Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field.

BACKGROUND: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. METHODS: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997-2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test. RESULTS: Median follow-up was 7.0 years (range: 0.01-22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06-5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19-0.94, p = 0.035) had lower risk of LRR. CONCLUSIONS: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review.

PURPOSE: Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. METHODS AND MATERIALS: A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. RESULTS: Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy-1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. CONCLUSIONS: This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

Rapid Interval Recurrence of Glioblastoma Following Gross Total Resection: A Possible Indication for GammaTileⓇ Brachytherapy.

Glioblastoma recurrence between initial resection and standard-of-care adjuvant chemoradiotherapy (CRT) is a negative prognostic factor in an already highly aggressive disease. Re-resection with GammaTileⓇ(GT Medical Technologies Inc., Tempe, AZ) placement affords expedited adjuvant radiation to mitigate the likelihood of such growth. Here, we report a glioblastoma patient who underwent re-resection and GammaTileⓇ (GT) placement within two months of the initial gross total resection due to regrowth that reached the size of the original presenting tumor. The patient subsequently received concurrent temozolomide and 60 Gy external beam to regions outside of the brachytherapy range, fulfilling the generally accepted Stupp regimen. The patient tolerated the treatment without complication. The dosimetrics and implications of the case presentation are reviewed.

Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death.

PURPOSE: To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS. RESULTS: Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated. CONCLUSIONS: In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS.

Receipt of brachytherapy is an independent predictor of survival in glioblastoma in the Surveillance, Epidemiology, and End Results database.

INTRODUCTION: There has been a resurgence of interest in brachytherapy as a treatment for glioblastoma, with several currently ongoing clinical trials. To provide a foundation for the analysis of these trials, we analyze the Surveillance, Epidemiology, and End Results (SEER) database to determine whether receipt of brachytherapy conveys a survival benefit independent of traditional prognostic factors. MATERIALS AND METHODS: We identified 60,456 glioblastoma patients, of whom 362 underwent brachytherapy. We grouped patients based on receipt of brachytherapy and compared clinical and demographic variables between groups using Student's t-test and Pearson's chi-squared test. We assessed survival using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Median overall survival was 16 months in patients who received brachytherapy compared to 9 months in those who did not (log-rank p < 0.001). Patients who underwent brachytherapy tended to be younger (p < 0.001), suffered from smaller tumors (< 4 cm, p < 0.001), and were more likely to have undergone gross total resection (GTR, p < 0.001). In univariable Cox models, these variables were independently associated with improved overall survival. Additionally, improved survival was associated with known receipt of chemotherapy (HR 0.459, p < 0.001), external beam radiation (HR 0.447, p < 0.001), and brachytherapy (HR 0.637, p < 0.001). The association between brachytherapy and improved survival remained robust (HR 0.859, p = 0.031) in a multivariable model that adjusted for patient age, tumor size, tumor location, GTR, receipt of chemotherapy, and receipt of external beam radiation. CONCLUSION: Our SEER analysis indicates that brachytherapy is associated with improved survival in glioblastoma after controlling for age, tumor size/location, extent of resection, chemotherapy, and external beam radiation.

Reoxygenation and Repopulation of Tumor Cells after Ablative Hypofractionated Radiotherapy (SBRT and SRS) in Murine Tumors.

In this work, we investigated the change in tumor microenvironment caused by semi-ablative high-dose irradiation and its implication on tumor cell survival, reoxygenation of hypoxic cells and repopulation in FSaII tumors grown subcutaneously in the hind legs of C3H mice. Tumors were exposed to 10-30 Gy of X-ray radiation in a single exposure, and the vascularity and blood perfusion were assessed based on the levels of CD31 expression and Hoechst 33342 perfusion, respectively. The tumor hypoxia was assessed by staining for pimonidazole adduct formation and the expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9). Tumor cell survival was determined using in vivo-in vitro excision assay method. The proportion of hypoxic cells in the tumor was determined from the surviving cell fraction in tumors exposed to a test dose under aerobic and hypoxic conditions. Radiation expsoure markedly reduced the functional vascularity and blood perfusion, and profoundly increased the expression of HIF-1α and CA9 pointing to an increase in tumor hypoxia. The overall clonogenic cell survival progressively decreased during 2-5 days postirradiation, most likely due to the radiation-induced vascular dysfunction. In turn, the proportion of surviving hypoxic cells decreased over several days postirradiation, presumably due to reoxygenation of hypoxic cells. The oxygen supplied through small fractions of blood vessels that survived the high-dose exposure, together with a reduction of oxygen consumption due to massive cell death, appeared to be the cause of the reoxygenation of hypoxic cells. The surviving tumor cells then subsequently repopulated. The findings from this study using a murine tumor model suggest that the efficacy of stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) may be significantly improved by allowing an inter-fraction time for reoxygenation while avoiding repopulation.

