Purpose/Objective(s) A second allogeneic stem cell transplantation (allo-SCT) is an option following relapse after an initial SCT for hematologic malignancies. Conditioning with intensity-modulated total marrow irradiation (IM-TMI) is feasible and shows promise in optimizing the therapeutic ratio. We report on clinical outcomes and to identify IM-TMI dose to the oral cavity that would be associated with lower incidence of mucositis to help guide planning. Materials/Methods We conducted a retrospective analysis of patients undergoing second allo-SCT enrolled between Dec 2015 and Nov 2023 on a phase I dose-escalation trial of IM-TMI with fludarabine and melphalan. TMI doses were given twice daily, 1.5 Gy per fraction with total dose of 6, 9, or 12 Gy. The clinical target volume consisted of bones excluding mandible (except in 1 case), arms and lower extremities mid-femur down. We collected baseline patient and treatment characteristics and performed univariate analysis reported as mean (SD) or median [interquartile range]. Logistic regression (LR) was performed to evaluate potential predictors of oral mucositis incidence at 1 week following allo-SCT. Results Of 31 patients, 18 (58%) were male, predominantly white (83%), with median age of 49 [41, 64]. The mean BMI was 30.62 (22.33) and with a Karnofsky >90 (68%). Majority being treated for AML (74%). Most common disease status at time of 2nd allo-SCT included 1st relapse in 8 (26%) followed by 2nd complete remission in 5 (16.1%), and 3rd complete remission in 4 (13%). TMI dose of 9 Gy was delivered to 15 patients (48%), 12 Gy to 10 (32%), and 6 Gy to 5 (16%). The average dose to the oral cavity was 298.05 cGy (95.7), with the oral cavity receiving on average 32% of the prescribed dose. 16 patients (52%) experienced mucositis within a month following allo-SCT with IM-TMI; 14 occurred within 7 days, half grade 1 and grade 3 toxicities. Pearson correlation showed moderate association between oral cavity dose and mucositis grade at day 7 (r = 0.284). On LR analysis of predictors, the oral cavity mean dose (OR = 1.032) and age (OR = 0.878) were found to be significant predictors of mucositis incidence at day 7 (p = 0.04 and p = 0.03 respectively). In LR model with oral cavity mean dose and age categorized by the median value, an oral cavity mean dose greater than the median of 264.7 cGy was associated with an OR of 44.8 (p = 0.023). 5 of 31 patients (16%) had relapsed, 3 in the bone marrow and 2 with solid masses, at an average of 197 days (77.8) post allo-SCT. At a median follow up of 11 months, 11 patients (36%) were alive. Most common cause of death included persistence/progression of disease in 8 (40%) and infection in 9 patients (45%). Conclusion Our study adds to the evolving literature on the integration of TMI into conditioning regimens for allo-SCT, specifically in the second transplant setting. Given that the oral cavity mean dose and age are significant predictors of mucositis incidence at day 7, caution must be applied in the delivery of TMI to the oral cavity, specifically in this population.

