Pencil Beam Scanning Research Articles

Evaluation of Planning Techniques Involving Inverse Optimization in SBPT to Assess for Organs at Risk in Anal Cancer

<h3>Purpose/Objective(s)</h3> Proton beam therapy may be considered for anal cancer when desiring to reduce dose to surrounding organs at risk. This study was designed to evaluate and compare treatment planning techniques in pencil beam scanning proton therapy (PBS) to spare 5 organs-at-risk (OARs) for patients with anal cancer. <h3>Materials/Methods</h3> Seventeen patients (11 female and 6 male) previously treated for Stage I-III anal cancer were included in this study. A treatment planning system was utilized for contouring and treatment planning. Target volumes encompassed primary anal cancer tumors and the inguinal lymph nodes. Multi-Field optimization was utilized in creating two separate plans for each patient: a) Single Target sharing all three beams across the anal target and the involved lymph nodes that were optimized simultaneously, also referred to in here as IMPT, and b) Splitting of the target such that the anal target, and the lymph nodes were covered by their own individual beams but optimized simultaneously, also referred to as (IFSO). Both plans were designed with the same beam angles, two anterior oblique and one posterior-anterior beams. The optimization target volume (OTV) was defined with a 5mm isotropic margin around clinical target volume (CTV) to account for set-up uncertainties. A scanning target volume (STV) was defined as the OTV with a 5-mm isotropic expansion to guide the initial spot arrangement and account for lateral penumbrae. Five OARs (bladder, small bowel, large bowel, bilateral femoral heads, and genitalia) were evaluated using the dose-volume-histogram indices. The Sign test was used for statistical comparison between the two plans. <h3>Results</h3> There were no differences in target coverage between the two planning techniques. Dosimetric comparisons for select OARs between IMPT and IFSO demonstrated a 50% increase in small bowel V30 (<i>p</i><0.02), 66% increase in small bowel V15 (<i>p</i><0.002), and 82% increase in genitalia V20 (p <0.049). Additionally, adjacent organs at risk received significantly higher mean doses with IMPT compared to IFSO. Mean bladder dose was increased by 16% (<i>p</i><0.049) and mean dose to the left and right femoral heads were increased 158% and 149%(<i>p</i><0.049), respectively. There was no significant difference in maximum dose to the large bowel, small bowel, and femoral heads. There was no significant difference in V45 for small bowel and bladder and V20 for bone marrow V20. <h3>Conclusion</h3> IFSO based plans led to significantly better sparing of OARs in anal cancer treated with PBS. With the advent of LET-based optimization in PBS, IFSO could further improve the dosimetric outcomes for the treatment of anal cancer.

Density Overrides that Best Predict Bowel Changes during Pencil Beam Scanning Proton Radiotherapy for Prostate Cancer

<h3>Purpose/Objective(s)</h3> Changes in patient anatomy during pencil beam scanning proton radiotherapy (PBSPT) can result in substantial differences in dose distribution. In patients with prostate cancer receiving elective nodal irradiation (ENI), interfraction variability in bowel position or bowel filling can highlight this uncertainty. Such changes are often managed by assessing the plan on CT dataset copies with the bowel contour overridden to other densities. The ideal Hounsfield Unit (HU) overrides remain unclear, but extremes (HU=0 water and HU=-1000 air) are often utilized. The aim of the present study is to determine the bowel density overrides that are most predictive of bowel changes during a course of PBSPT. <h3>Materials/Methods</h3> Consecutive patients, from a single institution, receiving PBSPT with ENI for intact prostate cancer were retrospectively reviewed for the period between 10/2020-12/2021. Proton radiotherapy consisted of 50.4 Gy in 28 fractions to the pelvic lymph node stations with a simultaneous integrated boost to 70 Gy in 28 fractions to the prostate. Individually contoured loops of small bowel, large bowel, and rectum were overridden to HU of 0 to -1000 in 100 HU intervals. A bowel evaluation structure, consisting of a bowel bag cropped 3 cm away from the high-risk volume, was created; its dose volume histogram was reviewed; and values for the maximum point dose (Dmax), V105%, V45Gy, V20Gy were recorded for each plan. The dosimetry of bowel override plans were compared to the patient's Quality Assurance CT (QACT) scans. The bowel override plan which most closely matched the dosimetry of each QACT for each dosimetric parameter was determined, and the prevalence of closest prediction for each override value was tabulated. <h3>Results</h3> A total of 32 QACTs from 12 patients were included. For Dmax, HU=0, HU=-100, and HU=-700 predicted most accurately with 10 (31.3%), 5 (15.6%), and 4 (12.5%) closest predictions, respectively. For V105%, HU=-700 and HU=-1000 performed best with 6 (18.8%) and 7 (21.9%), respectively. For V45, HU=0 and HU=-500 predicted best with 13 (40.6%) and 5 (15.6%), respectively. For V20, HU=0, HU=-200, and HU=-600 predicted best with 18 (56.3%), 4 (12.5%), and 3 (9.4%), respectively. Overall, HU=0, -100, -600, -700, and -1000 predicted best with 42 (32.8%), 11 (8.6%), 10 (7.8%), 12 (9.4%), and 12 (9.4%) out of the 128 total dose metrics, respectively. This created a relative bimodal distribution with peaks in the 0 to -100 and -600 to -700 ranges. The nominal plan predicted best in 13 scenarios. <h3>Conclusion</h3> Bowel density override plans remain an important tool for assessment of PBSPT robustness to bowel filling changes throughout the course of therapy as the nominal CT relatively poorly predicts QACT dosimetry. The relatively bimodal distribution of accurate predictions in this study would suggest that the most predictive overrides would be HU∼0 and HU∼-650. Future investigation into multidataset robust optimization with these overrides to improve plan robustness is planned.

