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Molecular and functional imaging is increasingly being used to guide radiotherapy (RT) management and target delineation. This review summarizes existing data in several disease sites of various functional imaging modalities, chiefly positron emission tomography/computed tomography (PET/CT), with respect to RT target definition and management. For gliomas, differentiation between postoperative changes and viable tumor is discussed, as well as focal dose escalation and reirradiation. Head and neck neoplasms may also benefit from precise PET/CT-based target delineation, especially for cancers of unknown primary; focal dose escalation is also described. In lung cancer, PET/CT can influence coverage of tumor volumes, dose escalation, and adaptive management. For cervical cancer, PET/CT as an adjunct to magnetic resonance imaging planning is discussed, as are dose escalation and delineation of avoidance targets such as the bone marrow. The emerging role of choline-based PET for prostate cancer and its impact on dose escalation is also described. Lastly, given the essential role of PET/CT for target definition in lymphoma, phase III trials of PET-directed management are reviewed, along with novel imaging modalities. Taken together, molecular and functional imaging approaches offer a major step to individualize radiotherapeutic care going forward. [ABSTRACT FROM AUTHOR]

Background We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (S t O 2 ) and blood volume (tHb) were studied for associations with patient outcomes. Methods PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion S t O 2 and tHb was measured. Results Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but S t O 2 was higher in patients with CR. In tongue/FOM lesions, baseline S t O 2 [mean(SE)] was 54(4)% in patients (n = 12) with CR versus 23(8)% in patients (n = 6) with local recurrence/persistence (p = 0.01). Similarly, for intact disease, baseline S t O 2 was 54(3)% in patients (n = 10) with CR versus 28(8)% in patients (n = 5) without CR (p = 0.03). In patients with intact disease, higher baseline S t O 2 associated with 24-month local control (p = 0.02). Conclusions Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT. [ABSTRACT FROM AUTHOR]

Background and purpose Clinical decision support systems are a growing class of tools with the potential to impact healthcare. This study investigates the construction of a decision support system through which clinicians can efficiently identify which previously approved historical treatment plans are achievable for a new patient to aid in selection of therapy. Material and methods Treatment data were collected for early-stage lung and postoperative oropharyngeal cancers treated using photon (lung and head and neck) and proton (head and neck) radiotherapy. Machine-learning classifiers were constructed using patient-specific feature-sets and a library of historical plans. Model accuracy was analyzed using learning curves, and historical treatment plan matching was investigated. Results Learning curves demonstrate that for these datasets, approximately 45, 60, and 30 patients are needed for a sufficiently accurate classification model for radiotherapy for early-stage lung, postoperative oropharyngeal photon, and postoperative oropharyngeal proton, respectively. The resulting classification model provides a database of previously approved treatment plans that are achievable for a new patient. An exemplary case, highlighting tradeoffs between the heart and chest wall dose while holding target dose constant in two historical plans is provided. Conclusions We report on the first artificial-intelligence based clinical decision support system that connects patients to past discrete treatment plans in radiation oncology and demonstrate for the first time how this tool can enable clinicians to use past decisions to help inform current assessments. Clinicians can be informed of dose tradeoffs between critical structures early in the treatment process, enabling more time spent on finding the optimal course of treatment for individual patients. [ABSTRACT FROM AUTHOR]

