Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms.

Proton therapy has advantages and pitfalls comparing with photon therapy in radiation therapy. Among the limitations of protons in clinical practice we can selectively mention: uncertainties in range, lateral penumbra, deposition of higher LET outside the target, entrance dose, dose in the beam path, dose constraints in critical organs close to the target volume, organ movements and cost. In this review, we combine proposals under study to mitigate those pitfalls by using individually or in combination: (a) biological approaches of beam management in time (very high dose rate "FLASH" irradiations in the order of 100 Gy/s) and (b) modulation in space (a combination of mini-beams of millimetric extent), together with mechanical approaches such as (c) rotational techniques (optimized in partial arcs) and, in an effort to reduce cost, (d) gantry-less delivery systems. In some cases, these proposals are synergic (e.g., FLASH and minibeams), in others they are hardly compatible (mini-beam and rotation). Fixed lines have been used in pioneer centers, or for specific indications (ophthalmic, radiosurgery,…), they logically evolved to isocentric gantries. The present proposals to produce fixed lines are somewhat controversial. Rotational techniques, minibeams and FLASH in proton therapy are making their way, with an increasing degree of complexity in these three approaches, but with a high interest in the basic science and clinical communities. All of them must be proven in clinical applications.

Consensus Report From the Miami Liver Proton Therapy Conference.

An international group of 22 liver cancer experts from 18 institutions met in Miami, Florida to discuss the optimal utilization of proton beam therapy (PBT) for primary and metastatic liver cancer. There was consensus that PBT may be preferred for liver cancer patients expected to have a suboptimal therapeutic ratio from XRT, but that PBT should not be preferred for all patients. Various clinical scenarios demonstrating appropriateness of PBT vs. XRT were reviewed.

Using stable distributions to characterize proton pencil beams.

PURPOSE: To introduce and evaluate the use of stable distributions as a methodology to quantify the behavior of proton pencil beams in a medium. METHODS: The proton pencil beams of a clinically commissioned proton treatment facility are replicated in a Monte Carlo simulation system (FLUKA). For each available energy, the beam deposition in water medium is characterized by the dose deposition. Using a stable distribution methodology, each beam with a nominal energy E is characterized by the lateral spread at depth z: S(z; α, γ, E) and a total energy deposition ID (z, E). The parameter α describes the tailedness of the distributions, while γ is used to scale the size of the function. The beams can then be described completely by a function of the variation of the parameters with depth. RESULTS: Quantitatively, the fit of the stable distributions, compared to those implemented in some standard treatment planning systems, are equivalent for all but the highest energies (i.e., 230 MeV/u). The decrease in goodness of fit makes this methodology comparable to a double Gaussian approach. The introduction of restricted linear combinations of stable distributions also resolves that particular case. More importantly, the meta-parameterization (i.e., the description of the dose deposition by only providing the fitted parameters) allows for interpolation of nonmeasured data. In the case of the clinical commissioning data used in this paper, it was possible to only commission one out of five nominal energies to obtain a viable dataset, valid for all energies. An additional parameter ß allows to describe asymmetric beam profiles as well. CONCLUSIONS: Stable distributions are intrinsically suited to describe proton pencil beams in a medium and provide a tool to quantify the propagation of proton beams in a medium.

Technical Note: Defining cyclotron-based clinical scanning proton machines in a FLUKA Monte Carlo system.