Purpose/Objective(s)Stereotactic body radiotherapy (SBRT) is associated with high rates of metastasis control. However, given the adjacent organs-at-risk (OAR) and observed high rates of airway toxicity in the past, SBRT has historically not been routinely utilized for metastatic mediastinal and hilar lymphadenopathy (MHL). Immunotherapy is increasingly being used in metastatic patients and can cause clinically significant pneumonitis. In order to evaluate the feasibility, safety and efficacy of SBRT to MHL in the setting of immunotherapy, clinical outcomes of patients treated with immune-oncology (IO) agents and SBRT to MHL on three consecutive phase 1 clinical trials at a single institution were reviewed.Materials/MethodsA total of 213 patients with widely metastatic solid tumors were treated with combination multisite SBRT and IO on three consecutive phase 1 trials between 2016 and 2020. All metastases in each patient were not irradiated and metastases > 65 mL were partially irradiated. Those with mediastinal and hilar nodes targeted met eligibility criteria. MHL were prescribed 50 Gy in 5 fractions, but under coverage was allowed in order to prioritize meeting OAR constraints formulated from NRG protocols. IO was administered sequentially (within 7 days after completion of SBRT) or concurrently (before or at the start of SBRT). IO treatments included: pembrolizumab, ipilimumab with nivolumab, urelumab with nivolumab, and cabiralizumab with nivolumab. Endpoints included irradiated tumor control per Response Evaluation Criteria in Solid Tumors version 1.1, overall survival (OS), dosimetric coverage and toxicity per Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier method was used to estimate tumor control and OS.ResultsA total of 55 patients were treated to 89 MHL nodes with 18 patients receiving concurrent IO and 37 patients receiving sequential IO. The most common histologies included non-small cell lung cancer (49%), ovarian cancer (7%) and colon adenocarcinoma (5%). Median follow up was 15 months. Irradiated tumor control was excellent with 0 local failures (# of living patients) at 12 (n = 32), 18 (n = 19) and 24 (n = 13) months. Median OS was 18 months (95% confidence interval, 11-33). Even after prioritizing OAR sparing, dosimetric parameters for the gross tumor volume (GTV) were: mean dose 50.9 Gy, V95 82% and V100 75%. Regarding toxicity, 6 patients (11%) experienced grade 3 pneumonitis and 1 patient (2%) experienced grade 3 esophagitis with no grade 4 or 5 toxicity events.ConclusionIn the largest series of SBRT and immunotherapy for MHL, irradiated tumor control was excellent with acceptable toxicity. By prioritizing OARs during SBRT planning, 50 Gy/5 fraction SBRT to mediastinal and hilar nodes is feasible in the setting of immunotherapy.

In this pooled analysis of three prospective trials, SBRT to abdominal or pelvic lymph node metastases with immunotherapy is associated with acceptable toxicity and high rates of LC, even with target undercoverage to meet OAR constraints. This suggests a potential for this approach in clinical practice and study in future trials.

Liver metastases present at diagnosis in metastatic NSCLC correlate with worse PFS. Treated metastases control rates also correlate with OS. These metrics may help predict outcomes and inform whether additional aggressive therapy is required for patients with metastatic NSCLC.

To report our clinical experience of a dose escalation study using total marrow irradiation (TMI) with volumetric arc therapy (VMAT) as a part of conditioning regimen in a Phase I/II study of patients with hematologic malignancies receiving second allogeneic stem cell transplantation (allo-SCT). From December 2015 to November 2019, eighteen patients with hematologic malignancies undergoing second allo-SCT were treated with Linac based VMAT technique using 6 MV photon. TMI doses were given twice daily, 1.5 Gy per fraction with total dose starting with 6 Gy, 9 Gy and 12 Gy. A CT simulation was obtained from head to mid-femur. The gross target volume (GTV) consists of all bones excluding mandible, arms and lower extremities mid-femur down. A 3 mm margin was added to generate planning target volume (PTV). PTV was divided in 3 sub-targets: head/neck, thorax, and pelvis. One VMAT plan for each sub-target was optimized iteratively utilizing the adjacent plans as the base plans to account for their dose contributions to each other. PTV coverage for head/neck V99%, thorax V95% and pelvis V99% were all at least 95% while global hot spot was kept under 140% of the prescription dose. Across all dose levels, mean doses to brain, heart, lungs, bowel, liver, kidneys, eyes, oral cavity, lenses and body were respectively 63.9, 57.0, 68.3, 53.4, 59.8, 52.5, 40.6, 33.5, 27.7, and 62.1% of the prescription dose. In the 6 patients treated in the 12 Gy cohort, average mean lung dose (MLD) was 7.6 Gy (7.3-8.2 Gy), a dose reduction of 21% as compared to 9.9 Gy, lung toxicity predictor for traditional total body irradiation (TBI) technique. Mucositis is the main concern of the conditioning regimen, and it was capture on day 7, 14, 21 and 28 post-transplant as the main dose limited toxifies. The mean follow-up after TMI was 19 months (range: 2-125 months). The first patient suffered from grade 3 mucositis as DLT at the 9 Gy level, nevertheless, the oral cavity mean dose was only 46% of the prescription dose for that patient. The following 5 patient at level 9 Gy did not have DLT. So far, one of 5 patients at the level 12 Gy suffered from DLT of Grade 3 mucositis, but not other 4 patients, we are enrolling the 6th patient to the level of 12 Gy to define the maximal tolerated dose (MTD). There was no other DLT observed so far during the DLT period. Likely, 12 Gy will be declared as MTD. No lung reaction or any other toxicities were observed in the other 18 patients treated in this study. At time of last follow-up 13 out of 18 patients showed no evidence of disease. This study concludes that VMAT-TMI up to 12 Gy is feasible and well tolerated in the 18-patient cohort treated in this study. Encouraging low rates of toxicity and transplant results warrant treatment and the next dose level of 15Gy BID.

