The Applications and Pitfalls of Cone-Beam Computed Tomography-Based Synthetic Computed Tomography for Adaptive Evaluation in Pencil-Beam Scanning Proton Therapy.

PURPOSE: The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. METHODS: Seven common treatment sites were studied. Two sets of sCT per case were generated: direct-deformed (DD) sCT and image-correction (IC) sCT. The image qualities and dosimetric impact of the sCT were compared to the same-day vCT. RESULTS: The sCT agreed with vCT in regions of homogeneous tissues such as the brain and breast; however, notable discrepancies were observed in the thorax and abdomen. The sCT outliers existed for DD sCT when there was an anatomy change and for IC sCT in low-density regions. The target coverage exhibited less than a 5% variance in most DD and IC sCT cases when compared to vCT. The Dmax of serial organ-at-risk (OAR) in sCT plans shows greater deviation from vCT than small-volume dose metrics (D0.1cc). The parallel OAR volumetric and mean doses remained consistent, with average deviations below 1.5%. CONCLUSION: The use of sCT enables precise treatment and prompt early adaptation for proton therapy. The quality assurance of sCT is mandatory in the early stage of clinical implementation.

Dose rate and dose robustness for proton transmission FLASH-RT treatment in lung cancer.

Purposes: To evaluate the plan quality and robustness of both dose and dose rate of proton pencil beam scanning (PBS) transmission FLASH delivery in lung cancer treatment. Methods and materials: An in-house FLASH planning platform was used to optimize 10 lung cancer patients previously consecutively treated with proton stereotactic body radiation therapy (SBRT) to receive 3 and 5 transmission beams (Trx-3fds and Trx-5fds, respectively) to 34 Gy in a single fraction. Perturbation scenarios (n=12) for setup and range uncertainties (5 mm and 3.5%) were introduced, and dose-volume histogram and dose-rate-volume histogram bands were generated. Conventional proton SBRT clinical plans were used as a reference. RTOG 0915 dose metrics and 40 Gy/s dose rate coverage (V40Gy/s) were used to assess the dose and dose rate robustness. Results: Trx-5fds yields a comparable iCTV D2% of 105.3%, whereas Trx-3fds resulted in inferior D2% of 111.9% to the clinical SBRT plans with D2% of 105.6% (p<0.05). Both Trx-5fds and Trx-3fds plans had slightly worse dose metrics to organs at risk than SBRT plans. Trx-5fds achieved superior dosimetry robustness for iCTV, esophagus, and spinal cord doses than both Trx-3fds and conventional SBRT plans. There was no significant difference in dose rate robustness for V40Gy/s coverage between Trx-3fds and Trx-5fds. Dose rate distribution has similar distributions to the dose when perturbation exists. Conclusion: Transmission plans yield overall modestly inferior plan quality compared to the conventional proton SBRT plans but provide improved robustness and the potential for a toxicity-sparing FLASH effect. By using more beams (5- versus 3-field), both dose and dose rate robustness for transmission plans can be achieved.

Applications of various range shifters for proton pencil beam scanning radiotherapy.

BACKGROUND: A range pull-back device, such as a machine-related range shifter (MRS) or a universal patient-related range shifter (UPRS), is needed in pencil beam scanning technique to treat shallow tumors. METHODS: Three UPRS made by QFix (Avondale, PA, USA) allow treating targets across the body: U-shaped bolus (UB), anterior lateral bolus (ALB), and couch top bolus. Head-and-neck (HN) patients who used the UPRS were tested. The in-air spot sizes were measured and compared in this study at air gaps: 6 cm, 16 cm, and 26 cm. Measurements were performed in a solid water phantom using a single-field optimization pencil beam scanning field with the ALB placed at 0, 10, and 20 cm air gaps. The two-dimensional dose maps at the middle of the spread-out Bragg peak were measured using ion chamber array MatriXX PT (IBA-Dosimetry, Schwarzenbruck, Germany) located at isocenter and compared with the treatment planning system. RESULTS: A UPRS can be consistently placed close to the patient and maintains a relatively small spot size resulting in improved dose distributions. However, when a UPRS is non-removable (e.g. thick couch top), the quality of volumetric imaging is degraded due to their high Z material construction, hindering the value of Image-Guided Radiation Therapy (IGRT). Limitations of using UPRS with small air gaps include reduced couch weight limit, potential collision with patient or immobilization devices, and challenges using non-coplanar fields with certain UPRS. Our experience showed the combination of a U-shaped bolus exclusively for an HN target and an MRS as the complimentary device for head-and-neck targets as well as for all other treatment sites may be ideal to preserve the dosimetric advantages of pencil beam scanning proton treatments across the body. CONCLUSION: We have described how to implement UPRS and MRS for various clinical indications using the PBS technique, and comprehensively reviewed the advantage and disadvantages of UPRS and MRS. We recommend the removable UB only to be employed for the brain and HN treatments while an automated MRS is used for all proton beams that require RS but not convenient or feasible to use UB.

