Spontaneous-stimulated Raman co-localization dual-modal analysis approach for efficient identification of tumor cells.

The study of highly heterogeneous tumor cells, especially acute myeloid leukemia (AML) cells, usually relies on invasive analytical methods such as morphology, immunology, cytogenetics, and molecular biology classification, which are complex and time-consuming to perform. Mortality is high if patients are not diagnosed in a timely manner, so rapid label-free analysis of gene expression and metabolites within single-cell substructures is extremely important for clinical diagnosis and treatment. As a label-free and non-destructive vibrational detection technique, spontaneous Raman scattering provides molecular information across the full spectrum of the cell but lacks rapid imaging localization capabilities. In contrast, stimulated Raman scattering (SRS) provides a high-speed, high-resolution imaging view that can offer real-time subcellular localization assistance for spontaneous Raman spectroscopic detection. In this paper, we combined multi-color SRS microscopy with spontaneous Raman to develop a co-localized Raman imaging and spectral detection system (CRIS) for high-speed chemical imaging and quantitative spectral analysis of subcellular structures. Combined with multivariate statistical analysis methods, CRIS efficiently differentiated AML from normal leukocytes with an accuracy of 98.1 % and revealed the differences in the composition of nuclei and cytoplasm of AML relative to normal leukocytes. Compared to conventional Raman spectroscopy blind sampling without imaging localization, CRIS increased the efficiency of single-cell detection by at least three times. In addition, using the same approach for further identification of AML subtypes M2 and M3, we demonstrated that intracytoplasmic differential expression of proteins is a marker for their rapid and accurate classifying. CRIS analysis methods are expected to pave the way for clinical translation of rapid tumor cell identification.

Label-Free Identification of AML1-ETO Positive Acute Myeloid Leukemia Using Single-Cell Raman Spectroscopy.

Acute myeloid leukemia (AML) is a malignant hematological tumor disease. Chromosomal abnormality is an independent prognostic factor in AML. AML with t(8:21) (q22; q22)/AML1-ETO (AE) is an independent disease group. In this research, a new method based on Raman spectroscopy is reported for label-free single-cell identification and analysis of AE fusion genes in clinical AML patients. Raman spectroscopy reflects the intrinsic vibration information of molecules in a label-free and non-destructive manner, and the fingerprint Raman spectrum of cells characterizes intracellular molecular types and relative concentration information, so as to realize the identification and molecular metabolism analysis of different kinds of cells. We collected the Raman spectra of bone marrow cells from clinically diagnosed AML M2 patients with and without the AE fusion gene. Through comparison of the average spectra and identification analysis based on multivariate statistical methods such as principal component analysis and linear discriminant analysis, the distinction between AE positive and negative sample cells in M2 AML patients was successfully achieved, and the single-cell identification accuracy was more than 90%. At the same time, the Raman spectra of the two types of cells were analyzed by the multivariate curve resolution alternating least squares decomposition method. It was found that the presence of the AE fusion gene may lead to the metabolic changes of lipid and nucleic acid in AML cells, which was consistent with the results of genomic and metabolomic multi-omics studies. The above results indicate that single-cell Raman spectroscopy has the potential for early identification of AE-positive AML.

Current practices of craniospinal irradiation techniques in Turkey: a comprehensive dosimetric analysis.