BgRT is currently being developed to utilize PET emission data to guide radiotherapy delivery in real-time to multiple targets. The system combines a compact 6MV linear accelerator and binary multileaf collimator with PET, CT and MV imaging systems all on a ring gantry that rotates continuously at 60 RPM while the patient is translated through the system bore. Here we investigate the feasibility and dosimetric benefits of a prototype TPS for BgRT using a single isocenter technique for oligo-metastases patients treated with SBRT. Included in this study are five oligo-metastatic patients who are treated with SBRT combined with immunotherapy under an IRB protocol. Except for one patient, all had two peripheral lung lesions treated to a total dose of 45Gy (15Gyx3). The last patient had four oligo-metastases including lung (15Gyx3), mediastinum (10Gyx5), liver (15Gyx3) and para-spinal (10 Gyx3). Except for one patient, all were treated with a multiple isocenter technique using 3D, volumetric arc therapy (VMAT) or intensity modulated radiation therapy (IMRT) depending on size and location of target. All five patients were re-planned with the prototype TPS currently under development using a single isocenter technique without using PET-guidance. Prototype TPS plans were normalized to achieve the same clinical target coverage level (+/- 2.5%). The 3D dose distributions and dose volume histograms (DVH) for all targets and organs at risks (OAR) were compared between the clinical and prototype TPS plans. Prototype TPS improved the dose to normal lung compared to other planning techniques delivering on average 16.2% and 6.6% less dose at 20 and 11 Gy levels, respectively. The D0.03cc of heart, esophagus, spinal cord, trachea/bronchus, skin and great vessels were all within acceptable protocol dose limits and were comparable between the prototype TPS and clinical plans. The dose coverage for all targets was within 2.3% of the clinical plans. The prototype TPS plans showed higher dose within the PTV; the volume receiving 110% or greater inside PTVs was on average 3.3 times larger in prototype TPS plans. SBRT for oligo-metastasis has been shown to improve outcome in select patients; however, the number of lesions that can be treated efficiently in the clinic is currently limited. The single isocenter treatment technique as implemented in the prototype TPS has the potential to improve planning efficiency, critical organ sparing, and delivery making treatment of multiple lesions clinically feasible. Further studies need to be directed to dose verification and efficiency of planning and delivery.

