to target (PTV) size for V10Gy, V20Gy, V30Gy, and V40Gy for uninvolved brain are shown;

[0036] Figure 5A and Figure 5B Histograms of the patient's minimum local gamma analysis and global gamma analysis are shown;

[0037] Figure 6 Table showing global gamma analysis for repainted and non-repainted cases;

[0038] Figure 7A and Figure 7B is a table listing the outcomes of recurrent high-grade gliomas treated with systemic therapy in prospective trials;

[0039] Figure 8 a line graph showing the results of a battery of cognitive function tests performed on a patient;

[0040] Figure 9 A flowchart showing the steps of a method of tumor retreatment according to one aspect of the present disclosure;

[0041] Figure 10 is a schematic diagram of a system for tumor retreatment according to one aspect of the present disclosure;

[0042] Figure 11A and Figure 11B is a table listing the characteristics of five treated patients, describing the initial diagnosis, first course of radiotherapy characteristics, and reRT(TMPPR) characteristics;

[0043] Figure 12A Medical images showing a patient who has received multiple courses of radiation therapy;

[0044] Figure 12B is a table listing the dose course and cumulative dose information for PRDR-IMPT provided to the patient; and

[0045] Figure 12C Shown are medical images of a follow-up MRI performed four weeks after the patient received PRDR-IMPT treatment. DETAILED DESCRIPTION

[0046] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0047] As used herein, the terms "right," "left," "upper," and "lower," and their derivatives, shall relate to the orientation of the present invention in the accompanying drawings. However, it should be understood that the present invention may assume various alternative orientations, and thus, these terms should not be considered limiting. Furthermore, it should be understood that the present invention may assume various alternative variations and stage sequences, unless expressly provided otherwise. It should also be understood that the specific devices and processes shown in the accompanying drawings and described in the following specification are examples. Accordingly, the specific dimensions and other physical characteristics associated with the embodiments disclosed herein should not be considered limiting.

[0048] For the purpose of this specification, unless otherwise indicated, all numerical expressions (such as dimensions, physical properties, etc.) used in the specification and claims are understood to be modified by the term "about" in all cases. Unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are approximate values, which may vary depending on the desired properties to be obtained by the present invention. Although the numerical ranges and parameters illustrating the wide range of the present invention are approximate values, the numerical values ​​set forth in the specific examples are reported as accurately as possible. However, the numerical value of any measurement itself may contain some errors caused by the standard deviation in its respective test measurements.

[0049] Furthermore, it should be understood that any numerical range recited herein is intended to include all subranges subsumed therein. For example, a range of "1 to 10" is intended to include any and all subranges between the recited minimum value of 1 and the recited maximum value of 10 (inclusive of 1 and 10), i.e., all subranges starting with a minimum value equal to or greater than 1 and ending with a maximum value equal to or less than 10, as well as all subranges between, for example, 1 and 6.3, or between 5.5 and 10, or between 2.7 and 6.1.

[0050] As used herein, the terms "comprising," "comprised," or "comprised" and variations thereof are intended to be open ended. As used herein, the term "patient" or "subject" refers to a member of the animal kingdom, including but not limited to humans.

[0051] The present disclosure relates to a treatment method that the inventors refer to as time-modulated pulsed proton re-irradiation (TMPPR) therapy for the treatment of intracranial malignancies. The method involves delivering pulsed reduced dose rate (PRDR) radiotherapy for the re-irradiation of CNS tumors. The method also involves the step of dosimetric treatment plan evaluation to explore the potential dose delivery advantages of intensity modulated proton therapy (IMPT). To develop these methods, the inventors evaluated whether PRDR-IMPT has a dosimetric advantage over previously described photon PRDR plans. Based on these evaluations, the inventors have determined that proton therapy (PT) has an overall dosimetric advantage over photon therapy in the treatment of CNS malignancies. In particular, as shown in the examples provided herein, IMPT has been demonstrated by dosimetry to produce lower maximum, mean and median doses to critical brain substructures compared to passively scattered proton therapy or intensity modulated radiotherapy (IMRT) delivered using photons.

[0052] In some examples, the methods of the present disclosure include delivering therapy pulses to the tumor according to a pulsed reduced dose rate (PRDR) therapy mode. The therapy pulses can be PRDR intensity modulated proton therapy (IMPT) pulses, including proton pulses delivered to the tumor. In some examples, the PRDR-IMPT pulses can have an average effective therapeutic dose rate of approximately 7 cGy / minute in a single fractionated treatment. In some examples, multiple PRDR-IMPT pulses can be delivered to a treatment field that has been previously treated with PRDR photon therapy pulses (e.g., photon therapy pulses of approximately 0.2 Gy / pulse (2 Gy / fx) with an interval of at least 3 minutes between pulses).

[0053] In some examples, reRT can be delivered to patients according to a fractionated radiosurgery or hypofractionated treatment regimen, such as providing a total dose (30-50 Gy) over a predetermined number of fractions (e.g., from 10 to 30 fractions). However, there are limited randomized data available to support the use of reRT for pulsed radiotherapy. In fact, the best data to date come from the RTOG1205 trial, which compared bevacizumab alone with radiotherapy [35 Gy in 10 fractions] and showed an advantage in 6-month progression-free survival (PFS) from 29% to 52%. However, no advantage in overall survival was observed. See Tsien CI, Pugh SL, Dicker AP, et al., NRG Oncology / RTOG 1205: A Randomized Phase II Trial of Concurrent Bevacizumab and Reirradiation Versus Bevacizumab Aloneas Treatment for Recurrent Glioblastoma. J Clin Oncol .2022:Jco2200164.

[0054] Regardless, while developing the treatment methods disclosed herein, the inventors have come to recognize that re-irradiation therapy (reRT) remains underutilized among available treatment options for intracranial malignancies due to the potential for irreversible treatment-related toxicity associated with other treatments. In particular, because tumors often recur within or adjacent to the irradiated area, re-irradiation therapy will often result in direct overlap with previously treated brain regions. Thus, re-irradiation therapy can actually reduce overall toxic effects compared to other treatments.