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: To determine the relationship between dose rate and other factors in the development of idiopathic pneumonia syndrome (IPS) in patients with acute lymphoblastic leukemia or acute myeloid leukemia who are undergoing total body irradiation (TBI)-based myeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT). METHODS AND MATERIALS: From 2006 to 2016, 202 patients with acute leukemia (111 acute lymphoblastic leukemia, 91 acute myeloid leukemia) ranging in age from 1 to 57 years (median, 25 years) underwent allogeneic HCT at University of Minnesota. Pretransplantation conditioning included cyclophosphamide (120 mg/kg) with (68%) or without fludarabine (75 mg/m2) followed by 13.2 Gy TBI given in 8 twice-daily fractions of 1.65 Gy over 4 days. Dose rate varied based on linear accelerator availability and ranged from 8.7 to 19.2 cGy/min. Patients were stratified by receipt of high-dose-rate (HDR; >15 cGy/min; 56%) or low-dose-rate (LDR; ≤15 cGy/min; 44%) TBI for all 8 fractions. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. RESULTS: IPS developed in 42 patients (21%) between 4 and 73 days (median, 16 days) after transplantation. HDR TBI was associated with a higher rate of IPS compared with LDR TBI (29% vs 10%; P < .01). On multiple regression analysis, HDR remained a significant predictor of IPS (hazard ratio, 2.6; 95% confidence interval, 1.2-5.3; P = .01), and this led to inferior 1-year overall survival (60% vs 76%; P = .01) and increased 1-year nonrelapse mortality (28% vs 15%; P = .02). CONCLUSIONS: TBI dose rates ≤15 cGy/min reduce the risk of posttransplantation IPS and improve overall survival. LDR TBI should be strongly considered as an easily implemented parameter to improve the safety of pretransplantation TBI-based conditioning.

Augmenting Total Body Irradiation with a Cranial Boost before Stem Cell Transplantation Protects Against Post-Transplant Central Nervous System Relapse in Acute Lymphoblastic Leukemia.

The purpose of this study was to determine the effect of a pretransplant cranial boost (CB) on post-transplant central nervous system (CNS) relapse and survival in acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using a total body irradiation (TBI)-containing preparation regimen. Two hundred thirteen ALL patients were treated consecutively at our institution with allogeneic HSCT. Conditioning included TBI (1320 cGy in 8 fractions given twice daily) and cyclophosphamide (120 mg/kg) with or without fludarabine (75 mg/m2). Patients were divided into 4 groups based on history of CNS disease and whether a CB was given. Of the 160 patients with no history of CNS disease, none received a CB (CNS-/CB-). Of the 53 patients with prior CNS disease, 41 had not received prior cranial irradiation. Thirty of these 41 received a CB of 900 to 1000 cGy in 5 daily fractions (CNS+/CB+), whereas the other 11 did not receive a CB because of physician preference (CNS+/CB-). The remaining 12 patients with prior CNS involvement had previously received cranial irradiation and thus were not candidates for a CB (CNS + PriorRT). Two-year CNS relapse risk, overall survival (OS), and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Seven patients experienced post-transplant CNS relapse: 4 in the CNS-/CB- group, 2 in the CNS+/CB- group, and 1 in the CNS + PriorRT group. None of the 30 patients who received a CB relapsed in the CNS. Two-year CNS relapse risk was 0% in the CNS+/CB+ group compared with 21% (95% CI, 0% to 45%) in the CNS+/CB- group (P = .03). Two-year OS and DFS did not differ between the groups. In conclusion, among ALL patients with prior CNS leukemia, there was a trend toward a reduced risk of post-transplant CNS relapse in patients who received a CB. However, the addition of a CB did not appear to have an impact on OS or DFS.

Consolidative Radiotherapy After Autologous Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B-cell Lymphoma.