A Phase I/II Clinical Trial of Proton Therapy for Chordomas and Chondrosarcomas

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) for chordomas and chondrosarcomas typically requires doses >70 Gy for optimal local tumor control. Proton therapy may afford safer dose escalation to the tumor, however, prospective data on outcomes and toxicity are lacking. We report results from a prospective clinical trial of proton beam radiation for the treatment of chordomas and chondrosarcomas. <h3>Materials/Methods</h3> Fifty-five patients with pathologically confirmed, non-metastatic chordoma or chondrosarcoma with an ECOG score <=2 were enrolled in a single-institution prospective trial of proton therapy from 2010-2018. Forty-seven patients received adjuvant RT, 5 received definitive RT, 1 received neoadjuvant RT, and 1 received RT for recurrence; 1 patient enrolled did not receive RT and was excluded from toxicity and survival analyses. Median dose was 78.3 Gy (cobalt Gray equivalent [CGE]) (range 50.4 – 79.2 Gy [CGE]) using protons only (n=21), combination protons/IMRT (n=33) with double-scatter or pencil beam scanning techniques, or IMRT only (n=2). Patients were followed with MRI or CT at three-month intervals. The primary endpoints were feasibility and <=20% rate of unexpected acute grade ≥3 toxicity. Secondary endpoints included cancer-specific outcomes and toxicity. Toxicities were scored using CTCAEv4.0. Kaplan Meier analysis was used to estimate local control, progression-free survival, and overall survival with respect to the date of RT completion. Local control was defined by most recent imaging; progression-free and overall survival were defined by most recent follow-up. <h3>Results</h3> Of the 54 patients who were analyzed (22 males, 32 female) with a median age of 54, 26 had skull base chordomas, 10 had sacral chordomas, 6 had spinal chordomas, 9 had base of skull chondrosarcomas, 1 had sacral chondrosarcoma, and 2 had sinonasal chondrosarcomas. Positive margins or gross disease was noted in 67% of patients at the time of RT. Median follow-up was 72 months, with an Overall survival of 45/54 (83%) patients alive at last follow-up. Local failure-free survival and progression-free survival were 70% and 68% respectively at a median follow up of 69 months. Feasibility endpoints were met, with only 3/55 (5.5%) patient RT plans failing to meet dosimetric constraints with protons and 4/54 (7.4%) experiencing a delay or treatment break >5 days. Five patients developed distant disease, 3 with a metastasis in the craniospinal axis, and 1 with a biopsy-confirmed inguinal lymph node metastasis, and 1 with distal iliac and femur metastases. Among the 9/54 patients who died, 4 deaths were not attributed to treatment or recurrence. There were no grade 4 toxicities. One grade 3 acute toxicity (sensory neuropathy) was recorded. The only 2 grade 3 late toxicities recorded, osteoradionecrosis and intranasal carotid blowout, occurred in a single patient. <h3>Conclusion</h3> We report favorable feasibility, local tumor control, survival, and toxicity following high-dose proton therapy for chordomas and chondrosarcomas.

SDDRO-DMF: Simultaneous Dose and Dose Rate Optimization with FLASH Predictive Modeling of Dose Modifying Factor