[0055] Studies have also determined that systemic therapy alone in the recurrent setting is associated with low (<10%) response rates. See Ellingson BM, Wen PY, Chang SM, et al. Objective response rate (ORR) targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival. Neuro Oncol .2023. In addition, although there is no prospective randomized evidence to support one therapy over the other, a secondary analysis of the Radiation Therapy Oncology Group (RTOG) 0525 trial observed an advantage for reirradiation, but its magnitude was limited because few patients underwent a second course of RT (4% reRT alone and 10% systemic therapy). See Shi W, Scannell Bryan M, Gilbert MR, et al. Investigating the Effect of Reirradiation or Systemic Therapy in Patients With Glioblastoma After Tumor Progression: A Secondary Analysis of NRG Oncology / Radiation Therapy Oncology Group (RTOG) Trial 0525. Int J Radiat Oncol Biol Phys. 2018;100(1):38-44.

[0056] Pulsed Reduced Dose Rate Therapy and Intensity Modulated Proton Therapy

[0057] Despite the lack of previously available randomized data to support its use, the inventors believe that pulsed reduced dose rate (PRDR) radiotherapy using proton delivery can be an effective reRT technology that reduces toxicity after previous radiotherapy in patients with recurrent / progressive central nervous system (CNS) tumors. In some examples, PRDR can include delivering radiotherapy subfractions at specific time intervals within a single fraction. While not intending to be bound by theory, this technology is believed to have two radiobiological advantages. First, the technology provides low-dose high radiosensitivity of proliferative tumor cells irradiated with doses less than 0.5 Gy. Second, the technology provides low dose rate low radiosensitivity to non-proliferative normal tissues, thereby improving the therapeutic index as tumor killing increases, and promoting repair of sublethal damage occurring in normal cells reduces toxicity.

[0058] Previous studies have also found such radiobiological advantages. In 2007, Cannon et al. documented their clinical experience with PRDR in the treatment of recurrent brain tumors, demonstrating significant radiological responses and clinical improvement without toxicity. See Cannon G, Tomé W, Robins H, Howard S. Pulsed reduced dose-rate radiotherapy: case report: a novel re-treatment strategy in the management of recurrent glioblastoma multiforme. Journal of neuro-oncology .2007;83(3). In a review of recent statistics on the use of photon PRDR in the treatment of patients with recurrent primary CNS malignancies, it was also observed that the median PRDR dose was 52Gy (22 to 60Gy), with a median cumulative dose of 110.3Gy delivered to a median tumor volume of 369.1cc. After a median follow-up of 8.7 months, 67% of patients experienced grade 2+ treatment-related toxicity. See Kutuk T, Tolakanahalli R, McAllister N, et al. Pulsed-Reduced Dose Rate (PRDR) Radiotherapy for Recurrent Primary Central Nervous System Malignancies: Dosimetric and Clinical Results. Cancers.2022;14(12).

[0059] As previously mentioned, the present inventors believe that proton therapy (PT) offers an overall dosimetric advantage over photon therapy for CNS malignancies. The latest form of PT, intensity-modulated proton therapy (IMPT), has been dosimetrically validated to produce lower maximum, mean, and median doses to critical substructures of the brain compared to passively scattered proton therapy or intensity-modulated radiotherapy (IMRT) delivered using photons. In particular, in recent studies, the present inventors have determined that IMPT is able to spare uninvolved brain (V) compared to IMRT. 20Gy ) and reduce D to the brain and optic chiasm 0.03cc For patients undergoing reRT, these reduced doses to key substructures may reduce the risk of treatment-related toxicities, enabling the delivery of defined doses.

[0060] However, despite the potential reduction in risks of reRT, the present inventors have recognized that intracranial reRT remains a challenging scenario, with no consensus on cumulative dose estimation or optimal dose and fractionation. To mitigate these photon PRDR toxicities, the present inventors hypothesized that, because proton therapy produces reduced low and intermediate doses to surrounding (often previously treated) tissues, a dose-reducing approach using proton delivery pulses could be an alternative for such patients.

[0061] Current guidelines consider reRT to be a possible approach for local treatment of recurrent glioblastoma among many options. In some examples, reRT can be delivered using a variety of techniques, including stereotactic radiosurgery (SRS), fractionated SRS, hypofractionation, conventional fractionated photon therapy, or even particle therapy. SRS, supported by multiple retrospective data sets, has traditionally been delivered to recurrent limited target volumes (4-10cc). In addition, multiple retrospective and prospective series have studied fractionated SRS (FSRS) or hypofractionated regimens for recurrent glioblastoma, where the target volumes were quite modest, ranging from 8.5-34cc (FSRS) and 33-145cc (hypofractionated reRT). Conventionally fractionated reRT has also been used to treat larger recurrences (most commonly 36Gy in 18 fractions) and has lower rates of radiation necrosis compared to lower fractionated regimens (including SRS / FSRS). Given the large treatment volumes involved in the patients (range: 109.1-442.6 cc), which are too large for hypofractionated treatment and the close anatomical relationship to critical structures, the inventors have recognized the advantages of combining the radiobiological advantages of delivering TMPPR with the advantages of using protons to deliver a meaningful dose to the tumor while sparing the rest of the uninvolved brain.

[0062] As shown in the results of Example 2 described in the Examples section of this disclosure, patients treated with TMPPR (1 complete response, 3 partial responses) showed promising responses. One of the patients achieved a complete response and showed clinical improvement associated with imaging findings on follow-up, including regression of a significant component of all enhancing and non-enhancing lesions (T1 enhancement and associated FLAIR infiltration), as well as elimination of midline shift and mass effect on adjacent brain parenchyma, and disappearance of previously elevated cerebral blood volume (rCBV) on perfusion MRI. At follow-up 5 months after TMPPR therapy, the patient's contralateral untreated brain (previously free of disease) developed leptomeningeal failure. Interestingly, the second patient treated with TMPPR also showed a partial response to treatment at the TMPPR area in the right frontal lobe. However, at longer follow-up, the patient's contralateral brain also developed leptomeningeal failure.

