Selection of patients for radiotherapy with protons aiming at reduction of side effects: The model-based approach (original) (raw)
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Controversies in Clinical Trials in Proton Radiotherapy: The Present and the Future
Seminars in Radiation Oncology, 2013
Proponents of proton radiotherapy have cited the dose distribution characteristics of proton beams as evidence of its superiority over photon radiotherapy. Outcomes after photon radiotherapy remain suboptimal owing to poor local control and normal-tissue toxicity in many clinical indications. Critics of proton radiotherapy have noted the relative lack of prospective data from clinical trials showing a benefit for proton radiotherapy despite its theoretical advantages. Questions remain with regard to physical uncertainties in proton dose delivery and variations in their radiobiological effect in different tissues and tumors. Although prospective data have been scant in the past, clinical trials using proton radiotherapy are now being conducted with increasing frequency. However, very few of these are randomized controlled trials comparing protons directly with photons. Randomized controlled trials should remain the ideal tool for research in proton radiotherapy: they should be focused on areas where clinical equipoise is present, ideally in tumor sites where there is a low risk of systemic failure, a high risk of local progression, and/or a high risk of toxicity with conventional therapy. Proton radiotherapy centers should develop prospective registries with the goal of long-term data collection on an international basis to support the evidence provided by observational studies and comparative effectiveness research trials. Semin Radiat Oncol 23:127-133
Relative biological effectiveness (RBE) values for proton beam therapy
International Journal of Radiation Oncology*Biology*Physics, 2002
Purpose: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of 1.0 or 1.1, since the available evidence has been interpreted as indicating that the magnitude of RBE variation with treatment parameters is small relative to our abilities to determine RBEs. As substantial clinical experience and additional experimental determinations of RBE have accumulated and the number of proton radiation therapy centers is projected to increase, it is appropriate to reassess the rationale for the continued use of a generic RBE and for that RBE to be 1.0-1.1. Methods and Materials: Results of experimental determinations of RBE of in vitro and in vivo systems are examined, and then several of the considerations critical to a decision to move from a generic to tissue-, dose/fraction-, and LET-specific RBE values are assessed. The impact of an error in the value assigned to RBE on normal tissue complication probability (NTCP) is discussed. The incidence of major morbidity in protontreated patients at Massachusetts General Hospital (MGH) for malignant tumors of the skull base and of the prostate is reviewed. This is followed by an analysis of the magnitude of the experimental effort to exclude an error in RBE of >10% using in vivo systems. Results: The published RBE values, using colony formation as the measure of cell survival, from in vitro studies indicate a substantial spread between the diverse cell lines. The average value at mid SOBP (Spread Out Bragg Peak) over all dose levels is Ϸ1.2, ranging from 0.9 to 2.1. The average RBE value at mid SOBP in vivo is Ϸ1.1, ranging from 0.7 to 1.6. Overall, both in vitro and in vivo data indicate a statistically significant increase in RBE for lower doses per fraction, which is much smaller for in vivo systems. There is agreement that there is a measurable increase in RBE over the terminal few millimeters of the SOBP, which results in an extension of the bioeffective range of the beam in the range of 1-2 mm. There is no published report to indicate that the RBE of 1.1 is low. However, a substantial proportion of patients treated at Ϸ2 cobalt Gray equivalent (CGE)/fraction 5 or more years ago were treated by a combination of both proton and photon beams. Were the RBE to be erroneously underestimated by Ϸ10%, the increase in complication frequency would be quite serious were the complication incidence for the reference treatment >3% and the slope of the dose response curves steep, e.g., a ␥ 50 Ϸ 4. To exclude >1.2 as the correct RBE for a specific condition or tissue at the 95% confidence limit would require relatively large and multiple assays. Conclusions: At present, there is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc. The experimental in vivo and clinical data indicate that continued employment of a generic RBE value and for that value to be 1.1 is reasonable. However, there is a local "hot region" over the terminal few millimeters of the SOBP and an extension of the biologically effective range. This needs to be considered in treatment planning, particularly for single field plans or for an end of range in or close to a critical structure. There is a clear need for prospective assessments of normal tissue reactions in proton irradiated patients and determinations of RBE values for several late responding tissues in laboratory animal systems, especially as a function of dose/fraction in the range of 1-4 Gy.
Clinical Trial Strategies to Compare Protons With Photons
Seminars in Radiation Oncology, 2018
The favorable beam properties of protons can be translated into clinical benefits by target dose escalation to improve local control without enhancing unacceptable radiation toxicity or to spare normal tissues to prevent radiation-induced side effects without jeopardizing local tumor control. For the clinical validation of the added value of protons to improve local control, randomized controlled trials are required. For the clinical validation of the added value of protons to prevent side effects, both model-based validation or randomized controlled trials can be used. Model-based patient selection for proton therapy is crucial, independent of the validation approach. Combining these approaches in rapid learning health care systems is expected to yield the most efficient and scientifically sound way to continuously improve patient selection and the therapeutic window, eventually leading to more cancer survivors with better quality of life.