SBRT may augment the effects of PD1 blockade to achieve durable responses. We conducted a phase I study for patients with multiple metastases to evaluate the effects of SBRT per the NRG-BR001 trial (NCT02608385) combined with PD1 blockade in the same patient. Here, we better characterize the radiation doses and volumes that were safely delivered to each organ system in a trial that established safety and efficacy of this approach. Between January 2016 and March 2017, 73 patients were treated with SBRT per NRG-BR001 followed by pembrolizumab 200mg IV Q3W within 7 days after the final SBRT fraction. Gross tumor volumes (GTVs) were delineated for each lesion, with volume contraction down to 65cc if a single lesion was >65cc. For each of the 24 organs at risk (OARs), dose delivered was compared to protocol planning constraints for 3 and 5 fraction SBRT. Dose to OARs in a single patient receiving dose from both 3 and 5 fraction was attributed to the fractionation regimen that dominated the dose profile. A total of 151 metastases were radiated including 30 peripheral lung, 23 central lung, 15 mediastinal/cervical, 24 liver, 28 abdominal-pelvic, 16 osseous, and 15 spinal metastases. Median number of metastases treated was 2 (range 2-4). The mean volume of GTV for all metastases per patient was 42cc (range 3cc-129cc). Grade ≥2 toxicities at least possibly related to treatment were 10% for GI disorders, 5% for pneumonitis, 2% for hepatobiliary disorders, and 2% for skin/MSK disorders. No grade 4/5 organ system toxicities occurred. For 3 fraction plans (n=67), 11% of patients exceeded 70% of all BR001 dose limits for liver, compared to 15%, 38%, 33%, and 39% of patients for stomach, duodenum, jejunum, and large bowel respectively. This measure was exceeded by 16% of patients for skin and 73% of patients for the rib. For 5 fraction plans (n=29), <5% of patients exceeded 70% percent of all BR001 dose limits for lungs and the spinal canal, 7% for skin, 18% for heart and esophagus, ≥20% for brachial plexus, great vessels, tracheobronchial tree, and rib. Delivery of SBRT for large target volumes (∼40cc) is technically feasible while achieving low doses to OAR. Multi-site SBRT in combination with PD1 blockade was safety tolerated when treating critical central, abdominopelvic, and peripheral OARs nearing BR001 limits with acceptable toxicity in the corresponding organ systems. This suggests than many patients could be planned to a higher dose to the PTV while still achieving OAR limits using adaptive techniques that will be tested in the next clinical trial.

BgRT is currently being developed to utilize PET emission data to guide radiotherapy delivery in real-time to multiple targets. The system combines a compact 6MV linear accelerator and binary multileaf collimator with PET, CT and MV imaging systems all on a ring gantry that rotates continuously at 60 RPM while the patient is translated through the system bore. Here we investigate the feasibility and dosimetric benefits of a prototype TPS for BgRT using a single isocenter technique for oligo-metastases patients treated with SBRT. Included in this study are five oligo-metastatic patients who are treated with SBRT combined with immunotherapy under an institutional review board protocol. Except for one patient, all had two peripheral lung lesions treated to a total dose of 45Gy (15Gyx3). The last patient had four oligo-metastases including lung (15Gyx3), mediastinum (10Gyx5), liver (15Gyx3) and para-spinal (10 Gyx3). Except for one patient, all were treated with a multiple isocenter technique using 3D, volumetric arc therapy (VMAT) or intensity modulated radiation therapy (IMRT) depending on size and location of target. All five patients were re-planned with the prototype TPS currently under development using a single isocenter technique without using PET-guidance. Prototype TPS plans were normalized to achieve the same clinical target coverage level (+/- 2.5%). The 3D dose distributions and dose volume histograms (DVH) for all targets and organs at risks (OAR) were compared between the clinical and prototype TPS plans. Prototype TPS improved the dose to normal lung compared to other planning techniques delivering on average 16.2% and 6.6% less dose at 20 and 11 Gy levels, respectively. The D0.03cc of heart, esophagus, spinal cord, trachea/bronchus, skin and great vessels were all within acceptable protocol dose limits and were comparable between the prototype TPS and clinical plans. The dose coverage for all targets was within 2.3% of the clinical plans. The prototype TPS plans showed higher dose within the PTV; the volume receiving 110% or greater inside PTVs was on average 3.3 times larger in prototype TPS plans. SBRT for oligo-metastasis has been shown to improve outcome in select patients; however, the number of lesions that can be treated efficiently in the clinic is currently limited. The single isocenter treatment technique as implemented in the prototype TPS has the potential to improve planning efficiency, critical organ sparing, and delivery making treatment of multiple lesions clinically feasible. Further studies need to be directed to dose verification and efficiency of planning and delivery.