<h3>Purpose/Objective(s)</h3> Compared to CONV-RT, FLASH-RT can provide additional biological dose sparing for OAR owing to the FLASH effect, besides physical dose sparing. However, biological and physical dose sparing often poses an optimization tradeoff for FLASH-RT. Moreover, the optimization of the FLASH effect (e.g., FLASH dose rate) does not directly quantify the dose improvement from CONV-RT to FLASH-RT. Therefore, there is a need to directly model and optimize the effective dose that accounts for the FLASH effect for FLASH-RT. <h3>Materials/Methods</h3> Here we present a novel FLASH treatment planning method SDDRO-DMF that optimizes the effective dose based on FLASH predictive modeling of dose modifying factor (DMF) via Simultaneous Dose and Dose Rate Optimization (SDDRO). The DMF model via logistic functions accounts for FLASH dose (8Gy) and dose rate (40Gy/s) thresholds and smoothly varies between 1 (CONV) and 0.7 (FLASH). The optimization objectives are based on dose-volume constraints on effective dose, which is the product of physical dose and DMF. SDDRO-DMF is solved by iterative convex relaxation algorithm with Quasi-Newton inner loops. In this study, SDDRO-DMF is implemented for transmission-beam (TB) based pencil beam scanning proton FLASH-RT. SDDRO-DMF was compared with IMPT-BP (i.e., CONV-RT via Bragg peaks (BP)), IMPT and SDDRO (two other methods for FLASH-RT via TB) for clinical HN and lung cases. <h3>Results</h3> For fair comparison, all plans had the same clinical objectives and used the same normalization of D95%=100% for PTV. The effective dose was directly derived from SDDRO-DMF and retrospectively generated for other methods using the same DMF model. The effective dose results are summarized in the table, which suggest that SDDRO-DMF generally achieved the best high-dose sparing of OAR (e.g., PTV-10mm (10mm expansion of PTV)): for HN, Dmax constraint 36Gy for carotid was only met by SDDRO-DMF; for Lung2, Dmax constraint 26Gy for brachial plexus was also only met by SDDRO-DMF. <h3>Conclusion</h3> We have developed a new FLASH treatment planning method SDDRO-DMF that can incorporate FLASH predictive model of DMF and subsequently optimize the effective dose that quantifies the net change from CONV-RT to FLASH-RT. The results show that SDDRO-DMF can further improve high-dose sparing of OAR from SDDRO, and potentially enable proton SBRT via FLASH-RT that could otherwise fail to meet OAR dose constraints via CONV-RT.

Comparative Evaluation of Brachial Plexus Sparing for Comprehensive Reirradiation of High Risk Recurrent or New Primary Breast Cancer

<h3>Purpose/Objective(s)</h3> Recurrent or new primary breast cancer with an indication for comprehensive regional nodal irradiation (RNI) in the setting of prior radiotherapy (RT) to the supraclavicular area (SCV) and upper axilla presents a unique treatment challenge due to cumulative brachial plexus (BP) dose tolerance. Brachial plexopathy is a debilitating potential consequence of RT, and BP dose monitoring is needed for comprehensive reirradiation (reRT). We hypothesize that pencil beam scanning proton therapy (PBS-PT) and photon volumetric-modulated arc therapy (VMAT) are conformal techniques that allow BP relative dose-sparing, while maintaining target volume (TV) dose. A comparative evaluation was performed to assess each approach. <h3>Materials/Methods</h3> In this IRB-approved retrospective study, all patients with ipsilateral recurrent or new primary breast cancer previously treated with photon RT, then receiving PBS-PT reRT to TV with at least partial BP overlap, were identified. VMAT plans were developed by photon breast dosimetrists using matched individualized BP dose constraints (BP maximum 17.1-53.9 Gy) used in the PBS-PT course. BP and TV DVH parameters were assessed. Patient and tumor characteristics, treatment parameters, clinical outcomes, and toxicities were collected. The median follow-up from the start of reRT was 10.5 months. <h3>Results</h3> Ten consecutive patients were identified. Median patient age was 58 years (41-82), with median time between RT courses of 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (42.6-60.0), 50.4 Gy(RBE) (45.0-64.4), and 102.4 Gy(RBE) (95.0-120.0), respectively. PBS-PT and VMAT plans matched BP doses, with the median maximum and mean BP cumulative doses 86.6 Gy (RBE) and 60.7 Gy (RBE) for PBS-PT and 87.5 Gy and 60.2 Gy for VMAT, respectively. TV coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were generally lower for VMAT vs. IMPT plans: axilla level II were 84.8%, 91.8%, and 75.7% vs. 90.9% (p=0.17), 88.3% (p=0.04), and 84.5% (p<0.01); axilla level III were 89.8%, 75.1%, and 64.0% vs. 95.4% (p=0.39), 91.8% (p=0.12), and 86.5% (p=0.32); and SCV were 83.0%, 74.3%, and 67.2% vs. 90.9% (p=0.41), 82.1% (p=0.13), and 68.2% (p=0.76), respectively. One patient developed symptoms of brachial plexopathy with neuropathy in the ulnar nerve distribution without pain or weakness. This patient had the highest maximum cumulative BP dose of the entire cohort (106.1 Gy(RBE)). <h3>Conclusion</h3> VMAT and PBS-PT provide conformal RT plans that can provide BP dose sparing but some surrounding compromise of the adjacent TV at risk. In this cohort, PBS-PT improved BP sparing and TV coverage versus VMAT. Further study with uniform TV and prescription parameters will be useful for direct comparison of the two modalities as the approach to this clinical situation continues to be refined. Longer follow-up will be needed to characterize the implication of cumulative BP dose on risk of developing clinically-significant brachial plexopathy.