OBJECTIVE: This study evaluates various craniospinal irradiation (CSI) techniques used in Turkish centers to understand their advantages, disadvantages and overall effectiveness, with a focus on enhancing dose distribution. METHODS: Anonymized CT scans of adult and pediatric patients, alongside target volumes and organ-at-risk (OAR) structures, were shared with 25 local radiotherapy centers. They were tasked to develop optimal treatment plans delivering 36 Gy in 20 fractions with 95% PTV coverage, while minimizing OAR exposure. The same CT data was sent to a US proton therapy center for comparison. Various planning systems and treatment techniques (3D conformal RT, IMRT, VMAT, tomotherapy) were utilized. Elekta Proknow software was used to analyze parameters, assess dose distributions, mean doses, conformity index (CI), and homogeneity index (HI) for both target volumes and OARs. Comparisons were made against proton therapy. RESULTS: All techniques consistently achieved excellent PTV coverage (V95 > 98%) for both adult and pediatric patients. Tomotherapy closely approached ideal Dmean doses for all PTVs, while 3D-CRT had higher Dmean for PTV_brain. Tomotherapy excelled in CI and HI for PTVs. IMRT resulted in lower pediatric heart, kidney, parotid, and eye doses, while 3D-CRT achieved the lowest adult lung doses. Tomotherapy approached proton therapy doses for adult kidneys and thyroid, while IMRT excelled for adult heart, kidney, parotid, esophagus, and eyes. CONCLUSION: Modern radiotherapy techniques offer improved target coverage and OAR protection. However, 3D techniques are continued to be used for CSI. Notably, proton therapy stands out as the most efficient approach, closely followed by Tomotherapy in terms of achieving superior target coverage and OAR protection.

Recognition of Nucleophosmin Mutant Gene Expression of Leukemia Cells Using Raman Spectroscopy.

As a label-free, nondestructive, and in situ detection method, Raman spectroscopy analysis of single cells has potential application value in biomedical fields such as cancer diagnosis. In this study, the Raman spectral characteristics of nucleophosmin (NPM1)-mutant acute myeloid leukemia (AML) cells and nonmutated AML cells were investigated, and the reasons for the differences in spectral peaks were explained in combination with transcriptomic analysis. Raman spectra of two AML cell lines without NPM1 mutation (THP-1 and HL-60) and the OCI-AML3 cell line carrying the NPM1 mutant gene were cultured and collected experimentally. It was found that the average Raman spectra of NPM1 mutant and nonmutated cells had intensity differences in multiple peaks corresponding to chondroitin sulfate (CS), nucleic acid, protein, and other molecules. The differentially expressed genes were identified by quantitative analysis of the gene expression matrix of the two types of cells, and their roles in the regulation of CS proteoglycan and protein synthesis were analyzed. The results showed that the differences between the two types of cells expressed by the single-cell Raman spectral information were consistent with the differences in transcriptional profiles. This research could advance the application of Raman spectroscopy in cancer cell typing.

Characterization of 250 MeV Protons from the Varian ProBeam PBS System for FLASH Radiation Therapy.

Shoot-through proton FLASH radiation therapy has been proposed where the highest energy is extracted from a cyclotron to maximize the dose rate (DR). Although our proton pencil beam scanning system can deliver 250 MeV (the highest energy), this energy is not used clinically, and as such, 250 MeV has yet to be characterized during clinical commissioning. We aim to characterize the 250-MeV proton beam from the Varian ProBeam system for FLASH and assess the usability of the clinical monitoring ionization chamber (MIC) for FLASH use. We measured the following data for beam commissioning: integral depth dose curve, spot sigma, and absolute dose. To evaluate the MIC, we measured output as a function of beam current. To characterize a 250 MeV FLASH beam, we measured (1) the central axis DR as a function of current and spot spacing and arrangement, (2) for a fixed spot spacing, the maximum field size that achieves FLASH DR (ie, > 40 Gy/s), and (3) DR reproducibility. All FLASH DR measurements were performed using an ion chamber for the absolute dose, and irradiation times were obtained from log files. We verified dose measurements using EBT-XD films and irradiation times using a fast, pixelated spectral detector. R90 and R80 from integral depth dose were 37.58 and 37.69 cm, and spot sigma at the isocenter were σx = 3.336 and σy = 3.332 mm, respectively. The absolute dose output was measured as 0.343 Gy*mm2/MU for the commissioning conditions. Output was stable for beam currents up to 15 nA and gradually increased to 12-fold for 115 nA. Dose and DR depended on beam current, spot spacing, and arrangement and could be reproduced with 6.4% and 4.2% variations, respectively. Although FLASH was achieved and the largest field size that delivers FLASH DR was determined as 35 × 35 mm2, the current MIC has DR dependence, and users should measure dose and DR independently each time for their FLASH applications.

Effect of the initial energy layer and spot placement parameters on IMPT delivery efficiency and plan quality.