To evaluate dose-volume relationships between the individual muscular and structural components of mastication their effect on trismus in locoregionally advanced head and neck cancer (HNC). This was a prospective, longitudinal study of 35 patients with stage III-IV HNC treated on the Accelerated Fractionation by Concomitant Boost (AFX-CB) arm of the Phase 2 EPIC Trial. All patients received 2 cycles of induction chemotherapy (Cetuximab 400 mg/m2 week 1; then 250 mg/m2, Paclitaxel 100 mg/m2 weeks 1-7, and Carboplatin AUC = 6 weeks 1 and 5) followed by the AFX-CB regimen as evaluated in RTOG 9003 and 0522 (72 Gy to primary tumor and involved nodes in 42 fractions and 54 Gy to elective neck in 30 fractions over 6 weeks) using intensity modulated radiation therapy with concurrent Cetuximab 250 mg/m2 (day 1, weekly x7) and Cisplatin 100mg/m2 (weeks 1,4). Patients were comprehensively evaluated for trismus using subjective and objective measures. Pre-therapy, all patients underwent prospective evaluation with CT scan of the head neck and detailed history and physical examination. Patients were re-evaluated with CT scan and physical examination every 3 to 4 months for the first two years followed by every 6 to 12 months thereafter. Dose to the pterygoid, masseter, and temporalis muscles and the mandibular condyle were calculated and correlated to outcome. Pre-therapy, no patients were found to have trismus. At 6 and 12 months, 14.3% and 20% of patients developed trismus, respectively. Statistically significant relationships between trismus and mean doses to the pterygoid, masseter, and temporalis muscles were observed at 6 and 12 months (p<0.05). Mean dose to the mandibular condyle was not significantly correlated to trismus at 6 months (p = 0.43) or 12 months (p = 0.25). We prospectively demonstrate that a dose-volume relationship exists when using AFX-CB. In order to minimize toxicity, efforts to reduce dose to these structures of mastication is essential.

Purpose/Objective(s)Hypofractionated image-guided RT (HIGRT) is increasingly used for oligometastatic disease. Reported studies have treated small volume tumors (median GTVs: 4-14cc, (Rusthoven, 2009, Milano, 2006)). Recently, we have treated larger volume oligometastases with HIGRT. Here we report the toxicity and outcomes of consecutively treated large volume oligometastases.Materials/MethodsHIGRT patients treated from 10/2005-3/2010 were reviewed. Metastases were considered large volume if largest PTV exceeded 50 cc. Patients underwent CT simulation using 4DCT and gating as appropriate. GTVs were delineated on each CT slice with a 5-7 mm expansion to create the PTV. 3D CRT was used for radiation planning. RT was typically prescribed to the 85% isodose line. Patients were treated with either ten fraction regimen (4-5Gy/fraction) or 3-5 fraction regimen (8-14 Gy/fraction). PTV volume was obtained from planning software. Toxicity was obtained from both prospectively collected databases and retrospectively from patient charts. Statistical analysis was performed using JMP (v8).ResultsA total of 68 patients with 93 treated lesions > 50 cc were identified. Median age: 63 (30-91). Median PTV volume was 119 cc (50.1-1222.1). The median # of lesions was 1 (r: 1-7); A maximum of 3 large volume lesions were treated in a single patient. Primary tumors were mostly lung (40%), renal (19%), breast (10%), colorectal (9%), and head and neck (7%).Treated sites included lung (n = 32, 34%), mediastinal (n = 