Risk of Secondary Malignant Neoplasms in Children Following Proton Therapy vs. Photon Therapy for Primary CNS Tumors

<h3>Purpose/Objective(s)</h3> Central nervous system tumors are the second most common primary neoplasms seen in children and radiation therapy is a key component in management of most of these tumors. Secondary malignant neoplasms (SMNs) are rare but dreaded complications, particularly in the pediatric population. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT). Multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors. <h3>Materials/Methods</h3> A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs protons. <h3>Results</h3> Twenty-four studies (21 with conventional RT and 4 with PBT) were included for meta-analysis after performing the systematic review. A total of 418 SMNs and 645 any secondary neoplasms were seen in 38163 patients overall. The most common secondary neoplasms seen were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), thyroid cancers (4.2%), and basal cell carcinomas (1.3%). The overall median follow-up was 8.8 years (range: 3.3 to 23.2 years), while the median latency to a secondary cancer was 9.8 years (range: 5 to 23 years). The median latency to a secondary cancer for photons and protons was 11.9 years (range: 5 to 23 years) and 5.9 years (range: 5 to 6.7 years), respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1% – 2.6%, I²=94%) with photons and 1.5% (95% CI: 0 - 4.5%, I²=81%) with protons. There was no significant difference among the two subgroups (p = 0.91). Similarly, the pooled incidence of all secondary neoplasms was not different among the two subgroups [photons: 3.6% (95% CI: 2.5% – 4.8%, I²=96%) vs protons: 1.5% (95% CI: 0 – 4.5%, I²=80%); p = 0.21]. <h3>Conclusion</h3> We observed a slightly lower rate of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors, although the difference was not statistically significant. We observed a shorter latency to secondary cancers with proton therapy compared to photon-based radiation, which may be related to secondary neutron exposure. With increasing use of techniques that decrease the irradiated tissue volume outside the clinical target volume, like pencil beam scanning proton therapy and VMAT, further studies with longer follow-up are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.

Machine-Specific Delivery Sequence Model of Compact Superconducting Synchrocyclotron Proton Therapy Systems – A Multi-Institutional Investigation

<h3>Purpose/Objective(s)</h3> Proton pencil beam scanning delivery sequence varies among institutions due to the vendor, machine type, and configuration. However, having a reliable model of delivery time and sequence is critical to maximizing throughput when proton beam time is limited. In this study, we used an experimental approach to build a precise beam delivery time (BDT) and sequence prediction model for a new compact superconducting synchrocyclotron proton system (PTC#1) and compare it with a different institution using an older version of the same system (PTC#2). We investigated treatment efficiency and the interplay effect for the treatment of mobile tumors. <h3>Materials/Methods</h3> The machine delivery log files from PTC#1 were retrospectively analyzed to model beam delivery parameters. We compared the PTC#1 delivery sequence with PTC#2's published machine-specific model using the same type of proton system. A total of twenty clinical beams from head neck, lung, breast, and esophagus treatment sites were used for model comparison. Also, we used a single clinical treatment day to compare treatment efficiency. The interplay effect is evaluated and compared based on these two different delivery sequence models. A digital thoracic 4DCT phantom image set with a rigid target in the right lung was used for the study. Different delivery techniques such as standard delivery (N_vol=1) and volumetric repainting delivery (N_vol=2-5) were simulated. <h3>Results</h3> The results showed PTC#1 has a much faster spot scanning speed than PTC#2 thanks to a new generation of scanning magnets. The spot switching time (SSWT) is 0s within 11.3mm in x-direction and 8 mm in y-direction. Compared to PTC#2, the average SSWT reduces by 94.37%±3.82% (50.76s±35.10s) in PTC#1. PTC#1 also demonstrated improved burst switching transmission efficiency, which reduced burst switching time (BST) by 39.84%±3.64% (6.00s±2.21s) on average. The energy layer switching time (ELST) dominates the PTC#1 delivery time instead of SSWT for PTC#2 (Table). The total BDT was reduced by 54.61%±12.12% (53.45s±34.47s) on average. Based on the single day patient mix, it was estimated that 67 min irradiation time could be saved by upgrading the scanning magnets in PTC#2 (10% daily patient treatment throughput improvement). The results also indicated the interplay effect would be reduced as volumetric repainting number increased. The system in PTC#2 had better target coverage and homogeneity than PTC#1 for=1-3. Their target coverage converges at=5. <h3>Conclusion</h3> A precise machine-specific delivery sequence model is highly recommended in the interplay effect evaluation and clinical decision. It provided the first quantitative analysis of the impact of the new scanning magnets regarding the improvement in the treatment delivery efficiency.