[0063] In summary, the three patients in Example 2 had a partial response to TMPPR, and these patients also received peri-radiation systemic therapy. These results resulted in a high overall response rate, which has not been seen in previous studies of other treatment strategies. In addition, clinical trial results of systemic therapy for patients with first recurrence or progression of high-grade gliomas have shown varying degrees of success, with objective response rates (ORR) ranging from 5% to 41.5%. However, significant responses or complete responses to these treatments are uncommon, with no significant response observed with lomustine monotherapy and only 2.4% with combination therapy of bevacizumab and irinotecan. When Reardon et al. compared bevacizumab with nivolumab, they found that for bevacizumab, the complete response rate was 2.6% and the partial response rate was 20.5%. See Effect of Nivolumab vs Bevacizumab in PatientsWith Recurrent Glioblastoma: The CheckMate 143 Phase 3Randomized ClinicalTrial by ReardonDA, Brandes AA, Omuro A, et al. JAMA Oncol. 2020;6(7):1003-1010. In addition, another study using bevacizumab alone showed an ORR of only 35% (1 CR, 17 PR).

[0064] like Figure 7A and Figure 7B As shown in the table, new systemic therapies have been studied in clinical trial settings and have shown moderate activity against high-grade gliomas. Specifically, Figure 7A and Figure 7B The table in the table lists the results of systemic therapy for recurrent high-grade glioma in the following prospective clinical trial: Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study, by Perry JR, Bélanger K, Mason WP, et al. J Clin Oncol .2010;28(12):2051,2057;Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine,lomustine,and vincristine inrecurrent high-grade glioma, J Clin Oncol.2010; 28(30): 4601 - 4608; Lomustine and Bevacizumab in Progressive Glioblastoma by Wick W, Gorlia T, Bendszus M, et al. N Engl J Med . 2017; 377(20): 1954 - 1963; Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomized controlled phase 2 trial by Taal W, Oosterkamp HM, Walenkamp AM, et al. Lancet Oncol. 2014; 15(9): 943 - 953; Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma by Kreisl TN, Kim L, Moore K, et al. J Clin Oncol. 2009; 27(5): 740 - 745; Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma by Friedman HS, Prados MD, Wen PY, et al. J Clin Oncol . 2009; 27(28): 4733 - 4740; Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma by Batchelor TT, Mulholland P, Neyns B, et al. J Clin Oncol.2013;31(26):3212-3218; Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma, by Wick W, Puduvalli VK, Chamberlain MC, et al. J Clin Oncol. 2010;28(7):1168-1174; and Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma, J Clin Oncol .2010;28(30):4601-4608.

[0065] More recently, the Checkmate 143 trial, which compared nivolumab with bevacizumab in the first relapse setting, failed to show an advantage in terms of OS (9.8 months vs. 10 months); rather, the ORR was higher in the bevacizumab group (7.8 months vs. 23.1%), with only 2 (1.3%) of 153 patients receiving nivolumab achieving a complete response. Furthermore, the combination of nivolumab and ipilimumab did not show any complete responses (CRs), and the PR rate was almost identical to that of nivolumab monotherapy (2 vs. 1, respectively).

[0066] Recently, Ellingson et al. described the objective response rates (ORRs) for recurrent high-grade glioma (≤3 recurrences, but the majority were first recurrences) in the following previous clinical trials (68 treatment arms; 4793 patients): chemotherapy 6.1%, biologics 3.37%, immunotherapy 7.97%, and antiangiogenic agents 26.8%. See Ellingson BM, Wen PY, Chang SM, et al. Objective response rate (ORR) targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival. Neuro Oncol.2023. The combined data of chemotherapy, biologics, and immunotherapy showed a strong correlation between ORR and median overall survival (OS), with ORR values ​​greater than 25% resulting in a median OS of more than 15 months.

[0067] Neurocognitive decline is one of the major concerns of brain irradiation, especially for patients who have multiple recurrent tumors and have received surgery, multiple lines of systemic therapy, and reRT. In Example 2 of the present disclosure, the inventors objectively tested a patient's baseline (before TMPPR) and follow-up (four weeks after TMPPR) cognitive function test combination, such as Figure 8 As shown in the , multiple neurocognitive domains were preserved. Given that proton therapy (PT) can reduce the dose to surrounding normal structures such as the hippocampus and temporal lobe (which are organs associated with neurocognition), sparing these normal tissues is considered a potential advantage of this technology. Prospective data show that proton therapy can preserve neurocognitive function in patients with low-grade gliomas compared with historical controls.

[0068] However, the inventors also acknowledge that there is still a lack of consensus on reRT to the brain in terms of tolerance to critical organs and the debilitating or even fatal effects that may result. For example, Mayer et al. reviewed several previous studies on the tolerance of the brain to reRT for gliomas based on clinical data. They found that the risk of radiation necrosis increased when the equivalent dose of 2Gy fractions (EQD2) exceeded 100Gy. It is worth noting that only the cumulative dose to the normal brain was reported, and the total target volume involved was not taken into account. See Mayer R, Sminia P. Reirradiation Tolerance of the Human Brain. International Journal of Radiation Oncology*Biology*Physics. 2008; 70(5): 1350-1360. Stiefel et al. conducted a retrospective analysis of 76 patients (including primary tumors and metastatic tumors) who had previously received at least two courses of radiotherapy. For brain D 0.1cc For patients with more than 100 Gy (EQD2), D 0.1cc The median dose was 114 Gy (range 100-161.5) and resulted in only 2 cases of high-grade (> grade 3) toxicity. In addition, they concluded that it is safe to keep the cumulative dose to the brain to 120 Gy EQD2, to the brainstem to less than 100 Gy, and to the optic chiasm and optic nerve to less than 75 Gy EQD2. See Stiefel I, C. High-dose re-irradiation of intracranial lesions-Efficacy and safety including dosimetric analysis based on accumulated EQD2Gy dose EQD calculation by Tanadini-Lang S et al. Clin Transl Radiat Oncol. 2021;27:132-138. Furthermore, previous studies of photon PRDR have traditionally limited the dose to the brainstem or optic chiasm during reirradiation to 50 Gy, regardless of the dose received in the previous RT course.

[0069] Despite this lack of consensus, the present inventors believe that the disclosed approach has demonstrated the ability to provide therapeutic advantages with low levels of toxicity, particularly given the large volume of reRT (median CTV of 298 cc) and the high median maximum cumulative dose to critical structures (such as the brain [ 0.5cc =116.3Gy(RBE) and D 1cc =115.8Gy(RBE)], brainstem[D 0.5cc =100.3Gy(RBE) and D 1cc =92.6Gy(RBE)], optic chiasm [D 0.03cc = 65.9 Gy (RBE)] and the ipsilateral optic nerve [D 0.03cc =67.2 Gy (RBE)]), the disclosed approach has been able to deliver an appropriate defined dose without any severe treatment-related acute toxicity (grade 2 alopecia and one case of grade 2 radionecrosis).