RBE for proton radiation therapy – a Nordic view in the international perspective
Acta Oncologica
Background: This paper presents an insight into the critical discussions and the current strategies of the Nordic countries for handling the variable proton relative biological effectiveness (RBE) as presented at The Nordic Collaborative Workshop for Particle Therapy that took place at the Skandion Clinic on 14th and 15th of November 2019. Material and methods: In the current clinical practice at the two proton centres in operation at the date, Skandion Clinic, and the Danish Centre for Particle Therapy, a constant proton RBE of 1.1 is applied. The potentially increased effectiveness at the end of the particle range is however considered at the stage of treatment planning at both places based on empirical observations and knowledge. More elaborated strategies to evaluate the plans and mitigate the problem are intensely investigated internationally as well at the two centres. They involve the calculation of the dose-averaged linear energy transfer (LET d) values and the assessment of their distributions corroborated with the distribution of the dose and the location of the critical clinical structures. Results: Methods and tools for LET d calculations are under different stages of development as well as models to account for the variation of the RBE with LET d , dose per fraction, and type of tissue. The way they are currently used for evaluation and optimisation of the plans and their robustness are summarised. A critical but not exhaustive discussion of their potential future implementation in the clinical practice is also presented. Conclusions: The need for collaboration between the clinical proton centres in establishing common platforms and perspectives for treatment planning evaluation and optimisation is highlighted as well as the need of close interaction with the research academic groups that could offer a complementary perspective and actively help developing methods and tools for clinical implementation of the more complex metrics for considering the variable effectiveness of the proton beams.
Proton vs carbon ion beams in the definitive radiation treatment of cancer patients
Radiotherapy and Oncology, 2010
Background and purpose: Relative to X-ray beams, proton [ 1 H] and carbon ion [ 12 C] beams provide superior distributions due primarily to their finite range. The principal differences are LET, low for 1 H and high for 12 C, and a narrower penumbra of 12 C beams. Were 12 C to yield a higher TCP for a defined NTCP than 1 H therapy, would LET, fractionation or penumbra width be the basis? Methods: Critical factors of physics, radiation biology of 1 H and 12 C ion beams, neutron therapy and selected reports of TCP and NTCP from 1 H and 12 C irradiation of nine tumor categories are reviewed. Results: Outcome results are based on low dose per fraction 1 H and high dose per fraction 12 C therapy. Assessment of the role of LET and dose distribution vs dose fractionation is not now feasible. Available data indicate that TCP increases with BED with 1 H and 12 C TCPs overlaps. Frequencies of GIII NTCPs were higher after 1 H than 12 C treatment. Conclusions: Assessment of the efficacy of 1 H vs 12 C therapy is not feasible, principally due to the dose fractionation differences. Further, there is no accepted policy for defining the CTV-GTV margin nor definition of TCP. Overlaps of 1 H and 12 C ion TCPs at defined BED ranges indicate that TCPs are determined in large measure by dose, BED. Late GIII NTCP was higher in 1 H than 12 C patients, indicating LET as a significant factor. We recommend trials of 1 H vs 12 C with one variable, i.e. LET. The resultant TCP vs NTCP relationship will indicate which beam yields higher TCP for a specified NTCP at a defined dose fractionation.
International Journal of Radiation Oncology*Biology*Physics, 2011
To investigate in a simulation study whether using a variable relative biological effectiveness (RBE) in calculation and optimization of intensity-modulated proton therapy (IMPT) instead of using an RBE of 1.1 would result in significant changes in the RBE-weighted dose (RWD) distributions. For 4 patients with head-and-neck tumors, three IMPT plans were prepared respectively. The first plan was physically optimized (IMPT-PO plan), and the RWD was calculated with a constant RBE of 1.1. Then the plan's RWD was recalculated (IMPT-R plan) using a variable RBE model taking into account the linear energy transfer (LET) and tissue-specific radiobiological parameters. The third IMPT plan was optimized using a biological optimization routine (IMPT-BO plan). Comparing the IMPT-PO and IMPT-R plans, we observed that the RWD in radioresistant tissues was more sensitive to the LET than in radiosensitive tissues. The IMPT-R plans were in general more inhomogeneous than the IMPT-PO plans. The differences of RWD distributions for all volumes between IMPT-PO and IMPT-BO plans complied with predefined dose-volume constraints. The average LET was significantly lower in IMPT-BO plans than in IMPT-R plans. In radioresistant normal tissues caution has to be used regarding the LET distribution because these are most sensitive to changes in the LET. Biological optimization of IMPT plans based on the organ-specific biological parameters and LET distributions is feasible.