Purpose This guideline presents evidence-based recommendations for stereotactic body radiation therapy (SBRT) in challenging clinical scenarios in early-stage non-small cell lung cancer (NSCLC). Methods and materials The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing: (1) application of SBRT to operable patients; (2) appropriate use of SBRT in tumors that are centrally located, large, multifocal, or unbiopsied; (3) individual tailoring of SBRT in “high-risk” clinical scenarios; and (4) SBRT as salvage therapy after recurrence. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology–approved tools for grading evidence quality and recommendation strength. Results Although few randomized trials have been completed for SBRT, strong consensus recommendations based on extensive, consistent publications were generated for several questions, including recommendations for fractionation for central tumors and surgery versus SBRT in standard-risk medically operable patients with early-stage NSCLC. Lower quality evidence led to conditional recommendations on use of SBRT for tumors >5 cm, patients with prior pneumonectomy, T3 tumors with chest wall invasion, synchronous multiple primary lung cancer, and as a salvage therapy after prior radiation therapy. These areas of moderate- and low-quality evidence highlight the importance of clinical trial enrollment as well as the role of prospective data registries. Conclusions SBRT has an important role to play in treating early-stage NSCLC, particularly for medically inoperable patients with limited other treatment options. Shared decision-making with patients should be performed in all cases to ensure the patient understands the risks related to SBRT, the side effects, and the alternative treatments available. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to assess survival for patients with malignant pleural mesothelioma (MPM), epithelial subtype, utilizing extended pleurectomy-decortication combined with intraoperative photodynamic therapy (PDT) and adjuvant pemetrexed-based chemotherapy. Methods From 2005 to 2013, 90 patients underwent lung-sparing surgery and PDT for MPM. All patients had a preoperative diagnosis of epithelial subtype, of which 17 proved to be of mixed histology. The remaining 73 patients with pure epithelial subtype were analyzed. All patients received lung-sparing surgery and PDT; 92% also received chemotherapy. The median follow-up was 5.3 years for living patients. Results Macroscopic complete resection was achieved in all 73 patients. Thirty-day mortality was 3% and 90-day mortality was 4%. For all 73 patients (89% American Joint Commission on Cancer stage III/IV, 69% N2 disease, median tumor volume 550 mL), the median overall and disease-free survivals were 3 years and 1.2 years, respectively. For the 19 patients without lymph node metastases (74% stage III/IV, median tumor volume 325 mL), the median overall and disease-free survivals were 7.3 years and 2.3 years, respectively. Conclusions This is a mature dataset for MPM that demonstrates the ability to safely execute a complex treatment plan that included a surgical technique that consistently permitted achieving a macroscopic complete resection while preserving the lung. The role for lung-sparing surgery is unclear but this series demonstrates that it is an option, even for advanced cases. The overall survival of 7.3 years for the node negative subset of patients, still of advanced stage, is encouraging. Of particular interest is the overall survival being approximately triple the disease-free survival, perhaps PDT related. The impact of PDT is unclear, but it is hoped that it will be established by an ongoing randomized trial. [ABSTRACT FROM AUTHOR]

Purpose: For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population.Methods and Materials: The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes.Results: From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor size was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P=.02) and OS (31.4 vs 14.3 months; P=.02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P=.01). Toxicities were uncommon; 5.2% experienced grade ≥2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and "elsewhere lung" (20.8%). The median time to each was 5 to 7 months.Conclusions: From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (≥50 Gy) with chemotherapy should be considered a standard option. [ABSTRACT FROM AUTHOR]

Purpose A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. Methods and materials We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤ 2 and ≤ 4 total sites of metastatic disease and who had been prescribed ≥ 50 Gy of thoracic radiation. Results Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival ( P = .02). In matched subset analysis, median survival was 9 months ( P < .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months ( P = .01). On multivariable analysis, radiation ( P < .01; odds ratio [OR], 0.33), fewer metastases ( P < .01; OR, 2.14), and female sex ( P < .01; OR, 0.41) were associated with improved survival. Conclusions Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC. [ABSTRACT FROM AUTHOR]

Purpose To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial. Methods For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions. Results The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT ( p  < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT ( p  < 0.01), doses to the spinal cord were lowest with DSP ( p  < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ. Conclusion On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient. [ABSTRACT FROM AUTHOR]

Background The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit. Methods 306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT + RT with ChT groups that matched on possible confounding variables. Results Patients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT + TRT, and 10.3% ( p < 0.001 ), 4.6% ( p < 0.001 ) and 6.3% for ChT only ( p < 0.001 ), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED > 50 Gy) TRT and received low dose (tBED ≤ 50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% ( p < 0.001), 12.9% ( p = 0.097) and 34.7% ( p = 0.029) for low dose radiotherapy. Conclusions TRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC. [ABSTRACT FROM AUTHOR]