[0070] Treatment methods using PRDR and IMPT

[0071] Figure 9 is a flow chart illustrating the steps of a method of tumor retreatment incorporating features of the pulsed reduced dose rate therapy and intensity modulated proton therapy of the present disclosure.

[0072] At step 10, the method includes the step of imaging the target tumor. For example, the imaging includes performing a computed tomography (CT) scan of the target region of the patient's body (e.g., a CT scan using a 1 mm slice thickness). The imaging may also include diagnostic magnetic resonance imaging (MRI), such as MRI imaging including a T1-weighted gadolinium (Gd) sequence and a T2-weighted fluid-attenuated inversion recovery (T2 / FLAIR) sequence.

[0073] The method also includes a step 12 of detecting or identifying a tumor to be treated (such as a central nervous system tumor and / or an intracranial tumor) in the captured medical image. In some examples, the identified tumor may be a tumor that has been previously treated by applying pulsed reduced dose rate (PRDR) photon therapy pulses to the tumor. For example, photon therapy can be applied as a series of discrete pulses, such as pulses of about 0.2 Gy / pulse (2 Gy / fx), with an interval of at least 3 minutes between pulses.

[0074] At step 14, the method may further include providing a first dose of therapy pulses to the identified tumor according to a pulsed reduced dose rate (PRDR) therapy mode. In some examples, the therapy pulses may be provided according to one or more of the following therapies: stereotactic radiosurgery (SRS), fractionated SRS, hypofractionation, fractionated proton therapy, or particle therapy. Furthermore, in some examples, providing the therapy pulses may include directing a radiation (e.g., proton) beam to at least one of the following regions of the patient's body: the patient's brain, brainstem, optic chiasm, ipsilateral and / or contralateral optic nerves, ipsilateral and / or contralateral cochlea, or ipsilateral and / or contralateral hippocampus. As previously described, the therapy pulses are PRDR intensity modulated proton therapy (IMPT) pulses that include proton pulses. In some examples, the therapy pulses are provided to a tumor that has previously been treated with a photon therapy pulse. In this case, a PRDR-IMPT pulse may be provided to, in effect, redraw the treatment field previously treated by the PRDR photon therapy pulse.

[0075] In some examples, PRDR-IMPT pulses can be delivered in fractions or partial doses that accumulate to a full dose over time. Figure 1A and Figure 1B As shown in , a dosage pattern or strategy may include administering short pulses (in Figure 1A and Figure 1B In some examples, the pulses may have an average effective therapeutic dose rate of about 7 cGy / minute in a single fractionated treatment. The fractions or pulses may be separated by time gaps, such as gaps of about 1 minute to about 10 minutes or about 4 minutes to about 5 minutes. In some preferred examples, a pulsed reduced dose rate (PRDR) therapy mode may include delivering a total dose of about 50 Gy RBE to about 75 Gy RBE divided into about 20 to about 40 fractions. In some examples, delivery of the total dose may occur over a period of about 20 minutes to about 50 minutes, or as Figure 1A , occurs within a period of approximately 45 minutes, or as Figure 1B As shown in , it occurs over a period of approximately 39.5 minutes.

[0076] At step 16, in some examples, the method may further include modulating the proton therapy pulse after delivering a portion of the total dose of the PRDR-IMPT pulse. In particular, the pulse rate or intensity may be modulated to protect organs at risk (OARs) and / or to protect other normal tissue near the tumor site. In some examples, up to about 70% of the total dose of the proton therapy pulse delivered to the tumor may be controlled by each beam of the ion beam applicator, and the remaining at least 30% of the total dose may be modulated for OAR protection.

[0077] At step 18, the method may further include administering an anti-cancer and / or chemotherapeutic agent to the patient. For example, the method may include administering to the patient an effective amount of a cancer therapy therapeutic agent, such as an anti-cancer drug, a chemotherapeutic agent, an immunotherapeutic agent, and / or a biological therapeutic agent. In some examples, at least one of bevacizumab or ivosidenib may be administered to the patient to treat the tumor. In some examples, the anti-cancer therapeutic agent may be delivered to the patient prior to initiating intensity modulated proton therapy and / or prior to the patient receiving pulsed reduced dose rate photon therapy. In other examples, the PRDR-IMPT treatment and the treatment with the therapeutic agent may be performed simultaneously. For example, the patient may receive the dose or therapeutic agent shortly before or after receiving the PRDR-IMPT therapy.

[0078] At step 20, the method may include providing an additional dose of therapy pulses to the identified tumor according to a pulsed reduced dose rate (PRDR) therapy mode. For example, the patient may receive a dose of therapy pulses daily for several days or weeks. In other examples, the patient may receive a dose of therapy pulses several times a day, such as once every 2 hours, 4 hours, 6 hours, or 12 hours. As previously discussed, the patient may also receive a dose of the therapeutic agent concurrently with the dose of therapy pulses.

[0079] Treatment system for PRDR-IMPT therapy

[0080] Figure 10 is a schematic diagram of a system for tumor retreatment that includes features of the pulsed reduced-dose-rate therapy and intensity-modulated proton therapy of the present disclosure.

[0081] like Figure 10As shown in , the system 110 includes a first beamlet emitter 112 for providing a first plurality of intensity modulated proton therapy (IMPT) pulses according to a pulsed reduced dose rate (PRDR) therapy mode; and a second beamlet emitter 114 for providing a second plurality of intensity modulated proton therapy (IMPT) pulses according to the PRDR therapy mode. The system also includes a controller 116, such as a portable computer or a microprocessor, electrically connected to the first beamlet emitter 112 and the second beamlet emitter 114. The controller 116 can be configured to cause the first plurality of IMPT pulses and the second plurality of IMPT pulses to be provided to the tumor in sequence, with a time gap between the delivery of one or more of the first plurality of pulses and one or more of the second plurality of pulses, the time gap being of a duration of about 1 minute to about 10 minutes, or about 4 minutes to about 5 minutes. As previously described, the system 110 can be used to treat central nervous system (CNS) malignancies or tumors, such as intracranial tumors. Furthermore, multiple PRDR-IMPT pulses delivered to CNS tumors can have an average dose rate of 7 cGy / min in fractionated treatment.