PURPOSE: Cyclotron-based pencil beam scanning (PBS) proton machines represent nowadays the majority and most affordable choice for proton therapy facilities, however, their representation in Monte Carlo (MC) codes is more complex than passively scattered proton system- or synchrotron-based PBS machines. This is because degraders are used to decrease the energy from the cyclotron maximum energy to the desired energy, resulting in a unique spot size, divergence, and energy spread depending on the amount of degradation. This manuscript outlines a generalized methodology to characterize a cyclotron-based PBS machine in a general-purpose MC code. The code can then be used to generate clinically relevant plans starting from commercial TPS plans. METHODS: The described beam is produced at the Provision Proton Therapy Center (Knoxville, TN, USA) using a cyclotron-based IBA Proteus Plus equipment. We characterized the Provision beam in the MC FLUKA using the experimental commissioning data. The code was then validated using experimental data in water phantoms for single pencil beams and larger irregular fields. Comparisons with RayStation TPS plans are also presented. RESULTS: Comparisons of experimental, simulated, and planned dose depositions in water plans show that same doses are calculated by both programs inside the target areas, while penumbrae differences are found at the field edges. These differences are lower for the MC, with a γ(3%-3 mm) index never below 95%. CONCLUSIONS: Extensive explanations on how MC codes can be adapted to simulate cyclotron-based scanning proton machines are given with the aim of using the MC as a TPS verification tool to check and improve clinical plans. For all the tested cases, we showed that dose differences with experimental data are lower for the MC than TPS, implying that the created FLUKA beam model is better able to describe the experimental beam.

Validation of rectal sparing throughout the course of proton therapy treatment in prostate cancer patients treated with SpaceOAR®.

The purpose of this study was to investigate the consistency of rectal sparing using multiple periodic quality assurance computerized tomography imaging scans (QACT) obtained during the course of proton therapy for patients with prostate cancer treated with a hydrogel spacer. Forty-one low- and intermediate-risk prostate cancer patients treated with image-guided proton therapy with rectal spacer hydrogel were analyzed. To assess the reproducibility of rectal sparing with the hydrogel spacer, three to four QACTs were performed for each patient on day 1 and during weeks 1, 3, and 5 of treatment. The treatment plan was calculated on the QACT and the rectum V90%, V75%, V65%, V50%, and V40% were evaluated. For the retrospective analysis, we evaluated each QACT and compared it to the corresponding treatment planning CT (TPCT), to determine the average change in rectum DVH points. We were also interested in how many patients exceeded an upper rectum V90% threshold on a QACT. Finally, we were interested in a correlation between rectum volume and V90%. On each QACT, if the rectum V90% exceeded the upper threshold of 6%, the attending physician was notified and the patient was typically prescribed additional stool softeners or laxatives and reminded of dietary compliance. In all cases of the rectum V90% exceeding the threshold, the patient had increased gas and/or stool, compared to the TPCT. On average, the rectum V90% calculated on the QACT was 0.81% higher than that calculated on the TPCT. The average increase in V75%, V65%, V50%, and V40% on the QACT was 1.38%, 1.59%, 1.87%, and 2.17%, respectively. The rectum V90% was within ± 1% of the treatment planning dose in 71.2% of the QACTs, and within ± 5% in 93.2% of the QACTs. The 6% threshold for rectum V90% was exceeded in 7 out of 144 QACTs (4.8%), identified in 5 of the 41 patients. We evaluated the average rectum V90% across all QACTs for each of these patients, and it was found that the rectum V90% never exceeded 6%. 53% of the QACTs had a rectum volume within 5 cm3 of the TPCT volume, 68% were within 10 cm3. We found that patients who exceeded the threshold on one or more QACTs had a lower TPCT rectal volume than the overall average. By extrapolating patient anatomy from three to four QACT scans, we have shown that the use of hydrogel in conjunction with our patient diet program and use of stool softeners is effective in achieving consistent rectal sparing in patients undergoing proton therapy.

A comparison between hydrogel spacer and endorectal balloon: An analysis of intrafraction prostate motion during proton therapy.