Radiation therapy has long played a major role in the treatment of gynecological malignancies. There is increasing interest in the utility of intensity-modulated radiotherapy (IMRT) and its application to treat gynecological malignancies. Herein, we review the state-of-the-art use of IMRT for gynecological malignancies and report how it is being used alone as well as in combination with chemotherapy in both the adjuvant and definitive settings. Based on dosimetric and clinical evidence, IMRT can reduce gastrointestinal, genitourinary, and hematological toxicities compared with 3D-conformal radiotherapy for gynecologic malignancies. We discuss how these attributes of IMRT may lead to improvements in disease outcomes by allowing for dose escalation of radiation therapy, intensification of chemotherapy, and limiting toxicity-related treatment breaks. Currently accruing trials investigating pelvic IMRT for cervical and endometrial cancers are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Acute hospital encounters in patients undergoing curative-intent radiation therapy (RT) have not previously been well characterized. Understanding acute visit patterns among RT patients yields insights for risk assessments and cancer urgent care clinics that could decrease hospitalization rates and reduce health care costs. This study aims to identify patient, disease-site, and treatment characteristics associated with emergency department visits and inpatient admissions in cancer patients treated with definitive RT.Methods and Materials: A retrospective cohort study was conducted using data from a quaternary-care cancer center. The cohort was defined as all consecutive patients aged ≥ 18 years who began RT between July 1, 2011, and December 31, 2013; were without metastases; and were treated with curative intent. An acute encounter was defined as an emergency department visit or inpatient admission during RT or within 30 days after the conclusion of RT.Results: Among 1852 unique RT courses, 666 RT courses (36.0%) involved at least 1 acute encounter, and a total of 1418 acute encounters were identified. RT courses with at least 1 acute encounter corresponded to patients more likely to be on their second (odds ratio [OR], 1.96; P < .001) or third (OR, 3.82; P < .05) RT course and undergoing concurrent chemotherapy (OR, 6.38; P < .001). Among the RT courses with at least 1 acute encounter, the most common disease site was thoracic (22.8%), followed by head and/or neck (22.2%) and gastrointestinal (18.3%). Central nervous system tumors had the greatest proportion of RT courses with acute encounters (77.1%).Conclusions: In this retrospective analysis, more than one-third of curative-intent RT courses were associated with at least 1 acute hospital encounter during or shortly after irradiation. Given that acute encounters varied by patient, disease-site, and treatment characteristics, these findings can inform targeted preventive measures to reduce cancer-related acute hospital encounters and guide improved management protocols. [ABSTRACT FROM AUTHOR]

Purpose: To determine, in a retrospective analysis of a large cohort of stage III non-small cell lung cancer patients treated with curative intent at our institution, whether having a pathologic complete response (pCR) influenced overall survival (OS) or freedom from recurrence (FFR) in patients who underwent definitive (≥60 Gy) neoadjuvant doses of chemoradiation (CRT).Methods and Materials: At our institution, 355 patients with locally advanced non-small cell lung cancer were treated with curative intent with definitive CRT (January 2000-December 2013), of whom 111 underwent mediastinal reassessment for possible surgical resection. Ultimately 88 patients received trimodality therapy. Chi-squared analysis was used to compare categorical variables. The Kaplan-Meier analysis was performed to estimate OS and FFR, with Cox regression used to determine the absolute hazards.Results: Using high-dose neoadjuvant CRT, we observed a mediastinal nodal clearance (MNC) rate of 74% (82 of 111 patients) and pCR rate of 48% (37 of 77 patients). With a median follow-up of 34.2 months (range, 3-177 months), MNC resulted in improved OS and FFR on both univariate (OS: hazard ratio [HR] 0.455, 95% confidence interval [CI] 0.272-0.763, P = .004; FFR: HR 0.426, 95% CI 0.250-0.726, P = .002) and multivariate analysis (OS: HR 0.460, 95% CI 0.239-0.699, P = .001; FFR: HR 0.455, 95% CI 0.266-0.778, P = .004). However, pCR did not independently impact OS (P = .918) or FFR (P = .474).Conclusions: Mediastinal nodal clearance after CRT continues to be predictive of improved survival for patients undergoing trimodality therapy. However, a pCR at both the primary and mediastinum did not further improve survival outcomes. Future therapies should focus on improving MNC to encourage more frequent use of surgery and might justify use of preoperative CRT over chemotherapy alone. [ABSTRACT FROM AUTHOR]