[0082] In some examples, the controller 116 may also be configured to control modulation of the pulses. For example, the controller 116 may be configured to modify the pulses such that at most approximately 70% of the total dose provided by the first beamlet emitter 112 and the second beamlet emitter 114 is controlled by the beamlet emitters 112, 114, and the remaining at least 30% of the total dose is modulated for organ at risk (OAR) protection.

[0083] In some examples, the controller 116 can also be configured to control the duration and / or frequency of the pulses according to the PRDR therapy mode so that a full dose or total dose of therapy pulses is provided to the tumor within a reasonable time period. For example, the controller 116 can be configured to cause the first emitter 112 and the second emitter 114 to deliver a first plurality of pulses and a second plurality of pulses for a duration of about 20 minutes to about 50 minutes to provide a total dose of IMPT pulses to the tumor. In a specific example, the controller 116 can be configured to cause the first beamlet emitter 112 and the second beamlet emitter 114 to deliver a pulsed reduced dose rate (PRDR) therapy mode that includes delivering a total dose of about 50 GyRBE to about 75 GyRBE divided into about 20 to about 40 fractions. In some examples, the full dose of about 20 to about 40 fractions can be delivered over a time period of about 20 minutes to about 50 minutes.

[0084] Example

[0085] The following examples are presented to illustrate the general principles of the invention. The invention should not be considered limited to the specific examples presented.

[0086] Examples 1.1-1.3

[0087] Materials and methods

[0088] An exemplary photon PRDR workflow comprises 10 (dose) pulses of 0.2 Gy / pulse (2 Gy / fx) with a 3 minute interval between pulses. This workflow produces an average effective therapeutic dose rate of approximately 7 cGy / minute in a single fraction. To generate a similar average effective dose rate with IMPT, the treatment field is divided into two beamlets, which are delivered sequentially with the time gap between deliveries tailored to achieve an average dose rate of 7 cGy / minute in a single fraction. Most CNS cases are typically treated with three equally weighted IMPT beams at 1.8 Gy / fx, with each treatment field delivering 0.6 Gy per fraction to the target tumor. An average therapeutic dose rate of 7 cGy / minute in a fraction is possible if each field is subdivided into two deliverable beamlets with a time gap between beamlets of about 4 minutes to about 5 minutes.

[0089] In Example 1.1, to evaluate the dosimetric parameters of IMPT-PRDR, a comparative plan was developed for 15 CNS cases previously treated with IMRT-PRDR. The IMRT plan was developed based on the planning target volume (PTV) with a 3 mm expansion of the clinical target volume (CTV), while the IMPT plan was robustly optimized for the CTV with an uncertainty of 3 mm and a range uncertainty of 3.5%. Both the IMRT and IMPT plans were normalized such that 95% of the PTV received 100% of the prescribed dose.

[0090] In Example 1.2, six (n=6) patients who had previously received photon PRDR were randomly selected and retrospectively reformulated with IMPT using a standard treatment plan (e.g., a 3 mm dose grid and a modified SFO approach with 3 or 4 treatment fields). Each individual beam controlled 70% of the total dose, while the remaining 30% was allowed to be modulated to help protect critical OARs and normal brain tissue. For comparison, the IMPT and photon plans were normalized to 95% at Rx for PTV coverage. The PRDR-IMPT treatment strategy was used to redraw each treatment field once to achieve an average effective treatment dose rate of approximately 7 cGy / min in a single fraction. To quantify the dose accuracy of the unredrawn and redrawn proton plans, measurements were completed using the IBA Matrixx 2D array detector in the DigiPhant PT water phantom (right). All treatment fields were evaluated at a common depth of 3 cm in water.

[0091] The measurement results were analyzed using IBA software myQA. A global gamma criterion of 3% / 3mm>93% (clinical standard) was used to determine clinical acceptability. In addition, local gamma analysis and global gamma analysis were completed using the 2% / 2mm and 1% / 1mm criteria. The individual results for the six cases are listed in Table 1 and are shown below. Figure 2-6 In particular, Figure 2 Medical images providing an isodose comparison of a PRDR-IMRT plan and a PRDR-IMPT plan are shown, demonstrating how protons can reduce the dose to the unaffected brain. Figure 3 is a line graph showing the dose-volume histogram (DVH) comparison between the PRDR-IMRT plan and the PRDR-IMPT plan for a sample subject. Figures 4A-4D Four line graphs are included to compare PRDR photon and PRDR-IMPT plans according to target (PTV) size at V10Gy, V20Gy, V30Gy, and V40Gy for the uninvolved brain. The results show that for larger targets, especially for targets >300cc, IMPT plans have a dose-saving advantage over photons. Figure 5A and Figure 5B Figure 5 is a histogram showing the minimum local gamma analysis and global gamma analysis for the six test cases with analysis criteria of 3% / 3 mm, 2% / 2 mm, and 1% / 1 mm, where the 3% / 3 mm global gamma analysis was >93% for both the remapped and non-remapped fields. Figure 6 is a table showing global gamma analysis for the redrawn and non-redrawn cases, demonstrating that the 3% / 3mm global gamma analysis is >93% for both the redrawn and non-redrawn fields, which meets the clinical treatment standard.

[0092] like Figure 1A As shown in Example 1.3, a CNS treatment with three (3) fields at 1.8 Gy / Fx was redrawn once to form six sub-fields, each delivering approximately 0.3 Gy / fx. Adjusting the time delay between each field (5-7 minutes) was found to allow a total dose rate of 7 cGy / minute to be achieved. The total treatment time under image guidance was approximately 45 minutes.

[0093] result

[0094] Using IMPT-PRDR, the total fractionated treatment time (including imaging and patient setup) was estimated to be approximately 1 hour. The key drivers of this treatment time were the gap between fields and beamlet remapping. IMPT-PRDR treatment plans were dosimetrically compared to IMRT-PRDR treated cases and normalized to ensure comparable coverage of the PTV, and this was reflected in the CTV D99 being within 1% for the four initially planned cases. The mean median normal brain dose for the IMRT-PRDR plans was 16.6 Gy (range: 14.6 Gy to 28.0 Gy), while the mean median normal brain dose for the IMPT-PRDR plans was 13.0 Gy (range: 8.2 Gy to 16.4 Gy). On average, the IMPT-PRDR plans reduced the normal brain dose by 60% (p = 0.06), which is clinically significant, especially given the re-irradiation nature of these cases.