Proton Therapy Reduces Normal Tissue Dose in Extended-Field Pelvic Radiation for Endometrial Cancer.

PURPOSE: We dosimetrically compared pencil beam scanning (PBS) proton therapy and intensity-modulated radiation therapy (IMRT) for pelvic and para-aortic lymph node disease in endometrial carcinoma and present acute toxicities associated with extended-field PBS. PATIENTS AND METHODS: Twenty-five patients with locally advanced endometrial malignancies were enrolled in an image-guided registry study. Seven of these patients were treated with PBS, and 18 patients were treated with IMRT. Organs at risk included pelvic bone marrow (PBM), small bowel (SB), large bowel (LB), rectum, bladder, and kidneys. The IMRT and PBS dosimetric parameters were compared using Wilcoxon rank-sum tests. RESULTS: Compared with IMRT PBM dose-volume histograms, PBS resulted in significantly lower dose volumes from 0 to 26.0 Gy (P < .05) and higher dose volumes from 33.9 to 42.9 Gy (P < .05). Overall, PBS resulted in 22% lower median PBM volume irradiated to 10 Gy (RBE) (PBS 71.3% versus IMRT 93.4%, P < .001) and 14% lower median volume irradiated to 20 Gy (RBE) (PBS 65.1% versus IMRT 79.4%, P < .001). Compared with IMRT, PBS also significantly reduced SB dose volumes from 0 to 27.5 Gy, LB dose volumes from 0 to 31.6 Gy, bladder dose volumes from 0 to 27.3 Gy, and rectal dose volumes from 0 to 7.6 Gy (all P < .05). However, PBS resulted in higher rectal dose volumes compared with IMRT from 26.0 to 48.4 Gy. Grade 3+ hematologic toxicities were present in 2 (11%) IMRT-treated patients and no PBS-treated patients. No grade 3+ gastrointestinal or genitourinary toxicities were present in either treatment group. CONCLUSION: In endometrial carcinoma, extended-field PBS is clinically feasible, resulting in statistically significant dose reduction to PBM as well as SB, LB, and bladder in the lower dose regions.

Bag and loop small bowel contouring strategies differentially estimate small bowel dose for post-hysterectomy women receiving pencil beam scanning proton therapy.

Background Small bowel (SB) dose-volume relationships established during initial computed tomography (CT) simulations may change throughout therapy due to organ displacement and motion. We investigated the impact of organ motion on SB dose-volume histograms (DVHs) in women with gynecologic malignancies treated with pencil beam scanning (PBS) proton therapy and compared PBS SB DVHs to intensity-modulated radiation therapy (IMRT). Material and methods Post-hysterectomy patients (n = 11) treated for gynecologic cancers were enrolled on an image-guided proton therapy protocol involving CT simulation with full (CTF) and empty (CTE) bladders and weekly/biweekly on-treatment scans. IMRT plans were generated for comparative analysis. SB was contoured as bowel loops or bowel bag. Wilcoxon signed-rank tests were used for matched-pair comparisons of SB, bladder, and rectum dose-volumes between CT scans and between PBS and IMRT plans. Results In PBS loops analysis, on-treatment DVH was significantly higher than CTF for doses <45 Gy (p < 0.05), and not significantly different than CTE. Specifically, V15 for loops was higher on-treatment (median 240 cm(3)) compared to CTF (median 169 cm(3), p = 0.03). In PBS bag analysis, on-treatment DVH was not significantly different from CTF across all dose ranges. Bowel bag V45 was not significantly different between on-treatment (median 540 cm(3)) and CTF (median 499 cm(3), p = 0.53). Decreasing bladder volume was associated with increasing V15 for loops and V45 for bowel bag (p < 0.005, both). Comparing PBS and IMRT, PBS resulted in significantly lower DVHs at low dose regions (<38 Gy) and higher DVHs at high dose regions (42.5-45.5 Gy) in both loops and bag analysis. IMRT plans demonstrated higher on-treatment SB loop DVHs and only minimal differences in bowel bag DVHs compared to CTF. Conclusions SB DVHs were well estimated by CTF bowel bag and underestimated by CTF loops in the setting of inconsistent bladder filling. Verifying bladder filling prior to treatment or using CTE for planning may more conservatively estimate SB dose-volume relationships.

Pencil-beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity-modulated radiotherapy.