Purpose This study of a large, contemporary national database evaluated postoperative outcomes and overall survival (OS) for malignant pleural mesothelioma (MPM) by facility volume. Methods The National Cancer Database was queried for newly-diagnosed non-metastatic MPM undergoing definitive surgery (extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)). Patients were dichotomized into those receiving therapy at a high-volume facility (HVF), defined a priori at the 90th percentile of case volume, with all others categorized as lower-volume facilities (LVFs). Statistics included multivariable logistic regression, Kaplan-Meier analysis, propensity-matching, and multivariable Cox proportional hazards modeling. Sensitivity analysis varied the dichotomized HVF-LVF cutoff and evaluated effects on postoperative outcomes and OS. Results Of 1307 patients, 621 (48%) were treated at LVFs and 686 (52%) at HVFs. HVFs were more often in the Middle/South Atlantic regions, and less likely in New England, South, and Midwest. Notably, 75% of procedures at HVFs were P/Ds, versus 84% at LVFs (p < 0.001). Patients treated at HVFs experienced shorter length of postoperative hospitalization (p = 0.035), lower 30-day readmission rates (4.6% vs. 6.1%, p = 0.021), and lower 90-day mortality rates (10.0% vs. 14.6%, p = 0.029). Median OS for respective groups were 18 versus 15 months (p = 0.010), which were not significant following propensity-matching (p = 0.540). On multivariable analysis, facility volume did not independently predict for OS. Sensitivity analyses confirmed the postoperative outcomes and OS findings. Conclusions This is the largest investigation to date assessing facility volume and outcomes following surgery for MPM. Although no independent effects on OS were observed, postoperative outcomes were more favorable at HVFs. These findings have implications for postoperative management, patient counseling, referring providers, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background Contrary to prevailing notions of uniform efficacy regarding stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC), a recent report has indicated increased risk of local failure for squamous cell carcinoma (SCC). As those data have not been corroborated by other studies, we performed a multi-institutional analysis to evaluate the influence of histology on post-SBRT outcomes. Materials and methods Records from 152 consecutive patients who received SBRT for primary early-stage NSCLC at two academic medical centers were retrospectively assessed. Primary comparison was between SCC and adenocarcinoma. Patient outcomes including actuarial recurrences and overall survival were calculated using the Kaplan-Meier method. Univariable and multivariable logistic regression analyses addressed associated factors. Results At a median follow-up of 44 months, patients with SCC had an increased risk of local, (hazard ratio (HR) (95% confidence interval (CI)): 1.69 (1.05–2.73), p = 0.032), regional (HR (95% CI): 2.03 (1.24–3.33), p = 0.005), and distant failure (HR (95% CI): 1.71 (1.06–2.77), p = 0.036). Median times to local (32 m vs 50m, p = 0.023), regional (26 m vs 50 m, p = 0.011), and distant (26 m vs 50 m, p = 0.024) failure were all significantly reduced in SCC histology. SCC histology was also independently associated with an increased risk for death (HR: 1.80 (1.10–2.94), p = 0.019) and had a 5-yr overall survival of 26%, versus 41% for adenocarcinoma (p = 0.016). Conclusions This multi-institutional analysis corroborates that SCC histology is independently predictive for local, regional, and distant recurrence and worse overall survival. Future data are needed to determine if treatment paradigms should differ by histology for early stage NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: To use the Surveillance, Epidemiology, and End Results (SEER) database to compare cardiac-specific mortality (CSM) between left- and right-sided locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with definitive radiation therapy; and to stratify these patients over fixed time intervals to assess for differences in events by treatment era.Methods and Materials: The SEER database was queried for patients with stage III NSCLC who received radiation therapy to compare CSM between left- and right-sided primary cases at 5 time intervals: 1988-1992, 1993-1997, 1998-2002, 2003-2007, and 2008-2012. Cumulative incidence of CSM was compared between left- and right-sided patients using Gray's test. The multivariate Fine and Gray competing risk model was used to compare CSM while accounting for other-cause mortality.Results: Of 884,610 lung cancer patients, 52,624 met inclusion criteria; of these, 31,549 (60%) were right-sided and 21,075 (40%) were left-sided. When evaluating CSM in each of the 5 time periods, the overall incidence of CSM decreased over time. There was a statistically significant (P<.05) difference based on laterality in all time periods except 1988-1992 (P=.14). The subdistribution hazard ratio for CSM based on disease laterality in all time periods was 1.30 (95% confidence interval 1.18-1.42) and did not discernibly differ by time interval. On multivariate analysis using the Fine and Gray competing risk model, left-sided laterality independently predicted for CSS from 1993 to 2007 (P<.05).Conclusions: Cardiac-specific mortality has decreased over time, and left-sided disease independently predicted for CSS during 1993-2007 but not 2008-2012. The time course of cardiac mortality seems to be early, consistent with other studies. These findings underscore the importance of minimizing cardiac irradiation during radiation treatment planning. [ABSTRACT FROM AUTHOR]