[0095] Table 1

[0096]

[0097] in conclusion

[0098] Examples 1.1 to 1.3 illustrate a method for combined delivery of IMPT-PRDR that combines the radiobiological advantages of low-dose-rate therapy with the overall dose-saving advantages of proton therapy. It is believed that these advantages can be used in clinical trials to treat CNS cases that have received prior radiation therapy without requiring technical modifications to the IMPT system.

[0099] The present inventors have also recognized that the PRDR-IMPT treatment strategy allows for the delivery of an average effective treatment dose rate of approximately 7 cGy / min in a single fraction, which is similar to photon PRDR. In addition, the present inventors have also recognized that the PRDR-IMPT plan provides dosimetric protection of the uninvolved brain (V) when compared to photons. 20Gy ) and reduced D in the brainstem and optic chiasm 0.03cc In addition, if Figures 5A-6 As shown in , it was determined that measurements of redrawn IMPT fields showed less than 0.5% variation in a global gamma analysis of the 3% / 3mm standard when compared to non-redrawn IMPT fields.

[0100] Example 2

[0101] Methods and Materials

[0102] Data collection

[0103] For Example 2, five (5) patients were treated with TMPPR. Patients were evaluated for a course of TMPPR for recurrent or progressive CNS malignancies. All patients were evaluated in a multidisciplinary CNS tumor conference and were selected for TMPPR only if all conventional and clinical trial options had been exhausted. Data collected from electronic medical records included sex, age, tumor histology, Karnofsky score (KPS) at the time of TMPPR, number and date of previous interventions, radiation dose and fractionation schedule, and toxicity during treatment and follow-up.

[0104] The median age was 54 years (range: 32-72 years), and the median time from the initial radiotherapy course to re-RT was 23 months (range: 14-40 months). The median dose was 60GyRBE in 30 fractions, and all patients completed it without any delay. In the first treatment response assessment, the best objective response rate was a complete response (CR) (n=1) or partial response (PR) (n=3) in 4 patients. Limited toxicity was seen. In particular, CTCAE grade 2 alopecia was observed in all patients, and one of them had grade 2 radiation necrosis.

[0105] Time-modulated pulsed proton re-irradiation (TMPPR) workflow

[0106] a) Planning and treatment simulation imaging

[0107] In the simulation, the patient was placed in the supine position and a computed tomography (CT) scan was performed using a 1 mm slice thickness for treatment planning. The patient wore a thermoplastic mask ( QFix, Avondale, PA) face shields, custom headrests ( Patients were immobilized with a QFix (QFix, Avondale, PA) and a knee pad, with their hands gripping handles placed along their sides or rings across their chest to ensure reproducibility and comfort. Diagnostic magnetic resonance imaging (MRI), including T1-weighted gadolinium (Gd) and T2-weighted fluid-attenuated inversion recovery (T2 / FLAIR) sequences, was also performed and coregistered with the treatment planning CT scan to delineate the target volume.

[0108] b) Target volume and organ at risk identification and delineation

[0109] Planning and simulation images (MR and CT images) were coregistered in the treatment planning system (TPS)—RayStation v.9A (RaySearch Laboratories, Stockholm, Sweden)—to delineate the target volume and organs at risk (OARs). For the target volume, the gross tumor volume (GTV) was defined as the T1 contrast-enhancing lesion and the resection cavity. For patients with gliomas, FLAIR abnormalities were also included in the GTV. The clinical target volume (CTV) was defined as a variable GTV extension ranging from 0 cm (FLAIR only) to 1.5 cm isotropically, limited by anatomical barriers (bone, contralateral brain, brainstem, and optic tracts). For OARs, the uninvolved brain (whole brain minus the CTV), brainstem, optic chiasm, ipsilateral and contralateral optic nerves, ipsilateral and contralateral cochlea, and ipsilateral and contralateral hippocampus were delineated.

[0110] c) Treatment planning and delivery

[0111] For the TMPPR technique, reRT was planned and delivered using intensity modulated proton therapy (IMPT) and a modified single field optimization (SFO) approach with three fields, where each beam controlled 70% of the total dose and the remaining 30% was modulated for OAR sparing. Plans were robustly optimized to the CTV and evaluated on a 2 mm dose grid with a range uncertainty of 3.5% and a setup uncertainty of 3 mm. Beam angle selection was performed to ensure large hinge angles between the three fields and that at most only one of the three fields ultimately impacted an OAR. Each field was redrawn once, resulting in six equally weighted subfields, each delivering a maximum dose of approximately 0.3 Gy / fraction to the CTV. The maximum beam dose contribution was capped at 0.4 Gy per fraction to limit modulation. The time delay between each field (5 minutes) was adjusted to produce a total time-averaged effective dose rate of <7 cGy / minute.

[0112] All CT datasets, dose distributions, and structure sets from previous radiotherapy sessions were imported into RayStation TPS to generate composite dose distributions for dosimetric evaluation. After composite dose distributions were generated, the cumulative equivalent dose (EQD2) distributions for each OAR in 2 Gy fractions from previous and current treatment plans were evaluated. The following dose parameters were then extracted: mean dose (EQD2 value), maximum dose of 0.03 cc (EQD2 value), maximum dose of 0.5 cc (EQD2 value), and maximum dose of 1 cc (EQD2 value) to the OARs (including the brain (excluding the CTV), brainstem, optic chiasm, ipsilateral and contralateral optic nerves, ipsilateral and contralateral cochlea, and ipsilateral and contralateral hippocampus) and target volumes.

[0113] For daily positioning, cone beam CT (CBCT) is performed and aligned with the reference CT to deliver the dose accurately and precisely to the target volume. Patient position correction is performed using a 6-DOF treatment table. Proton therapy is performed by The PLUS proton therapy accelerator (Ion Beam Applications SA) was used for delivery. The delivery time of each subfield and subsequent delays were annotated and recorded in the treatment record for each fraction.