PURPOSE: Improving efficiency of intensity modulated proton therapy (IMPT) treatment can be achieved by shortening the beam delivery time. The purpose of this study is to reduce the delivery time of IMPT, while maintaining the plan quality, by finding the optimal initial proton spot placement parameters. METHODS: Seven patients previously treated in the thorax and abdomen with gated IMPT and voluntary breath-hold were included. In the clinical plans, the energy layer spacing (ELS) and spot spacing (SS) were set to 0.6-0.8 (as a scale factor of the default values). For each clinical plan, we created four plans with ELS increased to 1.0, 1.2, 1.4, and SS to 1.0 while keeping all other parameters unchanged. All 35 plans (130 fields) were delivered on a clinical proton machine and the beam delivery time was recorded for each field. RESULTS: Increasing ELS and SS did not cause target coverage reduction. Increasing ELS had no effect on critical organ-at-risk (OAR) doses or the integral dose, while increasing SS resulted in slightly higher integral and selected OAR doses. Beam-on times were 48.4 ± 9.2 (range: 34.1-66.7) seconds for the clinical plans. Time reductions were 9.2 ± 3.3 s (18.7 ± 5.8%), 11.6 ± 3.5 s (23.1 ± 5.9%), and 14.7 ± 3.9 s (28.9 ± 6.1%) when ELS was changed to 1.0, 1.2, and 1.4, respectively, corresponding to 0.76-0.80 s/layer. SS change had a minimal effect (1.1 ± 1.6 s, or 1.9 ± 2.9%) on the beam-on time. CONCLUSION: Increasing the energy layers spacing can reduce the beam delivery time effectively without compromising IMPT plan quality; increasing the SS had no meaningful impact on beam delivery time and resulted in plan-quality degradation in some cases.

Intensity Modulated Proton Therapy Treatment Planning for Postmastectomy Patients with Metallic Port Tissue Expanders.

PURPOSE: Proton beam therapy can significantly reduce cardiopulmonary radiation exposure compared with photon-based techniques in the postmastectomy setting for locally advanced breast cancer. For patients with metallic port tissue expanders, which are commonly placed in patients undergoing a staged breast reconstruction, dose uncertainties introduced by the high-density material pose challenges for proton therapy. In this report, we describe an intensity modulated proton therapy planning technique for port avoidance through a hybrid single-field optimization/multifield optimization approach. METHODS AND MATERIALS: In this planning technique, 3 beams are utilized. For each beam, no proton spot is placed within or distal to the metal port plus a 5 mm margin. Therefore, precise modeling of the metal port is not required, and various tissue expander manufacturers/models are eligible. The blocked area of 1 beam is dosimetrically covered by 1 or 2 of the remaining beams. Multifield optimization is used in the chest wall target region with blockage of any beam, while single-field optimization is used for remainder of chest wall superior/inferior to the port. RESULTS: Using this technique, clinical plans were created for 6 patients. Satisfactory plans were achieved in the 5 patients with port-to-posterior chest wall separations of 1.5 cm or greater, but not in the sixth patient with a 0.7 cm separation. CONCLUSIONS: We described a planning technique and the results suggest that the metallic port-to-chest wall distance may be a key parameter for optimal plan design.

Outcomes of and treatment planning considerations for a hybrid technique delivering proton pencil-beam scanning radiation to women with metal-containing tissue expanders undergoing post-mastectomy radiation.