INTRODUCTION: We evaluated the role of consolidative radiotherapy (RT) for patients undergoing high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: We reviewed the medical records of 72 consecutive patients who had undergone ASCT for relapsed or refractory DLBCL at our institution from 2006 to 2014. Pretransplant conditioning consisted of HDC and total body irradiation. Of the 72 patients, 13 received post-transplant consolidative RT at the discretion of the consulted radiation oncologist. RESULTS: Consolidative RT was associated with significantly improved 2-year locoregional control (LRC) (92% vs. 68%; P = .04). However, no difference was seen in either the 2-year progression-free survival (PFS) (69% vs. 54%; P = .25) or overall survival (OS) (85% vs. 59%; P = .44). Analysis of the subgroup of 19 patients with persistent residual masses ≥ 2 cm on post-transplant imaging demonstrated a significant improvement in LRC (100% vs. 36%; P < .01), PFS (88% vs. 27%; P = .01), and OS (100% vs. 45%; P = .02) with consolidative RT. CONCLUSION: The use of consolidative RT after HDC and ASCT for relapsed or refractory DLBCL appears to significantly improve LRC. For patients with masses ≥ 2 cm after ASCT, improved 2-year PFS and OS were seen. Prospective trials are needed to further identify the patients who would derive the most benefit from consolidative RT in the ASCT setting.

Role of Consolidative Radiation Therapy After Autologous Hematopoietic Cell Transplantation for the Treatment of Relapsed or Refractory Hodgkin Lymphoma.

PURPOSE: To evaluate the role of the addition of consolidative radiation therapy after high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) for relapsed or refractory Hodgkin lymphoma (HL). METHODS AND MATERIALS: Medical records were reviewed from a total of 80 consecutive patients who underwent high-dose chemotherapy with AHCT treated under a single protocol at University of Minnesota between November 2005 and January 2014. Of these, 32 patients received radiation therapy after AHCT as planned consolidation. RESULTS: At a median follow-up of 25 months, the 2-year overall survival (OS) and progression-free survival (PFS) for the entire cohort was 96% and 52%, respectively. Consolidative radiation therapy was found to significantly improve the 2-year PFS (67% vs 42%, P<.01) without a significant change in OS (100% vs 93%, P=.15). On subgroup analysis, consolidative radiation therapy was shown to improve PFS in patients with bulky disease (62% vs 39%, P=.02), B-symptoms (48% vs 28%, P=.05), primary refractory disease (47% vs 32%, P=.02), and those with a partial response on pretransplant imaging (47% vs 32%, P=.02). The improvement seen on 2-year PFS with consolidative radiation therapy remained significant on multivariate analysis (hazard ratio 4.64, 95% confidence interval 1.98-10.88). Minimal toxicity was observed among the patients receiving radiation therapy. CONCLUSIONS: The addition of consolidative radiation therapy after high-dose chemotherapy and AHCT demonstrated a significant improvement in 2-year PFS and no impact on OS. Radiation therapy was well tolerated, with minimal toxicity. Our study supports a role of consolidative radiation therapy in patients with HL treated with AHCT.

Fast Megavoltage Computed Tomography: A Rapid Imaging Method for Total Body or Marrow Irradiation in Helical Tomotherapy.

PURPOSE: Megavoltage computed tomographic (MVCT) imaging has been widely used for the 3-dimensional (3-D) setup of patients treated with helical tomotherapy (HT). One drawback of MVCT is its very long imaging time, the result of slow couch speeds of approximately 1 mm/s, which can be difficult for the patient to tolerate. We sought to develop an MVCT imaging method allowing faster couch speeds and to assess its accuracy for image guidance for HT. METHODS AND MATERIALS: Three cadavers were scanned 4 times with couch speeds of 1, 2, 3, and 4 mm/s. The resulting MVCT images were reconstructed using an iterative reconstruction (IR) algorithm with a penalty term of total variation and with a conventional filtered back projection (FBP) algorithm. The MVCT images were registered with kilovoltage CT images, and the registration errors from the 2 reconstruction algorithms were compared. This fast MVCT imaging was tested in 3 cases of total marrow irradiation as a clinical trial. RESULTS: The 3-D registration errors of the MVCT images reconstructed with the IR algorithm were smaller than the errors of images reconstructed with the FBP algorithm at fast couch speeds (2, 3, 4 mm/s). The scan time and imaging dose at a speed of 4 mm/s were reduced to 30% of those from a conventional coarse mode scan. For the patient imaging, faster MVCT (3 mm/s couch speed) scanning reduced the imaging time and still generated images useful for anatomic registration. CONCLUSIONS: Fast MVCT with the IR algorithm is clinically feasible for large 3-D target localization, which may reduce the overall time for the treatment procedure. This technique may also be useful for calculating daily dose distributions or organ motion analyses in HT treatment over a wide area. Automated integration of this imaging is at least needed to further assess its clinical benefits.