[0114] Treatment monitoring and follow-up

[0115] Acute toxicity was monitored weekly during treatment. Follow-up assessments were performed 4-6 weeks after completion of radiotherapy and every 2-3 months thereafter. These assessments involved clinical examination and the use of contrast-enhanced brain MRI. The Response Assessment in Neuro-Oncology (RANO) radiographic response criteria were used to assess treatment response, including complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The grade of toxicity was assessed based on the criteria outlined in the National Cancer Institute's CTCAE v5.0. Radionecrosis was defined as the presence or extension of contrast enhancement in previously irradiated areas (excluding recurrent tumors) and was verified by multiparametric imaging and advanced techniques such as MRI perfusion. These cases were discussed in depth at a multidisciplinary tumor conference attended by experts from different fields such as neuroradiology, neurosurgery, neuro-oncology, and radiation oncology.

[0116] Recurrence patterns by site

[0117] The dose-volume histogram (DVH) is used to determine the spatial relationship between the volume of the recurrent tumor and the delivered dose distribution (previous irradiation). DVH analysis classifies the recurrence into different categories based on the location of the recurrence. If the DVH finds that more than 95% of the recurrence volume is located within the original high-dose field, it is classified as central failure. Recurrences with a recurrence volume distribution of more than 80% to 95%, between 20% and 80%, and less than 20% are designated as in-field recurrence, marginal recurrence, and distant recurrence, respectively.

[0118] Neurocognitive assessment

[0119] Patients were also included in an ongoing neurocognitive prospective observational registry (NCT05504681). To assess neurocognitive abilities, patients used a tablet-based application called the Brainlab Cognition app (Brainlab AG, Munich, Germany). The app presented patients with a comprehensive set of questions designed to assess various aspects of neurocognitive function. These questions covered measures of learning and memory, involving verbal recall, review, and recognition tests (for immediate recall, delayed recall, and delayed recognition, respectively). In addition, the app assessed attention and processing speed using a symbol matching test, verbal fluency using a "words starting with..." exercise, fine motor skills, speed using a number sequencing test, and executive function using a number and letter sequencing test.

[0120] Statistical analysis

[0121] Descriptive statistics were calculated. For continuous variables, medians and ranges were presented. For categorical variables, sample sizes and percentages were calculated.

[0122] result

[0123] Patient characteristics

[0124] The first five consecutive patients with recurrent high-grade intracranial malignancies treated with TMPPR were included in this analysis, e.g. Figure 11A and Figure 11B The median age was 54 years (range: 32-72 years), and 3 patients (60%) were female.

[0125] Initial radiation therapy was delivered using proton-based RT in three patients and photon-based RT in two, with a median dose and per-fraction dose of 60 Gy (RBE) (range: 59.4-75 Gy [RBE]) and 2 Gy (RBE) (range: 1.8-2.5 Gy [RBE]), respectively. Four patients also received temozolomide (TMZ). Lesions were located in the frontal region only in two patients, in the frontotemporal region in two patients, and in the frontoparietal region in one patient. Four lesions were located on the right side, and one on the left side. The most common histological structure previously treated with reRT was WHO grade 4 glioblastoma (IDH wild-type; MGMT methylated) in three patients, followed by one WHO grade 4 astrocytoma (IDH mutant; MGMT unmethylated) and one WHO grade 3 supratentorial ependymoma.

[0126] Re-irradiation characteristics (TMPPR)

[0127] All patients had at least one recurrence before TMPPR (median 3 recurrences, range: 1-6), for which they had received one previous course of radiotherapy, at least one surgery (median: 3, range: 1-4), and one line of systemic therapy (median: 2, range: 1-4). The recurrence / progression sites of all five patients were located at the edge of the previous RT field (because the recurrence volume within the previous high-dose radiotherapy field was between 20% and 80%), such as Figure 12A Four patients received TMPPR alone for local treatment, and one patient underwent surgical resection followed by TMPPR. The median CTV was 298.9 cc (range: 109.1-442.6 cc), and the median total dose was 54 Gy (RBE) (range: 50.4-59.4 Gy [RBE]) in 30 fractions (median, range: 28-33). All five patients tolerated TMPPR without any delays or complications.

[0128] All patients underwent at least one follow-up MRI after completion of TMPPR. One patient required an MRI 10 days after the end of TMPPR because of worsening neurologic symptoms consistent with disease progression at the epicenter of the TMPPR. This patient was diagnosed with disease progression and was transferred to hospice care.

[0129] The TMPPR course dose and the cumulative dose received by OAR are as follows: Figure 12B As described in the table in. Brainstem D 0.03cc 、D 0.5cc 、D 1cc and D mean The median cumulative doses received were 107.4 Gy (RBE) (range: 0.7-133.1), 100.3 Gy (RBE) (range: 0.6-132.5), 92.6 Gy (RBE) (range: 0.2-131.7), and 28.9 Gy (RBE) (range: 0.1-45.2). 0.03cc 、D 0.5cc 、D 1cc and D mean The median cumulative doses were 117.3 Gy (RBE) (range: 107.4-132.4), 116.3 Gy (RBE) (range: 104.5-132.2), 115.8 Gy (RBE) (range: 100.4-131.5), and 30.8 Gy (RBE) (range: 10.6-45.2). 0.03cc and D meanThe median cumulative doses of the ipsilateral optic nerve were 67.2 Gy (RBE) (range: 0.6-102.9) and 39.5 Gy (RBE) (range: 0.3-98.8), respectively. 0.03cc and D mean The median cumulative doses were 65.9 Gy (RBE) (range: 3.8-102.7) and 44.5 Gy (RBE) (range: 1.1-75.9), respectively.

[0130] Daily fractionation consisted of delivery of three fields, each subdivided into two subfields, for a total of six subfields. Figure 1B As shown in the protocol, the total duration of each daily fraction was approximately 39.5 minutes. Initial localization and imaging took 10 minutes; given the length of each fraction, interim imaging was obtained between the third and fourth subfield deliveries (overlapping with a 3.5-minute wait time) to confirm localization. The beam-on time for each subfield was approximately 2 minutes (for a total beam-on time of 12 minutes). Finally, the wait time between each beam-on time for each subfraction delivery was 3.5 minutes (for a total of 17.5 minutes).