BACKGROUND: Following mastectomy, immediate breast reconstruction often involves the use of temporary tissue expanders (TEs). TEs contain metallic ports (MPs), which complicate proton pencil-beam scanning (PBS) planning. A technique was implemented for delivering PBS post-mastectomy radiation (PMRT) to patients with TEs and MPs. METHODS: A protocol utilizing a hybrid single- and multi-field optimization (SFO, MFO) technique was developed. Plans were robustly optimized using a Monte Carlo algorithm. A CTV_eval structure including chest wall (CW) and regional nodal (RNI) targets and excluding the TE was evaluated. Organ at risk (OAR) dosimetry and acute toxicities were analyzed. RESULTS: Twenty-nine women were treated with this technique. A 2-field SFO technique was used superior and inferior to the MP, with a 3 or 4-field MFO technique used at the level of the MP. Virtual blocks were utilized so that beams did not travel through the MP. A port-to-CW distance of 1 cm was required. Patients underwent daily image-guidance to ensure the port remained within a 0.5 cm internal planning volume (ITV). Median RT dose to CTV_eval was 50.4 Gy (45.0-50.4). Median 95% CTV_eval coverage was 99.5% (95-100). Optically stimulated luminescent dosimeter (OSLD) readings were available for 8 patients and correlated to the dose measurements in the treatment planning system (TPS); median OSLD ratio was 0.99 (range, 0.93-1.02). CONCLUSIONS: Delivering PMRT with PBS for women with metal-containing TEs using a hybrid SFO/MFO technique is feasible, reproducible, and achieves excellent dose distributions. Specialized planning and image-guidance techniques are required to safely utilize this treatment in the clinic.

Plan quality effects of maximum monitor unit constraints in pencil beam scanning proton therapy for central nervous system and skull base tumors.

PURPOSE/OBJECTIVE(S): With reports of CNS toxicity in patients treated with proton therapy at doses lower than would be expected based on photon data, it has been proposed that heavy monitor unit (MU) weighting of pencil beam scanning (PBS) proton therapy spots may potentially increase the risk of toxicity. We evaluated the impact of maximum MU weighting per spot (maxMU/spot) restrictions on PBS plan quality, prior to implementing clinic-wide maxMU/spot restrictions. MATERIALS/METHODS: PBS plans of 11 patients, of which 3 plans included boosts, for a total of 14 PBS sample cases were included. Per sample case, a single dosimetrist created 4 test plans, gradually reducing the maxMU/spot in the plan. Test Plan 1, unrestricted in maxMU/spot, was the reference for all restricted plan comparisons (comparison sets 2 vs. 1; 3 vs. 1; and 4 vs. 1). The impact of MU/spot restrictions on plan quality metrics were analyzed with Wilcoxon signed rank test analyses. Treatment delivery time was modeled for a representative case. RESULTS: A total of 14 PBS sample cases, 7 (50%) single-field optimized, 7 (50%) multi-field optimized, 9 (64%) delivering > 3500 cGy, 9 (64%) with 3 beams, and 7 (50%) without a range shifter were included. There were no differences in plan quality metrics of target coverage (V95% and V100% prescription), conformality and gradient indices, hot spot volume (V105% prescription), and dose to normal brain (V10%/30%/50%/70%/90%/100% prescription) with reductions of allowable maxMU/spot across all comparison sets (p > 0.05). Max MU/spot restrictions did not increase treatment delivery time when analyzed for a representative case. CONCLUSION: MaxMU/spot restrictions within the thresholds evaluated in this study did not degrade overall plan quality metrics. Future studies should evaluate spot weighting with linear energy transfer/relative biologic effectiveness-informed planning to determine if spot weighting manipulation impacts clinical outcomes and mitigates toxicity.

Simulation of an HDR "Boost" with Stereotactic Proton versus Photon Therapy in Prostate Cancer: A Dosimetric Feasibility Study.