Purpose: To develop and implement a practical repainting method for efficient interplay effect mitigation in proton pencil beam scanning (PBS).Methods and Materials: A new flexible repainting scheme with spot-adapted numbers of repainting evenly spread out over the whole breathing cycle (assumed to be 4 seconds) was developed. Twelve fields from 5 thoracic and upper abdominal PBS plans were delivered 3 times using the new repainting scheme to an ion chamber array on a motion stage. One time was static and 2 used 4-second, 3-cm peak-to-peak sinusoidal motion with delivery started at maximum inhalation and maximum exhalation. For comparison, all dose measurements were repeated with no repainting and with 8 repaintings. For each motion experiment, the 3%/3-mm gamma pass rate was calculated using the motion-convolved static dose as the reference. Simulations were first validated with the experiments and then used to extend the study to 0- to 5-cm motion magnitude, 2- to 6-second motion periods, patient-measured liver tumor motion, and 1- to 6-fraction treatments. The effect of the proposed method was evaluated for the 5 clinical cases using 4-dimensional (4D) dose reconstruction in the planning 4D computed tomography scan. The target homogeneity index, HI = (D2 - D98)/Dmean, of a single-fraction delivery is reported, where D2 and D98 is the dose delivered to 2% and 98% of the target, respectively, and Dmean is the mean dose.Results: The gamma pass rates were 59.6% ± 9.7% with no repainting, 76.5% ± 10.8% with 8 repaintings, and 92.4% ± 3.8% with the new repainting scheme. Simulations reproduced the experimental gamma pass rates with a 1.3% root-mean-square error and demonstrated largely improved gamma pass rates with the new repainting scheme for all investigated motion scenarios. One- and two-fraction deliveries with the new repainting scheme had gamma pass rates similar to those of 3-4 and 6-fraction deliveries with 8 repaintings. The mean HI for the 5 clinical cases was 14.2% with no repainting, 13.7% with 8 repaintings, 12.0% with the new repainting scheme, and 11.6% for the 4D dose without interplay effects.Conclusions: A novel repainting strategy for efficient interplay effect mitigation was proposed, implemented, and shown to outperform conventional repainting in experiments, simulations, and dose reconstructions. This strategy could allow for safe and more optimal clinical delivery of thoracic and abdominal proton PBS and better facilitate hypofractionated and stereotactic treatments. [ABSTRACT FROM AUTHOR]