[0131] Clinical Outcomes and Treatment-Related Toxicity

[0132] All patients tolerated TMPPR treatment well. The best objective radiographic responses included one complete response (CR), three partial responses (PR), and one progressive disease (PD). The first patient underwent a scan while receiving bevacizumab and ivosidenib without corticosteroids, which showed significant resolution of the large, multilobular enhancing mass, a significant decrease in the infiltrative T2 / FLAIR signal, resolution of the right ventricular mass effect, and resolution of the previously elevated relative cerebral blood volume (rCBV) on perfusion MRI. These imaging features were consistent with a complete response to treatment.

[0133] All patients (100%) had grade 2 alopecia (one with grade 1 fatigue and another with grade 1 headache). One patient had grade 2 symptomatic radiation necrosis. This patient received bevacizumab and the radiographic improvement on the second follow-up MRI (12 weeks after TMPPR) was compared with the first follow-up MRI (4 weeks after TMPPR), as shown in Figure 2. Figure 12C As shown in the image.

[0134] Three patients consented to participate in a prospective observational neurocognitive function registry. One patient underwent baseline assessment but did not complete the neurocognitive evaluation after treatment; the other patient continued follow-up only via telemedicine visits. One patient completed both baseline and follow-up assessments, demonstrating stable neurocognitive function across multiple test domains, such as Figure 8The graph is shown in FIG, which has been previously described in this disclosure.

[0135] Although the present invention has been described in detail for illustrative purposes based on what are presently considered to be the most practical and preferred embodiments, it should be understood that these detailed descriptions are for illustrative purposes only and that the present invention is not limited to the disclosed embodiments, but rather is intended to cover modifications and equivalent arrangements. Furthermore, it should be understood that the present invention contemplates that, to the extent possible, one or more features of any embodiment may be combined with one or more features of any other embodiment.

Claims

1. A method for retreatment of a tumor, comprising: Delivering therapy pulses to the tumor according to the Pulsed Reduced Dose Rate (PRDR) therapy mode, Wherein the therapy pulses are PRDR intensity modulated proton therapy (IMPT) pulses comprising proton pulses provided to the tumor.

2. The method of claim 1, wherein the tumor was previously treated by applying pulsed reduced dose rate (PRDR) photon therapy pulses to the tumor.

3. The method of claim 2, wherein the PRDR photon therapy pulses are approximately 0.2 Gy / pulse (2 Gy / fx), and the interval between the PRDR photon therapy pulses is at least 3 minutes.

4. The method of claim 1, wherein the PRDR-IMPT pulses have an average effective therapeutic dose rate of about 7 cGy / min in one fractionated treatment.

5. The method of claim 1, wherein there is a time gap of about 4 minutes to about 5 minutes between the PRDR-IMPT pulses.

6. The method of claim 1, wherein the PRDR-IMPT pulses are provided to redraw a treatment field previously treated by a PRDR photon therapy pulse.

7. The method of claim 1, wherein the tumor comprises a central nervous system (CNS) tumor and / or an intracranial tumor.

8. The method of claim 1, wherein a pulsed reduced dose rate (PRDR) therapy mode comprises delivering a dose of about 50 Gy RBE to about 75 Gy RBE in about 20 to about 40 fractions.

9. The method of claim 8, wherein the fractions are delivered to the patient over a period of about 20 minutes to about 50 minutes.

10. The method of claim 1, wherein up to about 70% of the total dose of the proton therapy pulses delivered to the tumor is controlled by each beam of an ion beam applicator, and the remaining at least 30% of the total dose is modulated for organ at risk (OAR) protection.

11. The method of claim 1 , wherein the therapy pulses are provided according to one or more of the following therapies: stereotactic radiosurgery (SRS), fractionated SRS, hypofractionation, fractionated proton therapy, or particle therapy.

12. The method of claim 1, wherein providing the therapy pulses comprises directing a radiation beam to at least one of the following regions of the patient's body: the brain, the brainstem, the optic chiasm, the ipsilateral and / or contralateral optic nerves, the ipsilateral and / or contralateral cochlea, or the ipsilateral and / or contralateral hippocampus.

13. The method of claim 1, further comprising administering to the patient an effective amount of at least one of bevacizumab and ivosidenib to treat the tumor.

14. A system for retreatment of a tumor, comprising: a first beamlet emitter for providing a first plurality of intensity modulated proton therapy (IMPT) pulses according to a pulsed reduced dose rate (PRDR) therapy mode; a second beamlet emitter for providing a second plurality of intensity modulated proton therapy (IMPT) pulses according to the PRDR therapy mode; as well as a controller electrically connected to the first beamlet emitter and the second beamlet emitter, wherein the controller is configured to cause the first plurality of IMPT pulses and the second plurality of IMPT pulses to be provided to the tumor in sequence with a time gap between delivery of one or more of the first plurality of IMPT pulses and one or more of the second plurality of IMPT pulses.

15. The system of claim 14, wherein the controller is configured to cause the first beamlet emitter and the second beamlet emitter to provide PRDR-IMPT pulses having an average effective treatment dose rate of approximately 7 cGy / minute in one fractionated treatment.

16. The system of claim 14, wherein a time interval between delivery of one or more of the first plurality of IMPT pulses and one or more of the second plurality of IMPT pulses is about 4 minutes to about 5 minutes.

17. The system of claim 14, wherein the tumor is a central nervous system (CNS) tumor and / or an intracranial tumor.

18. The system of claim 14, wherein up to about 70% of a total dose provided by the first and second beamlet emitters is controlled by the beamlet emitters, and a remaining at least 30% of the total dose is modulated for organ at risk (OAR) protection.

19. The system of claim 14, wherein the controller is configured to cause the first beamlet emitter and the second beamlet emitter to deliver the first plurality of IMPT pulses and the second plurality of IMPT pulses within a time period of about 20 minutes to about 50 minutes to provide a total dose of the IMPT pulses to the tumor.

20. The system of claim 14, wherein the controller is configured to cause the first beamlet emitter and the second beamlet emitter to deliver the pulsed reduced dose rate (PRDR) therapy mode, which includes delivering a total dose of about 50 Gy RBE to about 75 Gy RBE divided into about 20 to about 40 fractions.

Images