PURPOSE/OBJECTIVES: To compare the dose escalation potential of stereotactic body proton therapy (SBPT) versus stereotactic body photon therapy (SBXT) using high-dose rate prostate brachytherapy (HDR-B) dose-prescription metrics. PATIENTS AND METHODS: Twenty-five patients previously treated with radiation for prostate cancer were identified and stratified by prostate size (≤ 50cc; n = 13, > 50cc; n = 12). Initial CT simulation scans were re-planned using SBXT and SBPT modalities using a prescription dose of 19Gy in 2 fractions. Target coverage goals were designed to mimic the dose distributions of HDR-B and maximized to the upper limit constraint for the rectum and urethra. Dosimetric parameters between SBPT and SBXT were compared using the signed-rank test and again after stratification for prostate size (≤ 50cm3 and >50cm3) using the Wilcoxon rank test. RESULTS: Prostate volume receiving 100% of the dose (V100) was significantly greater for SBXT (99%) versus SBPT (96%) (P ≤ 0.01), whereas the median V125 (82% vs. 73%, P < 0.01) and V200 (12% vs. 2%, P < 0.01) was significantly greater for SBPT compared to SBXT. Median V150 was 49% for both cohorts (P = 0.92). V125 and V200 were significantly correlated with prostate size. For prostates > 50cm3, V200 was significantly greater with SBPT compared to SBXT (14.5% vs. 1%, P = 0.005), but not for prostates 50cm3 (9% vs 4%, P = 0.11). Median dose to 2cm3 of the bladder neck was significantly lower with SBPT versus SBXT (9.6 Gy vs. 14 Gy, P < 0.01). CONCLUSION: SBPT and SBXT can be used to simulate an HDR-B boost for locally advanced prostate cancer. SBPT demonstrated greater dose escalation potential than SBXT. These results are relevant for future trial design, particularly in patients with high risk prostate cancer who are not amenable to brachytherapy.

Multiple Computed Tomography Robust Optimization to Account for Random Anatomic Density Variations During Intensity Modulated Proton Therapy.

PURPOSE: To propose a method of optimizing intensity modulated proton therapy (IMPT) plans robust against dosimetric degradation caused by random anatomic variations during treatment. METHODS AND MATERIALS: Fifteen patients with prostate cancer treated with IMPT to the pelvic targets were nonrandomly selected. On the repeated quality assurance computed tomography (QACTs) for some patients, bowel density changes were observed and caused dose degradation because the treated plans were not robustly optimized (non-RO). To mitigate this effect, we developed a robust planning method based on 3 CT images, including the native planning CT and its 2 copies, with the bowel structures being assigned to air and tissue, respectively. The RO settings included 5 mm setup uncertainty and 3.5% range uncertainty on 3 CTs. This method is called pseudomultiple-CT RO (pMCT-RO). Plans were also generated using RO on the native CT only, with the same setup and range uncertainties. This method is referred to as single-CT RO (SCT-RO). Doses on the QACTs and the nominal planning CT were compared for the 3 planning methods. RESULTS: All 3 plan methods provided sufficient clinical target volumes D95% and V95% on the QACTs. For pMCT-RO plans, the normal tissue Dmax on QACTs of all patients was at maximum 109.1%, compared with 144.4% and 116.9% for non-RO and SCT-RO plans, respectively. On the nominal plans, the rectum and bladder doses were similar among all 3 plans; however, the volume of normal tissue (excluding the rectum and bladder) receiving the prescription dose or higher is substantially reduced in either pMCT-RO plans or SCT-RO plans, compared with the non-RO plans. CONCLUSIONS: We developed a robust optimization method to further mitigate undesired dose heterogeneity caused by random anatomic changes in pelvic IMPT treatment. This method does not require additional patient CT scans. The pMCT-RO planning method has been implemented clinically since 2017 in our center.

Proton Versus Intensity-Modulated Radiation Therapy: First Dosimetric Comparison for Total Scalp Irradiation.

PURPOSE: Total scalp irradiation (TSI) is used to treat malignancies of the scalp and face, including angiosarcomas, nonmelanoma skin cancers, and cutaneous lymphomas. Owing to the irregularity of the scalp contour and the presence of underlying critical organs at risk (OARs), radiation planning is challenging and technically difficult. To address these complexities, several different radiation therapy techniques have been used. These include the combined lateral photon-electron technique (3DRT), intensity-modulated radiation therapy (IMRT)/volumetric arc therapy (VMAT), helical tomotherapy (HT), and mold-based high-dose-rate brachytherapy (HDR BT). However, the use of proton radiation therapy (PRT) has never been documented. MATERIALS AND METHODS: A 71-year-old, immunosuppressed man presented with recurrent nonmelanoma skin cancer of the scalp. He was successfully treated at our center with PRT to deliver TSI. A comparative VMAT treatment plan was generated and dose to critical OARs was compared. RESULTS: We present the first clinical case report of PRT for TSI and dosimetric comparison to a VMAT plan. The PRT and VMAT plans provided equivalent target volume coverage; however, the PRT plan significantly reduced dose to the brain, hippocampi, and optical apparatus. CONCLUSION: TSI planned with PRT is relatively straightforward from a planning perspective and does not require a bolus. It also has the potential to decrease radiation therapy-related toxicity. However, PRT is relatively expensive and not universally available. The uncertainty surrounding the end-range of the proton beam is a consideration. Although there are potential disadvantages to using PRT for TSI, its use should be considered by treating radiation oncologists and referring physicians.