The purpose of this study was to evaluate intrafraction prostate motion in patients treated with proton therapy and an endorectal balloon or a hydrogel spacer using orthogonal x-rays acquired before and after each treatment field. This study evaluated 10 patients (662 fields throughout treatment) treated daily with an endorectal balloon (ERB) and 16 patients (840 fields throughout treatment) treated with a hydrogel spacer (GEL) without an ERB. Patient shifts were recorded before and after each treatment field, correlated with a treatment time, using x-ray imaging and implanted fiducial alignment. For each shift, recorded in X, Y, and Z, a 3D vector was calculated to determine the positional change. There was a statistically significant difference in the mean vector shift between ERB (0.06 cm) and GEL (0.09 cm), (P < 0.001). The mean includes a large number of zero shifts, but the smallest non-zero shift recorded was 0.2 cm. The largest shifts were, on average, in the Z direction (anterior to posterior). The average Z shift was +0.02 cm for both ERB and GEL. There was no statistical difference between ERB and GEL for shifts greater than 0.3 cm (P = 0.13) or greater than 0.5 cm (P = 0.36). For treatment times between 5 and 9 min, a majority of shifts were less than 0.2 cm, 85.9% for ERB and 73.2% for GEL. There was a significant positive correlation between the vector shifts and field time for both ERB (r = 0.2, P < 0.001) and GEL (r = 0.07, P < 0.04). We have shown that prostate motion is clinically comparable between an ERB and a hydrogel spacer, and the time dependencies are similar. A large majority of shifts for both ERB and hydrogel are well within a typical robust planning margin. For GEL patients, we chose to maintain slightly larger planning margins than for ERB due to already improved rectal sparing with GEL.

An end-to-end assessment of range uncertainty in proton therapy using animal tissues.

Accurate assessment of range uncertainty is critical in proton therapy. However, there is a lack of data and consensus on how to evaluate the appropriate amount of uncertainty. The purpose of this study is to quantify the range uncertainty in various treatment conditions in proton therapy, using transmission measurements through various animal tissues. Animal tissues, including a pig head, beef steak, and lamb leg, were used in this study. For each tissue, an end-to-end test closely imitating patient treatments was performed. This included CT scan simulation, treatment planning, image-guided alignment, and beam delivery. Radio-chromic films were placed at various depths in the distal dose falloff region to measure depth dose. Comparisons between measured and calculated doses were used to evaluate range differences. The dose difference at the distal falloff between measurement and calculation depends on tissue type and treatment conditions. The estimated range difference was up to 5, 6 and 4 mm for the pig head, beef steak, and lamb leg irradiation, respectively. Our study shows that the TPS was able to calculate proton range within about 1.5% plus 1.5 mm. Accurate assessment of range uncertainty in treatment planning would allow better optimization of proton beam treatment, thus fully achieving proton beams' superior dose advantage over conventional photon-based radiation therapy.

Dosimetric study of uniform scanning proton therapy planning for prostate cancer patients with a metal hip prosthesis, and comparison with volumetric-modulated arc therapy.

The main purposes of this study were to 1) investigate the dosimetric quality of uniform scanning proton therapy planning (USPT) for prostate cancer patients with a metal hip prosthesis, and 2) compare the dosimetric results of USPT with that of volumetric-modulated arc therapy (VMAT). Proton plans for prostate cancer (four cases) were generated in XiO treatment planning system (TPS). The beam arrangement in each proton plan consisted of three fields (two oblique fields and one lateral or slightly angled field), and the proton beams passing through a metal hip prosthesis was avoided. Dose calculations in proton plans were performed using the pencil beam algorithm. From each proton plan, planning target volume (PTV) coverage value (i.e., relative volume of the PTV receiving the prescription dose of 79.2 CGE) was recorded. The VMAT prostate planning was done using two arcs in the Eclipse TPS utilizing 6 MV X-rays, and beam entrance through metallic hip prosthesis was avoided. Dose computation in the VMAT plans was done using anisotropic analytical algorithm, and calculated VMAT plans were then normalized such that the PTV coverage in the VMAT plan was the same as in the proton plan of the corresponding case. The dose-volume histograms of calculated treatment plans were used to evaluate the dosimetric quality of USPT and VMAT. In comparison to the proton plans, on average, the maximum and mean doses to the PTV were higher in the VMAT plans by 1.4% and 0.5%, respectively, whereas the minimum PTV dose was lower in the VMAT plans by 3.4%. The proton plans had lower (or better) average homogeneity index (HI) of 0.03 compared to the one for VMAT (HI = 0.04). The relative rectal volume exposed to radiation was lower in the proton plan, with an average absolute difference ranging from 0.1% to 32.6%. In contrast, using proton planning, the relative bladder volume exposed to radiation was higher at high-dose region with an average absolute difference ranging from 0.4% to 0.8%, and lower at low- and medium-dose regions with an average absolute difference ranging from 2.7% to 10.1%. The average mean dose to the rectum and bladder was lower in the proton plans by 45.1% and 22.0%, respectively, whereas the mean dose to femoral head was lower in VMAT plans by an average difference of 79.6%. In comparison to the VMAT, the proton planning produced lower equivalent uniform dose (EUD) for the rectum (43.7 CGE vs. 51.4 Gy) and higher EUD for the femoral head (16.7 CGE vs. 9.5 Gy), whereas both the VMAT and proton planning produced comparable EUDs for the prostate tumor (76.2 CGE vs. 76.8 Gy) and bladder (50.3 CGE vs. 51.1 Gy). The results presented in this study show that the combination of lateral and oblique fields in USPT planning could potentially provide dosimetric advantage over the VMAT for prostate cancer involving a metallic hip prosthesis.