14, 15%) and abdominal lymph nodes (n = 6, 6%), bone (n = 18, 19%), adrenal (n = 9, 10%), liver (n = 5, 5%), visceral structures (n = 5, 5%), and musculoskeletal sites (n = 4, 4%). The most frequent dose fractionation was 50 Gy/5 Gy fractions (n = 45, 48%). Grade 3 acute toxicity was reported in 3 patients (4.4%) consisting of fatigue (2), and skin (1) toxicity. Five patients experienced late toxicity including 3 with Grade 3 pulmonary toxicity, and one Grade 4 GI toxicity in a patient with history of IBD treated to a lesion adjacent to bowel. One pathologic fracture was noted after treatment to a bony lesion. At mean follow-up of 13 months, crude lesion control was 85%. 12 Month actuarial lesion control was 83% [95% CI: 70.4-90.6%]. BEDs < 50 Gy negatively impacted local control. Twelve month local control of 90% [77-96%] was achieved for BED > 50, compared with 30% [4-63%] for 12 patients treated to BED < 50, p = 0.002. There was no statistical difference in local control by lesion size less than or greater than median volume. The predominant pattern of first failure was distant only, occurring in 53% of patients. Among 53 patients with ≥6 months follow-up, 12 (22%) are alive without progression of disease.ConclusionsHIGRT to large volume oligometastatic disease is tolerable and feasible with promising tumor control. Purpose/Objective(s)Hypofractionated image-guided RT (HIGRT) is increasingly used for oligometastatic disease. Reported studies have treated small volume tumors (median GTVs: 4-14cc, (Rusthoven, 2009, Milano, 2006)). Recently, we have treated larger volume oligometastases with HIGRT. Here we report the toxicity and outcomes of consecutively treated large volume oligometastases. Hypofractionated image-guided RT (HIGRT) is increasingly used for oligometastatic disease. Reported studies have treated small volume tumors (median GTVs: 4-14cc, (Rusthoven, 2009, Milano, 2006)). Recently, we have treated larger volume oligometastases with HIGRT. Here we report the toxicity and outcomes of consecutively treated large volume oligometastases. Materials/MethodsHIGRT patients treated from 10/2005-3/2010 were reviewed. Metastases were considered large volume if largest PTV exceeded 50 cc. Patients underwent CT simulation using 4DCT and gating as appropriate. GTVs were delineated on each CT slice with a 5-7 mm expansion to create the PTV. 3D CRT was used for radiation planning. RT was typically prescribed to the 85% isodose line. Patients were treated with either ten fraction regimen (4-5Gy/fraction) or 3-5 fraction regimen (8-14 Gy/fraction). PTV volume was obtained from planning software. Toxicity was obtained from both prospectively collected databases and retrospectively from patient charts. Statistical analysis was performed using JMP (v8). HIGRT patients treated from 10/2005-3/2010 were reviewed. Metastases were considered large volume if largest PTV exceeded 50 cc. Patients underwent CT simulation using 4DCT and gating as appropriate. GTVs were delineated on each CT slice with a 5-7 mm expansion to create the PTV. 3D CRT was used for radiation planning. RT was typically prescribed to the 85% isodose line. Patients were treated with either ten fraction regimen (4-5Gy/fraction) or 3-5 fraction regimen (8-14 Gy/fraction). PTV volume was obtained from planning software. Toxicity was obtained from both prospectively collected databases and retrospectively from patient charts. Statistical analysis was performed using JMP (v8). ResultsA