Radiation dose-painting with protons vs. photons for head-and-neck cancer.

Background: Dose-painting has recently been investigated in early-phase trials in head-and-neck cancer (HNC) with the aim of improving local tumor control. At the same time proton therapy has been reported as potentially capable of decreasing toxicity. Here, we investigate whether protons could be applied in a dose-painting setting by comparing proton dose distributions with delivered photon plans from a phase-I trial of FDG-PET based dose-painting at our institution.Material and methods: Eleven oropharynx (5), hypopharynx (2) and larynx cancer (4) patients from the recently conducted phase I trial were used for comparison of proton and photon dose-painting techniques. Robust optimization (3.5%/3 mm) was used for proton plans. Plan robustness and difference in dose metrics to targets and organs at risk were evaluated.Results: The proton plans met target dose constraints, while having lower non-target dose than photon plans (body-minus-CTV, mean dose 3.9 Gy vs 7.2 Gy, p = .004). Despite the use of robust proton planning for plan max dose, photon plan max doses were more robust (p = .006). Max dose to medulla, brainstem and mandible were lower in the proton plans, while there was no significant difference in mean dose to submandibular- and parotid glands.Conclusion: Proton dose-painting for HNC seems feasible and can reduce the non-target dose overall, however not significantly to certain organs close to the target, such as the salivary glands. Max dose in proton plans had a lower robustness compared to photons, requiring caution to avoid unintended hot spots in consideration of the risk of mucosal toxicity.

Preserving Endocrine Function in Premenopausal Women Undergoing Whole Pelvis Radiation for Cervical Cancer.

PURPOSE: Whole pelvis radiation therapy (WPRT) in premenopausal women with cervical cancer can cause permanent ovarian damage, resulting in premature menopause. Oophoropexy, often considered as an initial step, demonstrates safety of sparing 1 ovary at the cost of delay in initiating WPRT. Therefore, we dosimetrically compared volumetric modulated arc radiotherapy (VMAT) and intensity modulated proton therapy (IMPT) techniques to allow for ovarian-sparing WPRT. MATERIALS AND METHODS: Ten patients previously treated for cervical cancer at our institution were included in this institutional review board-approved analysis. A modified clinical treatment volume (CTV) was designed, sparing 1 ovary (left or right), as determined by the physician (ovarian-sparing CTV) and disease extent, including physical exam, positron emission tomography/computed tomography and magnetic resonance imaging. An ovarian-sparing planning target volume was determined as the ovarian-sparing CTV+5 mm for patients who were supine and 7 mm for those who were prone. All plans were calculated to a dose of 45 Gy with specific optimization goals for target volumes, while attempting to maintain a mean ovary dose (Dmean) < 15 Gy. Dosimetric goals were compared across the 2 modalities using the Mann-Whitney U test. RESULTS: Both treatment modalities were able to achieve primary clinical goal coverage to the uterus/cervix (P = .529, comparing VMAT versus IMPT), ovarian-sparing CTV (P = .796) and ovarian-sparing planning target volume (P = .004). All 10 IMPT plans were able to accomplish the ovary objective (14.0 ± 1.66 Gy). However, only 4 of the 10 VMAT plans were able to achieve a Dmean < 15 Gy to the prioritized ovary, with an average dose of 15.3 ± 4.10 Gy. CONCLUSION: Sparing an ovary in women undergoing WPRT for cervical cancer is dosimetrically feasible with IMPT without sacrificing coverage to important clinical targets. Future work will incorporate the brachytherapy dose to the ovarian-sparing CTV and assess the clinical response of this technique as a means to preserve ovarian endocrine function.