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) ( n = 6), head/neck (H&N) ( n = 4), lung ( n = 2), and gastrointestinal ( n = 2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively. Multiple PBT reRT studies for adult gliomas illustrate no grade ≥3 toxicities. Two pediatric CNS tumor studies demonstrated the safety and efficacy of reRT, with one total grade 3 toxicity and achievement of longer-term OS. PBT for H&N malignancies shows appropriate local/locoregional control and favorable toxicity profiles versus historical photon-based methods, including low (9–10%) rates of feeding tube placement. PBT for recurrent lung cancer can achieve favorable survival with expected toxicities/complications of reRT, especially with concurrent chemotherapy and centrally located recurrences. Lastly, PBT reRT in gastrointestinal malignancies induced very few high-grade complications. Hence, based on the limited existing data, PBT is a notably safe reRT modality for effective salvage of recurrent disease. Institutional experiences must continue to be reported: dosimetric correlations, late toxicities, and advanced PBT techniques. [ABSTRACT FROM AUTHOR]

Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT. Four-dimensional computed tomography-based motion management and robust optimization and evaluation are crucial for minimizing uncertainties associated with beam range and organ motion. Rigorous quality assurance is required to validate dose delivery both before and during the course of treatment. Active motion management (eg, breath hold), beam gating, rescanning, tracking, or adaptive planning may be needed for cases involving significant motion or changes in motion or anatomy over the course of treatment. [ABSTRACT FROM AUTHOR]

Purpose: Prolonged radiation treatment (RT) time (RTT) has been associated with worse survival in several malignancies. The present study investigated whether delays during RT are associated with overall survival (OS) in non-small cell lung cancer (NSCLC).Methods and Materials: The National Cancer Database was queried for patients with stage III NSCLC who had received definitive concurrent chemotherapy and fractionated RT to standard doses (59.4-70.0 Gy) and fractionation from 2004 to 2013. The RTT was classified as standard or prolonged for each treatment regimen according to the radiation dose and number of fractions. Cox proportional hazards models were used to evaluate the association between the following factors and OS: RTT, RT fractionation, demographic and pathologic factors, and chemotherapeutic agents.Results: Of 14,154 patients, the RTT was prolonged in 6262 (44.2%). Factors associated with prolonged RTT included female sex (odds ratio [OR] 1.21, P<.0001), black race (OR 1.20, P=.001), nonprivate health insurance (OR 1.30, P<.0001), and lower income (<$63,000 annually, OR 1.20, P<.0001). The median OS was significantly worse for patients with prolonged RTT than that for those with standard RTT (18.6 vs 22.7 months, P<.0001). Furthermore, the OS worsened with each cumulative interval of delay (standard RTT vs prolonged 1-2 days, 20.5 months, P=.009; prolonged 3-5 days, 17.9 months, P<.0001; prolonged 6-9 days, 17.7 months, P<.0001; prolonged >9 days, 17.1 months, P<.0001). On multivariable analysis, prolonged RTT was independently associated with inferior OS (hazard ratio 1.21, P<.0001). Prolonged RTT as a continuous variable was also significantly associated with worse OS (hazard ratio 1.001, P=.0007).Conclusions: Delays during RT appear to negatively affect survival for patients with locally advanced NSCLC. We have detailed the demographic and socioeconomic barriers influencing prolonged RTT as a method to address the health disparities in this regard. Cumulative interruptions of RT should be minimized. [ABSTRACT FROM AUTHOR]