Study of Linear Energy Transfer Effect on Rib Fracture in Breast Patients Receiving Pencil-Beam-Scanning Proton Therapy

<h3>Purpose/Objective(s)</h3> To study the linear energy transfer (LET) effect upon rib fracture (RF) in breast cancer patients treated with pencil-beam scanning proton therapy (PBS) using dose-linear energy transfer volume histogram (DLVH). <h3>Materials/Methods</h3> After IRB approval, we retrospectively identified RF cases detected after workup of chest wall pain or incidentally on imaging in breast cancer patients treated with PBS to the breast/chest wall and regional nodes from 2015-2020. Control patients were selected to match the RF patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year. For all plans, a chest wall was contoured, incorporating ribs and intercostal muscles within the 50% prescription isodose line. Both dose and LET were calculated using a planning tool dose engine. DLVH was generated for each patient, using dose and LET as the two axes. The DLVH index, <i>V</i>(<i>d, l</i>), defined as <i>V</i>(% for normalized volume or cc for absolute volume) of the structure with a dose of at least <i>d</i> Gy[RBE] and an LET of at least <i>l</i> keV/µm, was calculated for all combinations of <i>d</i> and <i>l</i>. Conditional logistic regression model was used to establish the relation of <i>V</i>(<i>d, l</i>) and the observed RF at each combination of <i>d</i> and <i>l</i>. The derived <i>p values</i> constitute a <i>p value</i> map in the 2D dose and LET plane. Concordance and its standard error (se) maps were generated to evaluate the performances for all DLVH indices. A correlation coefficient map was obtained to determine the correlation between the featured DLVH indices. <h3>Results</h3> Eight RF cases were identified, and 16 controls were matched. Of RF patients, seven were treated with post-mastectomy (PMRT) and one was treated with post-lumpectomy radiotherapy. Six RF patients treated with PMRT received a dose of 50 Gy[RBE] in 25 fractions to the chest wall and regional lymph nodes; of these, four received a simultaneous integrated boost (SIB) of 56.25 Gy[RBE] to the chest wall (n=2) or axillary nodes (n=2), and one received a sequential boost of 14 Gy[RBE] in 7 fractions to the chest wall. One RF patient that received PMRT was treated with 40.05 Gy[RBE] in fifteen fractions to the chest wall and regional lymphatics. The post-lumpectomy patient received 50 Gy[RBE] in 25 fractions to the whole breast and regional nodes with a SIB of 56.25 Gy[RBE] to the lumpectomy cavity. Two characteristics correlated with RF (<i>p</i><0.2): 1) Smaller <i>V</i>(50-54 Gy[RBE], 0-4.4keV/µm) of the RF patients with a maximum concordance of 0.813 (se 0.114); 2) Larger <i>V</i>(0-36 Gy[RBE], 5.2-6.8keV/µm) of the RF patients with a maximum concordance of 0.875 (se 0.119) compared with controls. These two features were independent from each other with a weak negative correlation (-0.185). <h3>Conclusion</h3> The increase of high LET in moderate dose regions of the chest wall from constraining the adjacent heart and lung dose during PBS treatment planning may result in increased risk of RF.

Radiation Therapy for Stage IIA/B Seminoma: Modeling Secondary Cancer Risk for Protons and VMAT vs. 3D Photons

<h3>Purpose/Objective(s)</h3> Radiation therapy to the para-aortic and iliac lymph nodes is an effective treatment for stage IIA and appropriately selected stage IIB seminoma patients. However, there are concerns for serious late complications, particularly an increased risk of secondary cancers due to the large areas of normal tissue irradiated. The purpose of this study was to quantify the expected differences in secondary cancer risk for stage II seminomas when evaluating proton pencil-beam scanning (PBS) and volumetric modulated arc therapy (VMAT) compared to conventional AP-PA photon (3D) treatment plans. <h3>Materials/Methods</h3> Five seminoma patients (four stage IIA receiving 30 Gy and one stage IIB receiving 36 Gy) ranging in age from 38 to 48 (mean 41.2) treated at our institution with PBS had two additional plans generated for comparison— one photon VMAT and one photon 3D. Dose differences to critical organs were examined and the risks of second primary cancers in those organs were calculated as the Excess Absolute Risk (EAR), reported in cancers per 10,000 person years, and Lifetime Attributable Risk (LAR), reported in percentage increase in risk, both projected to age 70. <h3>Results</h3> PBS reduced the mean organ dose compared to photons, on average by 60% but ranging from 30%-95% for different organs, except for the spinal cord which received the lowest mean dose with VMAT. PBS also reduced the EAR for all organs, with the greatest reduction for large and small bowel, liver, and stomach. Table 1 shows the average ratio of LAR between PBS, 3D, and VMAT for critical organs in five patients, and this ratio is greater than 1 for all organs for 3D compared to PBS. VMAT plans provide a mean dose reduction to some critical organs compared to 3D, particularly the spinal cord and pancreas, where VMAT also reduces the LAR compared to PBS. However, VMAT increases the low dose bath through other organs, leading to slightly increased LAR for the bladder, liver, and rectum compared to 3D. <h3>Conclusion</h3> The use of protons in stage IIA/B seminoma provides a favorable dose distribution with an expectation that this will transfer into decreased toxicity and reduced secondary cancer risk compared to conventional 3D photons. VMAT is another alternative to conventional 3D photons that provides a reduction in dose to some critical organs and comparable or reduced secondary cancer risk predictions for most organs.