BRAF Mutation Is Associated with Improved Local Control of Melanoma Brain Metastases Treated with Gamma Knife Radiosurgery.

OBJECTIVES: Evidence has implicated a possible role of tumor mutation status on local control (LC) with radiotherapy. BRAF is a proto-oncogene that is mutated in approximately 50% of patients with melanoma. We sought to analyze the influence of BRAF status on LC of melanoma brain metastases (MBM) following Gamma Knife radiosurgery (GK). METHODS: Among 125 patients treated with GK for MBM at our institution between 2006 and 2015, we identified 19 patients with 69 evaluable metastases whose BRAF mutation status was known and follow-up imaging was available. LC of individual metastases was compared based on BRAF mutation status using statistical techniques to control for measurements of multiple metastases within each patient. CNS progression was defined as either local failure or development of new lesions. RESULTS: Of the 69 metastases, BRAF was mutated in 30 and wild-type in 39. With a median follow-up of 30 months for all patients and a median follow-up of 5.5 months for treated lesions, 1-year LC was significantly better among metastases with mutated vs. wild-type BRAF (69 vs. 34%, RR = 0.3, 95% CI = 0.1-0.7, p = 0.01). BRAF mutation was found to be a significant predictor of LC after stereotactic radiosurgery (SRS) in both univariate [RR = 0.3 (95% CI 0.1-0.7, p = 0.01)] and multivariate [RR = 0.2 (95% CI 0.1-0.7, p = 0.01)] analyses. There was also a trend toward improved CNS progression free survival (PFS) at 1 year (26 vs. 0%, p = 0.06), favoring BRAF-mutated patients. CONCLUSION: In this retrospective study, MBM treated with GK had significantly improved LC for patients with BRAF mutation vs. wild-type. Our data suggest that BRAF mutation may sensitize tumors to radiosurgery, and that BRAF wild-type tumors may be more radioresistant.

Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery.

PURPOSE: The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo--in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. RESULTS: After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. CONCLUSIONS: Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.

Alternative donor hematopoietic cell transplantation for Fanconi anemia.

Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell-depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976.

Multi-institutional feasibility study of a fast patient localization method in total marrow irradiation with helical tomotherapy: a global health initiative by the international consortium of total marrow irradiation.

PURPOSE: To develop, characterize, and implement a fast patient localization method for total marrow irradiation. METHODS AND MATERIALS: Topographic images were acquired using megavoltage computed tomography (MVCT) detector data by delivering static orthogonal beams while the couch traversed through the gantry. Geometric and detector response corrections were performed to generate a megavoltage topogram (MVtopo). We also generated kilovoltage topograms (kVtopo) from the projection data of 3-dimensional CT images to reproduce the same geometry as helical tomotherapy. The MVtopo imaging dose and the optimal image acquisition parameters were investigated. A multi-institutional phantom study was performed to verify the image registration uncertainty. Forty-five MVtopo images were acquired and analyzed with in-house image registration software. RESULTS: The smallest jaw size (front and backup jaws of 0) provided the best image contrast and longitudinal resolution. Couch velocity did not affect the image quality or geometric accuracy. The MVtopo dose was less than the MVCT dose. The image registration uncertainty from the multi-institutional study was within 2.8 mm. In patient localization, the differences in calculated couch shift between the registration with MVtopo-kVtopo and MVCT-kVCT images in lateral, cranial-caudal, and vertical directions were 2.2 ± 1.7 mm, 2.6 ± 1.4 mm, and 2.7 ± 1.1 mm, respectively. The imaging time in MVtopo acquisition at the couch speed of 3 cm/s was <1 minute, compared with ≥15 minutes in MVCT for all patients. CONCLUSION: Whole-body MVtopo imaging could be an effective alternative to time-consuming MVCT for total marrow irradiation patient localization.

Effect of lung and target density on small-field dose coverage and PTV definition.