Proton beam therapy delivered using pencil beam scanning vs. passive scattering/uniform scanning for localized prostate cancer: Comparative toxicity analysis of PCG 001-09.

BACKGROUND AND PURPOSE: Patient-level benefits of proton beam therapy (PBT) relative to photon therapy for prostate cancer (PC) continue to be the focus of debate. Although trials comparing the two modalities are underway, most are being conducted using "conventional" PBT (passive scattering/uniform scanning [PS/US]) rather than pencil beam scanning (PBS). The dosimetric benefits of PBS are well-known, but comparative data are limited. This analysis compares PBS toxicity rates with those of PS/US in a prospective multicenter registry. METHODS: We evaluated acute/late gastrointestinal (GI) and genitourinary (GU) toxicity rates for men with low-to-intermediate risk PC enrolled in PCG 001-09. Acute toxicities with the two techniques were compared using χ2 tests, and the cumulative incidence methods for late toxicity. Multivariable analyses (MVAs) for acute toxicity were performed using logistic regression, and cox proportional hazards models for late toxicity. RESULTS: Patients were treated using PS/US (n = 1105) or PBS (n = 238). Acute grade ≥2 GI toxicity in PBS did not significantly differ from that with PS/US (2.9% and 2.1%, respectively; P = 0.47). Acute grade ≥2 GU toxicity was significantly higher with PBS (21.9% and 15.1%; P < 0.01). In MVA, PBS was significantly associated with increased acute grade ≥2 GU toxicity (RR = 1.57, p < 0.001). Late grade ≥2 GI and GU toxicities did not differ significantly between groups. CONCLUSIONS: This is the first multi-institutional comparative effectiveness evaluation of PBT techniques in PC. Differences in acute GU toxicity warrant further evaluation, and highlight the urgent need for prospective data using PBT.

Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies.

Radiation therapy is a frequently used modality for the treatment of solid cancers. Although the mechanisms of cell kill are similar for all forms of radiation, the in vivo properties of photon and proton beams differ greatly and maybe exploited to optimize clinical outcomes. In particular, proton particles lose energy in a predictable manner as they pass through the body. This property is used clinically to control the depth at which the proton beam is terminated, and to limit radiation dose beyond the target region. This strategy can allow for substantial reductions in radiation dose to normal tissues located just beyond a tumor target. However, the degradation of proton energy in the body remains highly sensitive to tissue density. As a consequence, any changes in tissue density during the course of treatment may significantly alter proton dosimetry. Such changes may occur through alterations in body weight, respiration, or bowel filling/gas, and may result in unfavorable dose deposition. In this manuscript, we provide a detailed method for the delivery of proton therapy using both passive scatter and pencil beam scanning techniques for prostate cancer. Although the described procedure directly pertains to prostate cancer patients, the method may be adapted and applied for the treatment of virtually all solid tumors. Our aim is to equip readers with a better understanding of proton therapy delivery and outcomes in order to facilitate the appropriate integration of this modality during cancer therapy.

Techniques for Treating Bilateral Breast Cancer Patients Using Pencil Beam Scanning Technology.