Surgical Resection and Intensity Modulated Proton Therapy for Esthesioneuroblastoma

<h3>Purpose/Objective(s)</h3> Esthesioneuroblastoma (ENB) is a rare locally aggressive neuroendocrine sinonasal malignancy commonly presenting with skull base and intracranial invasion, which is often managed using multimodality therapy with surgery and radiotherapy (RT). Advances in surgical techniques as well as RT have improved outcomes for these complex tumors. Proton therapy has dosimetric advantages over conventional X-ray based approaches and may further improve the therapeutic ratio. We report our early experience with intensity modulated proton therapy (IMPT) in the management of ENB. <h3>Materials/Methods</h3> We retrospectively reviewed treatment records of patients with ENB treated at our center with IMPT from 2015-2021. IMPT was delivered with a 2 to 5 field pencil-beam scanning plan, initially with single-field optimization, then multi-field optimization after 2018. All pathology was internally reviewed. Event outcomes were calculated from date of biopsy to time of locoregional recurrence or death. Survival statistics were calculated using the Kaplan-Meier (KM) method using a scientific 2-D graphing and statistics software. <h3>Results</h3> 15 patients were identified, median age 52 (range 32-78), gender (male 12, female 3), Kadish stage (B – 2; C – 12; D – 1), AJCC T classification (T3 – 3, T4b – 12), 2 had nodal metastasis at diagnosis, Hyams (grade 2 – 10; grade 3-4 – 5). Local disease extent included: anterior cranial fossa – 11, middle cranial fossa – 2, dura – 12, brain parenchyma 1, nasopharynx – 2, orbit – 6. The majority (n=14) were managed with surgical resection followed by postoperative RT, and one underwent primary chemoradiation. Surgery included bifrontal craniotomy + extended endoscopic resection (n=7) and extended endoscopic resection alone (n=7). IMPT was delivered in conventional fractionation (n=12) or hyperfractionated accelerated course (n=3), median dose 68 CGE (range 60-72), neck coverage (n=11). Four received concurrent platinum-based chemotherapy. At median follow up of 20 months (IQR 16-51), 2 patients have died, unrelated to disease progression. Three patients have recurred including 1 local, 1 regional, and 1 distant metastasis (out of field dural metastases). Both patients with locoregional recurrence have undergone surgical salvage and have no evidence of disease. IMPT was well tolerated with expected acute toxicities. One patient developed frontal lobe brain necrosis at 3 years post-treatment managed conservatively, and one underwent functional sinus surgery for sinus obstruction. No de novo high grade visual toxicity was observed. KM 2-year locoregional recurrence-free survival was 83% and OS 88%. <h3>Conclusion</h3> IMPT is feasible in ENB with early outcomes demonstrating excellent local control and favorable toxicity profile in this cohort of patients with very locally advanced disease. IMPT may allow for improved coverage of tumor volumes in close proximity to numerous critical structures. Additional follow up is needed to track long term disease control outcomes and late toxicities.

Microdosimetric investigation for multi-ion therapy by means of silicon on insulator (SOI) microdosimeter

Objective. Ion radiotherapy with protons or carbon ions is one of the most advanced clinical methods for cancer treatment. To further improve the local tumor control, ion radiotherapy using multiple ion species has been investigated. Due to complexity of dose distributions delivered by multi-ion therapy in a tumor, a validation strategy for the planned treatment efficacy must be established that can be potentially used in the quality assurance (QA) protocol for the multi-ion treatment plans. In previous work, we demonstrated that the microdosimetric approach using the silicon on insulator (SOI) microdosimeter is practical for validating cell surviving fraction (SF) of MIA PaCa-2 cells in the independent fields of helium, carbon, oxygen, and neon ion beams. Approach. This paper extends the previous study, and we demonstrate a microdosimetry based approach as a pilot study to build the QA protocol in the multi-ion therapy predicting the cell SF along the spread-out Bragg peak obtained by combined irradiations of He+O and C+Ne ions. Across the study, the SOI microdosimeter system MicroPlus was used for measurement of the lineal energy in individual ion fields followed by deriving the lineal energy of combined ion fields delivered by a pencil beam scanning system at HIMAC. Main results. The predicted cell SF based on derived lineal energy and dose in the combined fields was in good agreement with the planned cell SF by our in-house treatment planning system. Significance. The presented results indicated the potential benefit of the SOI microdosimeter system MicroPlus as the QA system in the multi-ion radiotherapy.

Technical note: Investigation of dose and LETd effect to rectum and bladder by using non-straight laterals in prostate cancer receiving proton therapy.