BACKGROUND: Concurrent chemoradiotherapy cures most patients with anal squamous cell carcinoma at the cost of significant treatment-related toxicities. Intensity-modulated radiotherapy (IMRT) reduces side effects compared to older techniques, but whether proton beam therapy (PBT) offers additional advantages is unclear. MATERIAL AND METHODS: Eight patients treated with PBT for anal cancer were chosen for this study. We conducted detailed plan comparisons between pencil-beam scanning PBT via two posterior oblique fields and seven-field IMRT. Cumulative dose-volume histograms were analyzed by Wilcoxon signed-rank test, and plan delivery robustness was assessed via verification computed tomography (CT) scans obtained during treatment. RESULTS: Compared to IMRT, PBT reduced low dose radiation (≤ 30 Gy) to the small bowel, total pelvic bone marrow, external genitalia, femoral heads, and bladder (all p < 0.05) without compromising target coverage. For PBT versus IMRT, mean small bowel volume receiving ≥ 15 Gy (V15) was 81 versus 151 cm(3), mean external genitalia V20 was 14 versus 40%, and mean total pelvic bone marrow V15 was 66 versus 83% (all p = 0.008). The lumbosacral bone marrow dose was higher with PBT due to beam geometry. PBT was delivered with ≤ 1.3% interfraction deviation in the dose received by 98% of the clinical target volumes. CONCLUSION: Pencil-beam scanning PBT is clinically feasible and can be robustly delivered for anal cancer patients. Compared with IMRT, PBT reduces low dose radiation to important organs at risk in this population. While the clinical benefit of these differences remains to be shown, existing data suggest that limiting low dose to the small bowel and pelvic bone marrow may reduce treatment toxicity.

Comparison of prostate proton treatment planning technique, interfraction robustness, and analysis of single-field treatment feasibility.

BACKGROUND: This study compares target coverage robustness among proton therapy plans for prostate cancer patients treated with 2 laterally opposed fields delivered daily or, alternatively, every other day as single lateral fields, using uniform scanning (US), single-field uniform dose (SFUD), pencil beam scanning (PBS) optimized for uniform target coverage only, SFUD PBS optimized for target coverage and organs at risk (OAR) sparing (SFUD-opt), and intensity modulated proton therapy (IMPT). METHODS AND MATERIALS: Ten prostate cancer patients treated with proton therapy underwent weekly verification computed tomographic (CT) scans. US, SFUD, SFUD-opt, and IMPT treatment plans were created and recalculated on weekly verification scans evaluating 2-field daily and single-field target coverage and OAR constraints. RESULTS: The average (±standard deviation) planning target volume conformity index for US, SFUD, SFUD-opt, and IMPT clinical plans was 0.53 ± 0.06, 0.78 ± 0.05, 0.78 ± 0.04, and 0.78 ± 0.03, respectively. The average 2-field internal target volume (ITV) coverage was significantly higher for both US and SFUD when individually compared with SFUD-opt and IMPT. There was no significant difference between US and SFUD ITV coverage when comparing 2-field daily versus single-field daily delivery. The average single-field coverage was greatest using US and SFUD with 99% of the ITV being covered by 96.8% ± 0.9% and 96.7% ± 1.3%, respectively, compared with 95.5% ± 0.7% for SFUD-opt. There were no significant differences among the 4 plans regarding OAR dose constraints assessed. CONCLUSIONS: Pencil beam scanning techniques are more conformal than US and, when optimized only for uniform target coverage from each field, can be equally as robust relative to anatomic interfraction variations for prostate cancer patients treated with a single field per day technique. The SFUD-opt and IMPT involve highly modulated pencil beam spots and may be less robust to daily interfraction anatomic variations.

A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas.

PURPOSE: Uncontrolled local growth is the cause of death in ∼ 30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk. METHODS: The authors compared DS, PBS, and IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test. RESULTS: Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p < 0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6-53.8 and 34.9-52.4 Gy for duodenum using DS and PBS, respectively; p < 0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (<5% and 10%, respectively; p < 0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning. CONCLUSIONS: Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.

Supine craniospinal irradiation using a proton pencil beam scanning technique without match line changes for field junctions.