total of 68 patients with 93 treated lesions > 50 cc were identified. Median age: 63 (30-91). Median PTV volume was 119 cc (50.1-1222.1). The median # of lesions was 1 (r: 1-7); A maximum of 3 large volume lesions were treated in a single patient. Primary tumors were mostly lung (40%), renal (19%), breast (10%), colorectal (9%), and head and neck (7%).Treated sites included lung (n = 32, 34%), mediastinal (n = 14, 15%) and abdominal lymph nodes (n = 6, 6%), bone (n = 18, 19%), adrenal (n = 9, 10%), liver (n = 5, 5%), visceral structures (n = 5, 5%), and musculoskeletal sites (n = 4, 4%). The most frequent dose fractionation was 50 Gy/5 Gy fractions (n = 45, 48%). Grade 3 acute toxicity was reported in 3 patients (4.4%) consisting of fatigue (2), and skin (1) toxicity. Five patients experienced late toxicity including 3 with Grade 3 pulmonary toxicity, and one Grade 4 GI toxicity in a patient with history of IBD treated to a lesion adjacent to bowel. One pathologic fracture was noted after treatment to a bony lesion. At mean follow-up of 13 months, crude lesion control was 85%. 12 Month actuarial lesion control was 83% [95% CI: 70.4-90.6%]. BEDs < 50 Gy negatively impacted local control. Twelve month local control of 90% [77-96%] was achieved for BED > 50, compared with 30% [4-63%] for 12 patients treated to BED < 50, p = 0.002. There was no statistical difference in local control by lesion size less than or greater than median volume. The predominant pattern of first failure was distant only, occurring in 53% of patients. Among 53 patients with ≥6 months follow-up, 12 (22%) are alive without progression of disease. A total of 68 patients with 93 treated lesions > 50 cc were identified. Median age: 63 (30-91). Median PTV volume was 119 cc (50.1-1222.1). The median # of lesions was 1 (r: 1-7); A maximum of 3 large volume lesions were treated in a single patient. Primary tumors were mostly lung (40%), renal (19%), breast (10%), colorectal (9%), and head and neck (7%).Treated sites included lung (n = 32, 34%), mediastinal (n = 14, 15%) and abdominal lymph nodes (n = 6, 6%), bone (n = 18, 19%), adrenal (n = 9, 10%), liver (n = 5, 5%), visceral structures (n = 5, 5%), and musculoskeletal sites (n = 4, 4%). The most frequent dose fractionation was 50 Gy/5 Gy fractions (n = 45, 48%). Grade 3 acute toxicity was reported in 3 patients (4.4%) consisting of fatigue (2), and skin (1) toxicity. Five patients experienced late toxicity including 3 with Grade 3 pulmonary toxicity, and one Grade 4 GI toxicity in a patient with history of IBD treated to a lesion adjacent to bowel. One pathologic fracture was noted after treatment to a bony lesion. At mean follow-up of 13 months, crude lesion control was 85%. 12 Month actuarial lesion control was 83% [95% CI: 70.4-90.6%]. BEDs < 50 Gy negatively impacted local control. Twelve month local control of 90% [77-96%] was achieved for BED > 50, compared with 30% [4-63%] for 12 patients treated to BED < 50, p = 0.002. There was no statistical difference in local control by lesion size less than or greater than median volume. The predominant pattern of first failure was distant only, occurring in 53% of patients. Among 53 patients with ≥6 months follow-up, 12 (22%) are alive without progression of disease. ConclusionsHIGRT to large volume oligometastatic disease is tolerable and feasible with promising tumor control. HIGRT to large volume oligometastatic disease is tolerable and feasible with promising tumor control.

