Magnetic resonance imaging (MRI) has been widely used in combination with computed tomography (CT) radiation therapy because MRI improves the accuracy and reliability of target delineation due to its superior soft tissue contrast over CT. The MRI-only treatment process is currently an active field of research since it could eliminate systematic MR-CT co-registration errors, reduce medical cost, avoid diagnostic radiation exposure, and simplify clinical workflow. The purpose of this work is to validate the application of a deep learning-based method for abdominal synthetic CT (sCT) generation by image evaluation and dosimetric assessment in a commercial proton pencil beam treatment planning system (TPS). This study proposes to integrate dense block into a 3D cycle-consistent generative adversarial networks (cycle GAN) framework in an effort to effectively learn the nonlinear mapping between MRI and CT pairs. A cohort of 21 patients with co-registered CT and MR pairs were used to test the deep learning-based sCT image quality by leave-one-out cross validation. The CT image quality, dosimetric accuracy and the distal range fidelity were rigorously checked, using side-by-side comparison against the corresponding original CT images. The average mean absolute error (MAE) was 72.87±18.16 HU. The relative differences of the statistics of the PTV dose volume histogram (DVH) metrics between sCT and CT were generally less than 1%. Mean 3D gamma analysis passing rate of 1mm/1%, 2mm/2%, 3mm/3% criteria with 10% dose threshold were 90.76±5.94%, 96.98±2.93% and 99.37±0.99%, respectively. The median, mean and standard deviation of absolute maximum range differences were 0.170 cm, 0.186 cm and 0.155 cm. The image similarity, dosimetric and distal range agreement between sCT and original CT suggests the feasibility of further development of an MRI-only workflow for liver proton radiotherapy.
Objectives: The patterns of care for salivary gland adenoid cystic carcinomas (ACC) are unknown. We sought to assess predictors of receiving postoperative radiation and/or chemotherapy for patients with nonmetastatic, definitively resected ACC, as well as report unexpected nodal disease. Methods: The National Cancer Data Base was queried for definitively resected nonmetastatic ACC from 2004 to 2014. Logistic regression, Kaplan-Meier, and Cox proportional-hazard models were utilized. Propensity-score matched analysis was employed to reduce confounding variables. Results: A total of 3,136 patients met entry criteria: 2,252 (71.8%) received postoperative radiation, with 223 (7.4%) also receiving concurrent chemotherapy. Median follow-up was 4.87 years. In clinically lymph node negative (cN0) patients, 7.4% had pathologically positive lymph nodes (pN) + after elective neck dissection. Patients who lived closer to their treatment facility and had positive margins were more likely to receive postoperative radiation. Black patients and uninsured patients were less likely to receive radiation. Older age, male sex, advancing stage, and positive surgical margins were associated with worse overall survival (OS). With limited follow-up, receipt of radiation or chemotherapy was not associated with OS. Conclusion: Postoperative radiation was frequently given for resected ACC, with a minority receiving chemotherapy. Black patients and uninsured patients were less likely to receive radiation. Postoperative radiation and/or chemotherapy had no association with OS but were given in greater frequency in more advanced disease, and our series is limited by short follow-up. The disparity findings for this rare disease need to be addressed in future studies. Level of Evidence: 2c Laryngoscope, 129:377–386, 2019.
Purpose: We sought to quantify the optimum number of beams by using a midline sagittal arrangement for midline brain tumors when considering the competing demands of a high degree of target conformation and maximizing reduction of nontarget brain dose. The volume of nontarget brain tissue receiving between 5 and 20 Gy (V5-V20) was selected to measure "low-dose bath" to normal brain. Materials and Methods: An exploratory model was developed with 6 midline brain targets created by using spheres of 1-, 3-, and 5-cm diameters located in superficial and deep locations. For each, five 3-dimensional proton treatment plans with uniform beam scanning were generated by using 1 to 5 fields. Dose-volume histograms were analyzed to calculate conformation number and V5-V20. A benefit/cost analysis was performed to determine the marginal gain in conformation number and the marginal cost of V5-V20 for the addition of each field and hypothesize the optimum number of treatment fields. We tested our hypothesis by re-planning 10 actual patient tumors with the same technique to compare the averages of these 50 plans to our model. Results: Our model and validation cohort demonstrated the largest marginal benefit in target conformation and the lowest marginal cost in normal brain V5-V20 with the addition of a second proton field. The addition of a third field resulted in a relative marginal benefit in target conformation of just 3.9% but a relative marginal cost in V5-V20 of 78.7%. Normal brain absolute V5-V20 increased in a nearly linear fashion with each additional field. Conclusions: When treating midline brain lesions with 3-dimensional proton therapy in an array of midline sagittal beams, our model suggests the most appropriate number of fields is 2. There was little marginal benefit in target conformation and increasing cost of normal brain dose when increasing the number of fields beyond this.