Parallel-opposed lateral beams are the conventional beam arrangements in proton therapy for prostate cancer. However, when considering linear energy transfer (LET) and RBE effects, alternative beam arrangements should be investigated. To investigate the dose and dose averaged LET (LETd ) impact of using new beam arrangements rotating beams 5°-15° posteriorly to the laterals in prostate cancer treated with pencil-beam-scanning (PBS) proton therapy. Twenty patients with localized prostate cancer were included in this study. Four proton treatment plans for each patient were generated utilizing 0°, 5°, 10°, and 15° posterior oblique beam pairs relative to parallel-opposed lateral beams. Dose-volume histograms (DVHs) from posterior oblique beams were analyzed. Dose-LETd -volume histogram (DLVH) was employed to study the difference in dose and LETd with each beam arrangement. DLVH indices, , defined as the cumulative absolute volume that has a dose of at least d (Gy[RBE]) and a LETd of at least l (keV/µm), were calculated for both the rectum and bladder to the whole group of patients and two-sub groups with and without hydrogel spacer. These metrics were tested using Wilcoxon signed-rank test. Rotating beam angles from laterals to slightly posterior by 5°-15° reduced high LETd volumes while it increased the dose volume in the rectum and increased LETd in bladders. Beam angles rotated five degrees posteriorly from laterals (i.e., gantry in 95° and 265°) are proposed since they achieved the optimal balance of better LETd sparing and minimal dose increase in the rectum. A reduction of V(50 Gy[RBE], 2.6 keV/µm) from 7.41 to 3.96 cc (p < 0.01), and a slight increase of V(50 Gy[RBE], 0 keV/µm) from 20.1 to 21.6 cc (p < 0.01) were observed for the group without hydrogel spacer. The LETd sparing was less effective for the group with hydrogel spacer, which achieved the reduction of V(50 Gy[RBE], 2.6 keV/µm) from 4.28 to 2.10 cc (p < 0.01). Posterior oblique angle plans improved LETd sparing of the rectum while sacrificing LETd sparing in the bladder in the treatment of prostate cancer with PBS. Beam angle modification from laterals to slightly posterior may be a strategy to redistribute LETd and perhaps reduce rectal toxicity risks in prostate cancer patients treated with PBS. However, the effect is reduced for patients with hydrogel spacer.

Proton Radiation Therapy After Chemotherapy in the Management of Aggressive Mediastinal Non-Hodgkin Lymphomas: A Particle Therapy Cooperative Group Lymphoma Subcommittee Collaboration

PurposeCombined modality therapy with multiagent chemotherapy and radiation therapy is a standard treatment option for aggressive mediastinal non-Hodgkin lymphomas (AMNHLs); however, concerns regarding acute and late radiation toxicities have fueled an effort to use systemic therapy alone. The use of proton therapy (PT) is a promising treatment option, but there are still limited data regarding clinical outcomes with this treatment modality. In this Particle Therapy Cooperative Group lymphoma subcommittee collaboration, we report outcomes of patients with AMNHL treated with pencil-beam scanning PT or double-scatter PT after chemotherapy. Methods and MaterialsThis was a multi-institutional retrospective observational cohort study of patients with AMNHL treated with PT following chemotherapy between 2011 and 2021. Progression-free survival (PFS), local recurrence–free survival (LRFS), and overall survival (OS) rates were estimated with the Kaplan-Meier method. PT toxicity was graded by the Common Terminology Criteria for Adverse Events version 5.0. A 2-tailed paired t test was used for dosimetric comparisons. ResultsTwenty-nine patients were identified. With a median follow-up time of 4.2 years (range, 0.2-8.9 years), the estimated 5-year PFS for all patients was 93%, 5-year LRFS was 96%, and estimated 5-year OS was 87%. Maximum acute grade 1 (G1) toxicities occurred in 18 patients, and 7 patients had maximum G2 toxicities. No G3+ radiation-related toxicities were observed. Average mean lung dose and lung V20 Gy were lower for patients treated with pencil-beam scanning PT compared with double-scatter PT (P = .016 and .006, respectively), while patients with lower mediastinal disease had higher doses for all evaluated dosimetric heart parameters. ConclusionsPT after chemotherapy for patients with AMNHL resulted in excellent outcomes with respect to 5-year PFS, LRFS, and OS without high-grade toxicities. Future work with larger sample sizes is warranted to further elucidate the role of PT in the treatment of AMNHL.

P091: Early analysis of the PRO-Hodgkin study: Clinical investigation of pencil beam scanning proton treatment in Hodgkin lymphoma patients

P091: Early analysis of the PRO-Hodgkin study: Clinical investigation of pencil beam scanning proton treatment in Hodgkin lymphoma patients

Advanced pencil beam scanning Bragg peak FLASH-RT delivery technique can enhance lung cancer planning treatment outcomes compared to conventional multiple-energy proton PBS techniques

To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application. Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensity-modulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V40Gy/s) were calculated as a metric of the FLASH-sparing effect. For higher dose thresholds, the Bragg peak plans achieved greater V40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were>5Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D2%(%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p<0.01) and that of Bragg peak 1200 MU plans of 115.95% (p<0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p>0.05). Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques.

Pencil beam scanning proton FLASH maintains tumor control while normal tissue damage is reduced in a mouse model.

Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model. Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63Gy/s field dose rate, 244MeV) or FLASH (71-89Gy/s field dose rate, 250MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25days post irradiation, and radiation induced fibrosis (RIF) within 24weeks post irradiation. TCD50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD50 (dose for 50% of mice displaying moist desquamation) of <40.1Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14). FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis.