To determine the relation between the incidence of RP and the SBRT dose distribution in a Phase I dose escalation study of multiple metastases. Patients with 1-5 sites of metastatic cancer with a life expectancy of >3 months and good performance status received escalating doses of radiation to all known sites of cancer with SBRT. Twenty-eight patients with 50 lesions in the lung were evaluated for this study. All patients underwent 4DCT simulation and FDG PET (if possible) for internal target volume (ITV) delineation on 4DCT images. Planning target volumes (PTV) varied from 5.7cc to 265.6cc and received 24 Gy to 48 Gy in 3 fractions. In addition, one of the patients received a dose fractionation of 10 x 5 Gy and another one 30 x 2 Gy to one of their lung sites, respectively. Optimized SBRT plans with 9-15 coplanar/noncoplanar beam arrangements were designed using a treatment planning system with convolution/superposition algorithm and tissue heterogeneity corrections. The gated SBRT treatments were delivered between July 2005 and December 2008. Dose volume histograms (DVH) were calculated for the total lung excluding the gross tumor and converted to normalized total dose (NTD) at 2 Gy fractions by using the linear quadratic model with α/β ratio of 3 Gy. Normal tissue complication probabilities (NTCP) were evaluated using the Lyman model as per Kwa et al. (1998). Late toxicities were scored using the NCI Common Terminology Criteria for Adverse Events v3.0. A 61% local control was achieved with 39% of patients surviving in this cohort at the time of study. Seven patients out of 28 experienced grade 2 or higher RP. An increasing RP rate with increasing NTDmean was observed to be significant with a mean NTD of 1514±402c Gy for >grade 2 versus 854±508c Gy for < grade 2 (p = 0.004). The Lyman NTCP modeling with the parameters NTD50 = 30.5 Gy and m = 0.30 produced a well-defined NTCP curve with mean values of 6.0±4.0% for >grade2 and 2.0±3.4% for or < 2 (p = 0.086). The dose-effect relation between the NTDmean and RP established for standard fractionated treatments of lung may be extended to the SBRT treatments of multiple lung lesions up to 3x16 Gy as a predictor of lung toxicity. This tool can facilitate the SBRT treatment planning and analysis process in a dose fractionation regimen not well experienced.

To investigate the potential benefits of non-coplanar large segmented direct machine parameter optimization (DMPO) for primary and metastatic lung SBRT. To assess the delivery accuracy of DMPO beam segments to a gated target in a motion phantom. Seven patients with primary or metastatic lung lesions treated with SBRT according to our institutional IRB protocol were included in this study. Patients with oligometastases received doses of 3 x 10-14 Gy and primary NSCLC patients received 50-60 Gy in 3-10 fractions depending on the tumor size and location. 3D custom treatment plans used 10-12 non-coplanar 6MV beam arrangements with manually optimized beam MLC aperture and weight to meet the clinical goals. Inverse planning was done using the identical beam arrangements. Beam apertures were reset and optimized through the DMPO (Pinnacle, Philips) algorithm with one segment per beam and the minimum segment area of half of the maximum PTV cross-section in the BEV. DMPO plans were normalized at the same identical target coverage level as those for 3D plans. The optimization routine used the collapsed-cone convolution dose calculation after 10 successive iterations. 3D dose distributions, dose volume histograms, and normal tissue complication probabilities (NTCP) were calculated for both 3D conformal and 1-segment/DMPO SBRT plans. Finally, a motion phantom with a lung-equivalent insert was fitted with a small tissue-equivalent material to represent a tumor in lung. Gafchromic EBT films were fitted between the sections of this phantom and were irradiated with optimized single-segment beams to evaluate the dose in the lung, in the target and at the edge of the target. One-segment/DMPO planning improved the conformality of SBRT over 3D CRT delivering on average 12% ± 7%, 8% ± 7%, and 2% ± 2% less dose to the lung at 20, 13, and 5Gy levels, respectively. The maximum dose to the heart, esophagus, and cord were comparable between the 1-segment DMPO and 3DCRT plans. Except for one case, there was no increase in the number of monitor units used with 1-segment/DMPO plans. One -segment/DMPO plans yielded a mean reduction of 17.1% and 30% in the normal lung EUD and estimated lung complication probability, respectively, over 3DCRT plans. A dose to distance agreement of 3%/3 mm between calculation and film measurement for a representative plan in a motion phantom with gating was verified at 99% of points within the fields. Single segment beam DMPO can be used to improve SBRT planning for lung lesions to meet the planning goals in an effective manner. This approach allows for easily deliverable and verifiable beam apertures for gated beam delivery. The automation of our method is a good alternative to more traditional methods and offers significant dosimetric benefits.