Background:
The prognostic relevance of human papillomavirus (HPV) status in non-oropharyngeal (OPX) squamous cell cancer (SCC) of the head and neck is controversial. We evaluated the impact of high-risk HPV status on overall survival (OS) in patients with non-OPX SCC using a large database approach.
Methods:
The National Cancer Data Base was queried to identify patients diagnosed from 2004–2014 with SCC of the OPX, hypopharynx (HPX), larynx, and oral cavity (OC) with known HPV status. Survival was estimated using Kaplan-Meier methods; distributions were compared with log-rank tests. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) methods were utilized; cohorts were matched on age, sex, Charlson-Deyo score, clinical group stage, treatments received, and anatomic subsite. Propensity analyses were stratified by group stage.
Results:
24,740 patients diagnosed from 2010–2013 were analyzed; 1,085 patients with HPX, 4804 with larynx, 4,018 with OC, and 14,833 with OPX SCC. The proportions of HPV positive cases by site were: 17.7% in HPX, 11% in larynx, 10.6% in OC, and 62.9% in OPX. HPV status was prognostic in multiple un-adjusted and propensity-adjusted non-OPX populations. HPV positivity was associated with superior OS in HPX SCC with hazard ratio (HR) of 0.61 (p<0.001, IPTW), in stage III-IVB laryngeal SCC (HR 0.79, p=0.019, IPTW), and in stage III-IVB OC SCC (HR 0.78, p=0.03, IPTW).
Conclusions:
Positive high-risk HPV status is associated with longer OS in multiple non-oropharynx head and neck populations – hypopharynx, locally-advanced larynx and oral cavity. If prospectively validated, these findings have implications for risk-stratification.
Background: The LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. Methods: Using the NCDB, patients with American Joint Committee on Cancer (AJCC) clinical stage T2–4, N0–1, M0 adenocarcinoma of the pancreas from 2004 to 2014 were analyzed. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions or ≥ 5 Gy per fraction [i.e., stereotactic body radiation therapy (SBRT)] were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. Results: 13,004 patients met inclusion criteria, of whom 7034 (54%) received CT and 5970 (46%) received CRT. After PSM, 5215 patients remained in each cohort. The CRT cohort demonstrated better overall survival (OS) compared with CT alone, with median and 1-year OS of 12 versus 10 months, and 50% and 41%, respectively (p OpenSPiltSPi 0.001). On multivariable analysis, CRT was associated with superior OS with hazard ratio of 0.79 (95% confidence interval 0.76–0.83) compared with CT alone. Conclusions: In our series, addition of definitive radiotherapy to CT was associated with better OS when compared with CT alone in LAPC. Definitive radiotherapy should remain a treatment option for LAPC, but optimal selection criteria remain unclear.
Background: To investigate the impact of proton radiotherapy (PBT) on overall survival (OS) and evaluate PBT usage trends for patients with gliomas in the National Cancer Data Base (NCDB). Methods: Patients with a diagnosis of World Health Organization (WHO) Grade I-IV glioma treated with definitive radiation therapy (RT) between the years of 2004-13 were identified. Patients were stratified based on WHO Grade and photon radiotherapy (XRT) vs. PBT. Univariate (UVA) and multivariable analysis (MVA) with OS were performed by Cox proportional hazards model and log-rank tests. Propensity score (PS) weighting was utilized to account for differences in patient characteristics and to minimize selection bias. Results: There were a total of 49,405 patients treated with XRT and 170 patients treated with PBT. Median follow-up time was 62.1 months. On MVA, the following factors were associated with receipt of PBT (all p < 0.05): WHO Grade I-II gliomas, treatment at an academic/research program, west geographic facility location, and surgical resection. After PS weighting, all patients treated with PBT were found to have superior median and 5 year survival than patients treated with XRT: 45.9 vs. 29.7 months (p = 0.009) and 46.1 vs. 35.5% (p = 0.0160), respectively. Conclusions: PBT is associated with improved OS compared to XRT for patients with gliomas. This finding warrants verification in the randomized trial setting in order to account for potential patient imbalances not adequately captured by the NCDB, such as tumor molecular characteristics and patient performance status. Importance of the Study: This is the first study that compares the outcomes of patients treated with photon based radiotherapy vs. proton based radiotherapy for patients with gliomas. In this retrospective analysis, the results demonstrate that proton therapy is associated with improved outcomes which support ongoing prospective, randomized clinical trials comparing the two modalities in patients with gliomas.
Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7–32.9) and 68.4% (95% CI = 45.1%–83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2–19.6) and 54% (95% CI = 31.5%–72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218.
With limited high-level evidence, we carried out a comparative effectiveness study for the effect of proton beam therapy (PBT) on overall survival compared to external-beam radiotherapy (EBRT) and brachytherapy (BT) among patients with localized prostate cancer using a national database. PBT was associated with a significant overall survival benefit compared to EBRT and had a similar performance as BT.
Background:
There are few comparative outcomes data regarding the therapeutic delivery of proton beam therapy (PBT) versus the more widely used photon-based external-beam radiation (EBRT) and brachytherapy (BT). We evaluated the impact of PBT on overall survival (OS) compared to EBRT or BT on patients with localized prostate cancer.
Patients and Methods:
The National Cancer Data Base (NCDB) was queried for 2004–2015. Men with clinical stage T1–3, N0, M0 prostate cancer treated with radiation, without surgery or chemotherapy, were included. OS, the primary clinical outcome, was fit by Cox proportional hazard model. Propensity score matching was implemented for covariate balance.
Results:
There were 276,880 eligible patients with a median follow-up of 80.9 months. A total of 4900 (1.8%) received PBT, while 158,111 (57.1%) received EBRT and 113,869 (41.1%) BT. Compared to EBRT and BT, PBT patients were younger and were less likely to be in the high-risk group. On multivariable analysis, compared to PBT, men had worse OS after EBRT (adjusted hazard ratio [HR] = 1.72; 95% confidence interval [CI], 1.51–1.96) or BT (adjusted HR = 1.38; 95% CI, 1.21–1.58). After propensity score matching, the OS benefit of PBT remained significant compared to EBRT (HR = 1.64; 95% CI, 1.32–2.04) but not BT (adjusted HR = 1.18; 95% CI, 0.93–1.48). The improvement in OS with PBT was most prominent in men ≤ 65 years old with low-risk disease compared to other subgroups (interaction P < .001).
Conclusion:
In this national data set, PBT was associated with a significant OS benefit compared to EBRT, and with outcomes similar to BT. These results remain to be validated by ongoing prospective trials.
Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 months’ posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P <.001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, P =.049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 months’ posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed.
Introduction: As immunotherapy has improved distant metastasis-free survival (DMFS) in Non-Small Cell Lung Cancer (NSCLC), isolated locoregional recurrences have increased. However, management of locoregional recurrences can be challenging. We report our institutional experience with definitive intent re-irradiation using Intensity Modulated Proton Therapy (IMPT). Method: Retrospective cohort study of recurrent or second primary NSCLC or LS-SCLC treated with IMPT. Kaplan-Meier method and log-rank test were used for time-to-event analyses. Results: 22 patients were treated from 2019 to 2021. After first course of radiation (median 60 Gy, range 45-70 Gy), 45% received adjuvant immunotherapy. IMPT re-irradiation began a median of 28.2 months (8.8-172.9 months) after initial radiotherapy. The median IMPT dose was 60 GyE (44-60 GyE). 36% received concurrent chemotherapy with IMPT and 18% received immunotherapy after IMPT. The median patient’s IMPT lung mean dose was 5.3 GyE (0.9-13.9 GyE) and 5 patients had cumulative esophagus max dose >100 GyE with 1-year overall survival (OS) 68%, 1-year local control 80%, 1-year progression free survival 45%, and 1-year DMFS 60%. Higher IMPT (HR 1.4; 95% CI 1.1-1.7, p=0.01) and initial radiotherapy mean lung doses (HR 1.3; 95% CI 1.0-1.6, p=0.04) were associated with worse OS. Two patients developed Grade 3 pneumonitis or dermatitis, one patient developed Grade 2 pneumonitis, and seven patients developed Grade 1 toxicity. There were no Grade 4 or 5 toxicities. Discussion: Definitive IMPT re-irradiation for lung cancer can prolong disease control with limited toxicity, particularly in the immunotherapy era.