We have studied the effect of target and lung density on block margin for small stereotactic body radiotherapy (SBRT) targets. A phantom (50 × 50 × 50cm(3)) was created in the Pinnacle (V9.2) planning system with a 23-cm diameter lung region of interest insert. Diameter targets of 1.6, 2.0, 3.0, and 4.0cm were placed in the lung region of interest and centered at a physical depth of 15cm. Target densities evaluated were 0.1 to 1.0g/cm(3), whereas the surrounding lung density was varied between 0.05 and 0.6g/cm(3). A dose of 100cGy was delivered to the isocenter via a single 6-MV field, and the ratio of the average dose to points defining the lateral edges of the target to the isocenter dose was recorded for each combination. Field margins were varied from none to 1.5cm in 0.25-cm steps. Data obtained in the phantom study were used to predict planning treatment volume (PTV) margins that would match the clinical PTV and isodose prescription for a clinical set of 39 SBRT cases. The average internal target volume (ITV) density was 0.73 ± 0.17, average local lung density was 0.33 ± 0.16, and average ITV diameter was 2.16 ± 0.8cm. The phantom results initially underpredicted PTV margins by 0.35cm. With this offset included in the model, the ratio of predicted-to-clinical PTVs was 1.05 ± 0.32. For a given target and lung density, it was found that treatment margin was insensitive to target diameter, except for the smallest (1.6-cm diameter) target, for which the treatment margin was more sensitive to density changes than the larger targets. We have developed a graphical relationship for block margin as a function of target and lung density, which should save time in the planning phase by shortening the design of PTV margins that can satisfy Radiation Therapy Oncology Group mandated treatment volume ratios.

Patient specific 3D printed phantom for IMRT quality assurance.

The purpose of this study was to test the feasibility of a patient specific phantom for patient specific dosimetric verification.Using the head and neck region of an anthropomorphic phantom as a substitute for an actual patient, a soft-tissue equivalent model was constructed with the use of a 3D printer. Calculated and measured dose in the anthropomorphic phantom and the 3D printed phantom was compared for a parallel-opposed head and neck field geometry to establish tissue equivalence. A nine-field IMRT plan was constructed and dose verification measurements were performed for the 3D printed phantom as well as traditional standard phantoms.The maximum difference in calculated dose was 1.8% for the parallel-opposed configuration. Passing rates of various dosimetric parameters were compared for the IMRT plan measurements; the 3D printed phantom results showed greater disagreement at superficial depths than other methods.A custom phantom was created using a 3D printer. It was determined that the use of patient specific phantoms to perform dosimetric verification and estimate the dose in the patient is feasible. In addition, end-to-end testing on a per-patient basis was possible with the 3D printed phantom. Further refinement of the phantom construction process is needed for routine use.

Peripheral dose heterogeneity due to the thread effect in total marrow irradiation with helical tomotherapy.

PURPOSE: To report potential dose heterogeneity leading to underdosing at different skeletal sites in total marrow irradiation (TMI) with helical tomotherapy due to the thread effect and provide possible solutions to reduce this effect. METHODS AND MATERIALS: Nine cases were divided into 2 groups based on patient size, defined as maximum left-to-right arm distance (mLRD): small mLRD (≤47 cm) and large mLRD (>47 cm). TMI treatment planning was conducted by varying the pitch and modulation factor while a jaw size (5 cm) was kept fixed. Ripple amplitude, defined as the peak-to-trough dose relative to the average dose due to the thread effect, and the dose-volume histogram (DVH) parameters for 9 cases with various mLRD was analyzed in different skeletal regions at off-axis (eg, bones of the arm or femur), at the central axis (eg, vertebrae), and planning target volume (PTV), defined as the entire skeleton plus 1-cm margin. RESULTS: Average ripple amplitude for a pitch of 0.430, known as one of the magic pitches that reduce thread effect, was 9.2% at 20 cm off-axis. No significant differences in DVH parameters of PTV, vertebrae, or femur were observed between small and large mLRD groups for a pitch of ≤0.287. Conversely, in the bones of the arm, average differences in the volume receiving 95% and 107% dose (V95 and V107, respectively) between large and small mLRD groups were 4.2% (P=.016) and 16% (P=.016), respectively. Strong correlations were found between mLRD and ripple amplitude (rs=.965), mLRD and V95 (rs=-.742), and mLRD and V107 (rs=.870) of bones of the arm. CONCLUSIONS: Thread effect significantly influences DVH parameters in the bones of the arm for large mLRD patients. By implementing a favorable pitch value and adjusting arm position, peripheral dose heterogeneity could be reduced.