PURPOSE: To propose and validate a craniospinal irradiation approach using a proton pencil beam scanning technique that overcomes the complexity of the planning associated with feathering match lines. METHODS AND MATERIALS: Ten craniospinal irradiation patients had treatment planned with gradient dose optimization using the proton pencil beam scanning technique. The robustness of the plans was evaluated by shifting the isocenter of each treatment field by ±3 mm in the longitudinal direction and was compared with the original nonshifted plan with metrics of conformity number, homogeneity index, and maximal cord doses. An anthropomorphic phantom study using film measurements was carried out on a plan with 5-cm junction length. To mimic setup errors in the phantom study, fields were recalculated with isocenter shifts of 1, 3, 5, and 10 mm longitudinally, and compared with the original plans and measurements. RESULTS: Uniform dose coverage to the entire target volumes was achieved using the gradient optimization approach with averaged junction lengths of 6.7 ± 0.5 cm. The average conformity number and homogeneity index equaled 0.78 ± 0.03 and 1.09 ± 0.01, respectively. Setup errors of 3 mm per field (6 mm in worst-case scenario) caused on average 4.6% lower conformity number 2.5% higher homogeneity index and maximal cord dose of 4216.1 ± 98.2 cGy. When the junction length was 5 cm or longer, setup errors of 6 mm resulted in up to 12% dosimetric deviation. Consistent results were reached between film measurements and planned dose profiles in the junction area. CONCLUSIONS: Longitudinal setup errors directly reduce the dosimetric accuracy of the proton craniospinal irradiation treatment with matched proton pencil beam scanning fields. The reported technique creates a slow dose gradient in the junction area, which makes the treatment more robust to longitudinal setup errors compared to conventional feathering methods.

Preserving Fertility in Adolescent Girls and Young Women Requiring Craniospinal Irradiation: A Case Report and Discussion of Options to Be Considered Prior to Treatment.

Craniospinal irradiation (CSI) is associated with infertility risk for adolescent/young adult women. We explore two methods of reducing ovarian exposure: oophoropexy (surgical removal of the ovaries from the path of the X-ray beam) and proton therapy (to allow the beam to stop without exposing the ovaries/uterus). In the case discussed, oophoropexy followed by X-ray CSI reduced ovarian dose to that at which 50% of oocytes are expected to survive, and the patient appears to have viable oocytes; this technique did not reduce uterine dose. Proton therapy would have eliminated the ovarian and uterine dose and the need for oophoropexy.

A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT).

With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as well as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients' average CT. All the plans delivered 50.4Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V18Gy), stomach (mean and V20Gy), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V18Gy), liver (mean dose), total bowel (V20Gy and mean dose), and small bowel (V15Gy absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose escalation and combining with radiosensitizing chemotherapy.

Breast cancer screening for childhood cancer survivors after craniospinal irradiation with protons versus x-rays: a dosimetric analysis and review of the literature.

INTRODUCTION: Screening for secondary malignancies is paramount in the pediatric cancer survivorship population, but the risk of secondary breast cancer after craniospinal radiation has not been well characterized previously. The aim of this study was to examine the dose to the breast from craniospinal irradiation (CSI) delivered with x-ray therapy versus proton beam therapy to contribute to understanding the specific screening needs of this population. METHODS: Six female patients who received CSI with double-scattered proton therapy at the Children's Hospital of Philadelphia were identified. For each patient, photon and proton beam plans were designed in order to compare the radiation dose to the breast. A comprehensive literature review was also performed. RESULTS: The dose to the breast tissues was near zero after proton therapy to the spine [average maximum and mean proton doses were 0.22 and 0.05 Gy(RBE), respectively]. In contrast, after photon treatment to the spine, average maximum and mean photon doses were 23 and 4 Gy, respectively (P<0.0001). CONCLUSIONS: These data suggest that early screening for breast cancer may be unnecessary after CSI with proton beam therapy; however, after x-ray therapy, early breast cancer screening should be considered given doses to the breast that approach the Children's Oncology Group-recommended threshold.

Cloning of the heat shock protein 90 and 70 genes from the beet armyworm, Spodoptera exigua, and expression characteristics in relation to thermal stress and development.

Two full-length cDNAs of heat shock protein (HSP) genes (Se-hsp90 and Se-hsp70) were cloned from the beet armyworm, Spodoptera exigua, and their expression was investigated in relation to cold shock, heat shock, and development. The open reading frames of Se-hsp90 and Se-hsp70 are 2,154 and 2,004 bp in length, encoding polypeptides of 717 and 667 amino acids with a molecular mass of 82.6 and 72.5 kDa, respectively. Both genes showed high similarity to their counterparts in other species. Transcriptional expression profiles revealed that both genes were significantly up-regulated under thermal stress. However, the temperature at which expression level became significantly higher than that of controls varied between genes. Intensity of response to temperature was more intense for Se-hsp70 than for Se-hsp90, regardless of temperature or developmental stage. However, intensities of response to temperature of either Se-hsp90 or Se-hsp70 varied with developmental stage. The basal expression of both genes was highest in young larvae and decreased with age. Translational expression of Se-Hsp70 was observed by using Western blot, the expression profiles of Se-Hsp70 protein were in high agreement with those of Se-hsp70 RNA under heat or cold stress in larvae and pupae. However, it does not completely accord with that of Se-hsp70 RNA expression during development without thermal stress. These results indicated that, in addition to heat shock responses, both Se-hsp90 and Se-hsp70 might be involved in development.