Image-guided method for TLD-based in vivo rectal dose verification with endorectal balloon in proton therapy for prostate cancer.

PURPOSE: To present a practical image-guided method to position an endorectal balloon that improves in vivo thermoluminiscent dosimeter (TLD) measurements of rectal doses in proton therapy for prostate cancer. METHODS: TLDs were combined with endorectal balloons to measure dose at the anterior rectal wall during daily proton treatment delivery. Radiopaque metallic markers were employed as surrogates for balloon position reproducibility in rotation and translation. The markers were utilized to guide the balloon orientation during daily treatment employing orthogonal x-ray image-guided patient positioning. TLDs were placed at the 12 o'clock position on the anterior balloon surface at the midprostatic plane. Markers were placed at the 3 and 9 o'clock positions on the balloon to align it with respect to the planned orientation. The balloon rotation along its stem axis, referred to as roll, causes TLD displacement along the anterior-posterior direction. The magnitude of TLD displacement is revealed by the separation distance between markers at opposite sides of the balloon on sagittal x-ray images. RESULTS: A total of 81 in vivo TLD measurements were performed on six patients. Eighty-three percent of all measurements (65 TLD readings) were within +5% and -10% of the planning dose with a mean of -2.1% and a standard deviation of 3.5%. Examination of marker positions with in-room x-ray images of measured doses between -10% and -20% of the planned dose revealed a strong correlation between balloon roll and TLD displacement posteriorly from the planned position. The magnitude of the roll was confirmed by separations of 10-20 mm between the markers which could be corrected by manually adjusting the balloon position and verified by a repeat x-ray image prior to proton delivery. This approach could properly correct the balloon roll, resulting in TLD positioning within 2 mm along the anterior-posterior direction. CONCLUSIONS: Our results show that image-guided TLD-based in vivo dosimetry for rectal dose verification can be perfomed reliably and reproducibly for proton therapy in prostate cancer.

A novel daily QA system for proton therapy.

We describe the design and use of a daily quality assurance (QA) system for proton therapy. The QA system is designed to check the overall readiness of proton therapy system consistently within certain reference tolerances by a home-made QA device (the QA device). The QA device is comprised of a commercially available QA device, rf-Daily QA 3, a home-made acrylic phantom, a set of acrylic compensators with various thicknesses, and a mechanical indexing jig. The indexing jig indexes the rf-Daily QA 3, as well as the acrylic phantom, onto the patient treatment couch. Embedded fiducial markers in the acrylic phantom are used to check X-ray image quality and positioning alignment accuracy of the imaging system. The rf-Daily QA 3 is used to check proton beam output, range and symmetry with one single beam delivery. We developed in-house software to calculate beam range and symmetry, based on various ion chambers' readings inside the rf-Daily QA 3. With a single setup and one beam irradiation, the QA system is employed to check couch movement, laser alignment, image registration, and reference proton beam characteristics. The simplicity and robustness of this QA system allows for a total QA time of less than 20 minutes per room. The system has been in use at three proton therapy centers since June 2009.