PURPOSE: Patients with bilateral breast cancer (BBC), who require postmastectomy radiation therapy or radiation as part of breast conservation treatment, present a unique technical challenge. Even with modern techniques, such as intensity modulated radiation therapy or volumetric modulated arc therapy (VMAT), adequate target coverage is rarely achieved without the expense of increased integral dose to important organs at risk (OARs), such as the heart and lungs. Therefore, we present several BBC techniques and a treatment algorithm using intensity-modulated proton therapy (IMPT) for patients treated at our center. MATERIALS AND METHODS: We describe 3 different BBC treatment techniques using IMPT on patients treated at our center, with comparison VMAT plans to demonstrate the dosimetric benefit of proton therapy in these patients. Following RADCOMP (Radiation Therapy Oncology Group, Philadelphia, Pennsylvania) guidelines, a single physician approved all target volumes and OARs. Plans were designed so that ≥ 95% of the prescribed dose covered ≥ 95% of all targets. Parameters for dosimetric volume histograms for the clinical targets and OARs are reported for the 2 radiation methods. RESULTS: All methods demonstrated acceptable target coverage with 95% of the prescription planning target volume reaching a mean (± SD) of 98.0% (± 0.87%) and 97.5% (± 2.39%), for VMAT and IMPT plans, respectively. Conformity and homogeneity were also similar between the 2 techniques. Proton therapy provided observed improvements in mean heart dose (average heart mean [SD], 9.98 Gy [± 0.87 Gy] versus 2.12 Gy [± 0.96 Gy]) and total lung 5% prescription dose (V5; mean [SD] total lung V5, 97.9% [± 2.84%]), compared with 39.8% [± 9.39%]). All IMPT methods spared critical OARs; however, the single, 0° anterior-posterior plan allowed for the shortest treatment time. CONCLUSION: Both VMAT and all 3 IMPT techniques provided excellent target coverage in patients with BBC; however, proton therapy was superior in decreasing the dose to OARs. A single-field optimization approach should be the IMPT method of choice when feasible.

Concepts of PTV and Robustness in Passively Scattered and Pencil Beam Scanning Proton Therapy.

Concepts of planning target volume and plan robustness in proton therapy are described. Implementation of these concepts into treatment planning is described. Proton plan sensitivity and interfractional and intrafractional anatomical variation are also discussed.

Proton beam therapy for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare disease with a poor prognosis. Surgical techniques have made incremental improvements over the last few decades while new systemic therapies, including immunotherapies, show promise as potentially effective novel therapies. Radiation therapy has historically been used only in the palliative setting or as adjuvant therapy after extrapleural pneumonectomy, but recent advances in treatment planning and delivery techniques utilizing intensity-modulated radiation therapy and more recently pencil-beam scanning (PBS) proton therapy, have enabled the delivery of radiation therapy as neoadjuvant or adjuvant therapy after an extended pleurectomy and decortication or as definitive therapy for patients with recurrent or unresectable disease. In particular, PBS proton therapy has the potential to deliver high doses of irradiation to the entire effected pleura while significantly reducing doses to nearby organs at risk. This article describes the evolution of radiation therapy for MPM and details how whole-pleural PBS proton therapy is delivered to patients at the Maryland Proton Treatment Center.

A comparison of two pencil beam scanning treatment planning systems for proton therapy.

OBJECTIVE: Analytical dose calculation algorithms for Eclipse and Raystation treatment planning systems (TPS), as well as a Raystation Monte Carlo model are compared to corresponding measured point doses. METHOD: The TPS were modeled with the same beam data acquired during commissioning. Thirty-five typical plans were made with each planning system, 31 without range shifter and four with a 5 cm range shifter. Point doses in these planes were compared to measured doses. RESULTS: The mean percentage difference for all plans between Raystation and Eclipse were 1.51 ± 1.99%. The mean percentage difference for all plans between TPS models and measured values are -2.06 ± 1.48% for Raystation pencil beam (PB), -0.59 ± 1.71% for Eclipse and -1.69 ± 1.11% for Raystation monte carlo (MC). The distribution for the patient plans were similar for Eclipse and Raystation MC with a P-value of 0.59 for a two tailed unpaired t-test and significantly different from the Raystation PB model with P = 0.0013 between Raystation MC and PB. All three models faired markedly better if plans with a 5 cm range shifter were ignored. Plan comparisons with a 5 cm range shifter give differences between Raystation and Eclipse of 3.77 ± 1.82%. The mean percentage difference for 5 cm range shifter plans between TPS models and measured values are -3.89 ± 2.79% for Raystation PB, -0.25 ± 3.85% for Eclipse and 1.55 ± 1.95% for Raystation MC. CONCLUSION: Both Eclipse and Raystation PB TPS are not always accurate within ±3% for a 5 cm range shifters or for small targets. This was improved with the Raystation MC model. The point dose calculations of Eclipse, Raystation PB, and Raystation MC compare within ±3% to measured doses for the other scenarios tested.