Purpose: To describe the impact of fractionation scheme and tumor location on toxicities in stereotactic body radiation therapy (SBRT) for ≥5-cm non-small cell lung cancer (NSCLC), as part of a multi-institutional analysis.Methods: Patients with primary ≥5-cm N0 M0 NSCLC who underwent ≤5-fraction SBRT were examined across multiple high-volume SBRT centers. Collected data included clinical/treatment parameters; toxicities were prospectively assessed at each institution according to the Common Terminology Criteria for Adverse Events. Patients treated daily were compared with those treated every other day (QOD)/other nondaily regimens. Stratification between central and peripheral tumors was also performed.Results: Ninety-two patients from 12 institutions were evaluated (2004-2016), with median follow-up of 12 months. In total there were 23 (25%) and 6 (7%) grade ≥2 and grade ≥3 toxicities, respectively. Grades 2 and 3 pulmonary toxicities occurred in 9% and 4%, respectively; 1 patient treated daily experienced grade 5 radiation pneumonitis. Of the entire cohort, 46 patients underwent daily SBRT, and 46 received QOD (n=40)/other nondaily (n=6) regimens. Clinical/treatment parameters were similar between groups; the QOD/other group was more likely to receive 3-/4-fraction schemas. Patients treated QOD/other experienced significantly fewer grade ≥2 toxicities as compared with daily treatment (7% vs 43%, P<.001). Patients treated daily also had higher rates of grade ≥2 pulmonary toxicities (P=.014). Patients with peripheral tumors (n=66) were more likely to receive 3-/4-fraction regimens than those with central tumors (n=26). No significant differences in grade ≥2 toxicities were identified according to tumor location (P>.05).Conclusions: From this multi-institutional study, toxicity of SBRT for ≥5-cm lesions is acceptable, and daily treatment was associated with a higher rate of toxicities. [ABSTRACT FROM AUTHOR]

Purpose: To analyze outcomes and predictors associated with proton radiation therapy for non-small cell lung cancer (NSCLC) in the National Cancer Database.Methods and Materials: The National Cancer Database was queried to capture patients with stage I-IV NSCLC treated with thoracic radiation from 2004 to 2012. A logistic regression model was used to determine the predictors for utilization of proton radiation therapy. The univariate and multivariable association with overall survival were assessed by Cox proportional hazards models along with log-rank tests. A propensity score matching method was implemented to balance baseline covariates and eliminate selection bias.Results: A total of 243,822 patients (photon radiation therapy: 243,474; proton radiation therapy: 348) were included in the analysis. Patients in a ZIP code with a median income of <$46,000 per year were less likely to receive proton treatment, with the income cohort of $30,000 to $35,999 least likely to receive proton therapy (odds ratio 0.63 [95% confidence interval (CI) 0.44-0.90]; P=.011). On multivariate analysis of all patients, non-proton therapy was associated with significantly worse survival compared with proton therapy (hazard ratio 1.21 [95% CI 1.06-1.39]; P<.01). On propensity matched analysis, proton radiation therapy (n=309) was associated with better 5-year overall survival compared with non-proton radiation therapy (n=1549), 22% versus 16% (P=.025). For stage II and III patients, non-proton radiation therapy was associated with worse survival compared with proton radiation therapy (hazard ratio 1.35 [95% CI 1.10-1.64], P<.01).Conclusions: Thoracic radiation with protons is associated with better survival in this retrospective analysis; further validation in the randomized setting is needed to account for any imbalances in patient characteristics, including positron emission tomography-computed tomography staging. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic body radiation therapy (SBRT) for ≥5 cm lesions is poorly defined, largely owing to the low sample sizes in existing studies. The present analysis examined the SBRT outcomes and assessed the effect of chemotherapy in this population.Methods and Materials: The National Cancer Data Base was queried for primary non-small cell lung cancer ≥5 cm treated with SBRT (≤10 fractions). Patient, tumor, and treatment parameters were extracted. The primary outcome was overall survival (OS). Statistical methods involved Kaplan-Meier analysis and multivariable Cox proportional hazards modeling.Results: From 2004 to 2012, data from 201 patients were analyzed. The median follow-up was 41.1 months. The median tumor size was 5.5 cm (interquartile range 5.0-6.0), with cT2a, cT2b, and cT3 disease in 24.9%, 53.2%, and 21.9%, respectively. The median total SBRT dose and fractionation was 50 Gy in 4 fractions, and 92.5% of the patients underwent SBRT with ≤5 fractions. The median OS was 25.1 months. Of the 201 patients, 15% received chemotherapy. The receipt of chemotherapy was associated with longer OS (median 30.6 vs 23.4 months; P=.027). On multivariable analysis, worse OS was seen with increasing age (hazard ratio [HR] 1.03; P=.012), poorly differentiated tumors (HR 2.06; P=.049), and T3 classification (HR 2.13; P=.005). On multivariable analysis, chemotherapy remained independently associated with improved OS (HR 0.57; P=.039).Conclusions: SBRT has utility in the setting of tumors ≥5 cm, with chemotherapy associated with improved OS in this subset. These hypothesis-generating data now raise the necessity of performing prospective analyses to determine whether chemotherapy confers outcome benefits after SBRT. [ABSTRACT FROM AUTHOR]