Commentary on the article: Sørensen BS et al., Pencil beam scanning proton FLASH maintains tumor control while normal tissue damage is reduced in a mouse model.

FLASH radiotherapy, in which radiation doses are delivered with ultrahigh dose rate, receives increasing attention, with the numbers of publications exponentially increasing since 2019. So far, the majority of the studies have investigated the FLASH normal tissue sparing effect. However, a solid biological [1] and physical [2] explanation is currently lacking. Furthermore, FLASH radiotherapy seems to have isotoxic effects on tumors, although based only on tumor regrowth and mouse survival data. Sørensen et al, investigated the effects of FLASH radiotherapy in C3H mouse mammary carcinoma bearing CDF1 mice, with tumor efficacy and normal tissue sparing as read-outs [3].

3D Proton Bragg Peak Visualization and Spot Shape Measurement with Polymer Gel Dosimeters

Proton pencil beam scanning is a dynamic beam delivery technique with excellent conformability to the tumor volume. The accuracy of spot size and scanning positions will have a significant effect on the delivered dose distribution. We employed polymer gel dosimeters to measure the spot size and the scanning positions for the Shanghai Advanced Proton Therapy facility (SAPT). Polymer gel dosimeters (MAGAT-f and PAGAT) were utilized to measure the full width at half maximum (FWHM) of the beam spot at various depths on the basis of their MRI readouts. The correlation between the spot FWHM and standard deviation (σ) was analyzed at different depths. The measured Bragg peak range was compared with the Monte Carlo (MC) simulation. Three-dimensional volume rendering of the Bragg peak was reconstructed for the 3D visualization to measure the spot size three-dimensionally. The R2 dose–response curve was investigated with polymer gel dosimeters. The deviations of the Bragg peak ranging between measurement and simulation were 0.13% and −0.53% for MAGAT-f and PAGAT, respectively. Our results ascertain the feasibility of a polymer gel dosimeter to measure the spot size and positions of a proton pencil beam.

Automated clinical decision support system with deep learning dose prediction and NTCP models to evaluate treatment complications in patients with esophageal cancer

Background and purposeThis study aims to investigate how accurate our deep learning (DL) dose prediction models for intensity modulated radiotherapy (IMRT) and pencil beam scanning (PBS) treatments, when chained with normal tissue complication probability (NTCP) models, are at identifying esophageal cancer patients who are at high risk of toxicity and should be switched to proton therapy (PT). Materials and methodsTwo U-Net were created, for photon (XT) and proton (PT) plans, respectively. To estimate the dose distribution for each patient, they were trained on a database of 40 uniformly planned patients using cross validation and a circulating test set. These models were combined with a NTCP model for postoperative pulmonary complications. The NTCP model used the mean lung dose, age, histology type, and body mass index as predicting variables. The treatment choice is then done by using a ΔNTCP threshold between XT and PT plans. Patients with ΔNTCP ≥ 10% were referred to PT. ResultsOur DL models succeed in predicting dose distributions with a mean error on the mean dose to the lungs (MLD) of 1.14 ± 0.93% for XT and 0.66 ± 0.48% for PT. The complete automated workflow (DL chained with NTCP) achieved 100% accuracy in patient referral. The average residual (ΔNTCP ground truth - ΔNTCP predicted) is 1.43 ± 1.49%. ConclusionThis study evaluates our DL dose prediction models in a broader patient referral context and demonstrates their ability to support clinical decisions.

Analysis of the Results of Proton Radiation Therapy of Patients with Squamous Cell Carcinoma of the Head and Neck

Purpose: To evaluate the severity of early radiation reactions and the first results of proton therapy treatment of patients with squamous cell carcinoma of the head and neck. Material and methods: From January 2019 to March 2022, more than 1 400 patients received proton therapy on the proton-cyclotron complex ProteusPlus235. The search for patients was carried out in the database of patients who received proton radiation therapy for oncological diseases in the FMBA system of Russia. The study included 62 patients with confirmed squamous cell carcinoma and the unifying model was: proton therapy in the mode of five-day fractionation of SFD 2 Gr, TFD 50 Gy for locoregional lymphatic collector zones and TFD 60–70 Gy for the area of the primary tumor focus and high-risk zones. The age group is from 18 to 78 years. According to the classification of ICD10 — 35 patients were diagnosed with C00–C14 “Malignant neoplasms of the lip, oral cavity and pharynx” (56,4 %), 27 patients with C30–C32 “Malignant neoplasms of the upper respiratory organs” (43,5 %). Results: The assessment of long-term treatment results and the severity of radiation complications requires a systematic and uniform approach and is the subject of further research, along with the development of optimal patient models for treatment by proton pencil-beam scanning therapy. Conclusions: Proton beam and proton chemoradiotherapy have demonstrated decreasing trends or comparable frequency and severity of radiation reactions compared to photon therapy. In this regard, the decision to choose a treatment method should be based on an assessment of clinical efficacy, relapse-free and event-free survival, which is the subject of further scientific research.