Objectives We aimed to report trends in stereotactic body radiation therapy (SBRT) utilization, dose prescriptions, and chemotherapy administration for stage I small cell lung cancer (SCLC) in the United States. Materials and methods The National Cancer Data Base (NCDB) was used to identify patients with cT1-2 N0 SCLC treated with SBRT between 2004 and 2013. Trends in SBRT use and dose prescription were analyzed over time. Multivariable logistic regression was used to determine factors associated with the administration of chemotherapy with SBRT. The Kaplan-Meier method was used to estimate overall survival. Results Of 9265 patients with clinical stage I SCLC who were examined for initial treatment allocation, 285 were treated with SBRT and represented the subject of the primary analysis. SBRT utilization increased from 2004 (0.4% of all stage I patients diagnosed that year) to 2013 (6.4%). During this same time period, definitive surgical management also increased from 14.9% of all patients in 2004 to 28.5% in 2013. The median SBRT biologically effective dose (BED 10 ) was 112.5 Gy (range, 72–290) and only 33 out of 285 (11.6%) received a BED 10 < 100 Gy. Nearly half of all patients (130/285, 45.6%) received chemotherapy, with 42.7% of those patients receiving their chemotherapy prior to SBRT. On multivariable logistic regression, only age < 75 (the median) vs. ≥75 years (OR 4.97, 95% CI 2.96–8.35, p < 0.001) and year of diagnosis 2004–2008 vs. 2009–2013 (OR 2.58, 95% CI 1.27–5.26, p = 0.009) were predictive of chemotherapy use with SBRT. After median follow up of 45 months, the median survival was 23.5 months. Conclusions Our findings suggest that SBRT utilization for stage I SCLC has increased between 2004 and 2013, highlighting the need for additional research to validate the feasibility of this management approach for inoperable patients. [ABSTRACT FROM AUTHOR]

Purpose: An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning.Methods and Materials: The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the target's distal surface.Results: The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology.Conclusions: A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes. [ABSTRACT FROM AUTHOR]

Radiation dose escalation has been shown to improve local control and survival in patients with non-small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography-based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions. [ABSTRACT FROM AUTHOR]

Hyperthermia has long been used for cancer treatment, either alone or in combination with chemotherapy, radiation therapy, or both. Its efficacy and versatility continue to be well demonstrated in randomized trials across a number of primary cancers, but barriers to its widespread adoption persist including effective delivery and verification systems. This article describes hyperthermia, details its biological mechanisms of action and immunological effects, and summarizes select preclinical data and key clinical trials combining hyperthermia with standard cancer treatments. Current challenges and emerging technologies that have the potential to make this translational therapy more accessible to a greater number of patients are also described. [ABSTRACT FROM AUTHOR]