Using a patient-specific diffusion model to generate CBCT-based synthetic CTs for CBCT-guided adaptive radiotherapy.

BACKGROUND: Cone beam computed tomography (CBCT) can be used to evaluate the inter-fraction anatomical changes during the entire course for image-guided radiotherapy (IGRT). However, CBCT artifacts from various sources restrict the full application of CBCT-guided adaptive radiation therapy (ART). PURPOSE: Inter-fraction anatomical changes during ART, including variations in tumor size and normal tissue anatomy, can affect radiation therapy (RT) efficacy. Acquiring high-quality CBCT images that accurately capture patient- and fraction-specific (PFS) anatomical changes is crucial for successful IGRT. METHODS: To enhance CBCT image quality, we proposed PFS lung diffusion models (PFS-LDMs). The proposed PFS models use a pre-trained general lung diffusion model (GLDM) as a baseline, which is trained on historical deformed CBCT (dCBCT)-planning CT (pCT) paired data. For a given patient, a new PFS model is fine-tuned on a CBCT-deformed pCT (dpCT) pair after each fraction to learn the PFS knowledge for generating personalized synthetic CT (sCT) with quality comparable to pCT or dpCT. The learned PFS knowledge is the specific mapping relationships, including personal inter-fraction anatomical changes between personalized CBCT-dpCT pairs. The PFS-LDMs were evaluated on an institutional lung cancer dataset, quantified by mean absolute error (MAE), peak signal-to-noise ratio (PSNR), normalized cross-correlation (NCC), and structural similarity index measure (SSIM) metrics. We also compared our PFS-LDMs with a mainstream GAN-based model, demonstrating that our PFS fine-tuning strategy could be applied to existing generative models. RESULTS: Our models showed remarkable improvements across all four evaluation metrics. The proposed PFS-LDMs outperformed the GLDM, demonstrating the effectiveness of our proposed fine-tuning strategy. The PFS model fine-tuned with CBCT images from four prior fractions, reduced the MAE from 103.95 to 15.96 Hounsfield units (HU), and increased the mean PSNR, NCC, and SSIM from 25.36 dB to 33.57 dB, 0.77 to 0.98, and 0.75 to 0.97, respectively. Applying our PFS fine-tuning strategy to a Cycle GAN model also showed improvements, with all four fine-tuned PFS Cycle GAN (PFS-CG) models outperforming the general Cycle GAN model. Overall, our proposed PFS fine-tuning strategy improved CBCT image quality compared to both the pre-correction and non-fine-tuned general models, with our proposed PFS-LDMs yielding better performance than the GAN-based model across all metrics. CONCLUSIONS: Our proposed PFS-LDMs significantly improve CBCT image quality with increased HU accuracy and fewer artifacts, thus better capturing inter-fraction anatomical changes. This lays the groundwork for enabling CBCT-based ART, which could enhance clinical efficiency and achieve personalized high-precision treatment by accounting for inter-fraction anatomical changes.

Tailoring language for genitourinary function in patients with newly diagnosed prostate cancer to facilitate discussions in diverse populations and overcome health literacy barriers.

BACKGROUND: Poor comprehension of prostate cancer (PCa) medical terms can create barriers to PCa treatment discussions. The authors measured comprehension of PCa terms and its relationship to health literacy in a group of Black men who were newly diagnosed with PCa. They examined whether tailoring communication with alternative colloquial words would be helpful and acceptable. METHODS: Patients were recruited from urology clinics (N = 152). After they met with their providers to discuss PCa treatment options, they participated in an educational supplement delivered as a structured interview. The supplement tailored PCa treatment information by allowing men to choose between colloquial and medical terms for genitourinary (GU) function. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine, and comprehension of common PCa terms was assessed using published methods. Pearson correlation was used to estimate the association between health literacy and comprehension of PCa terms. Spearman rank correlation (r) was used to assess the relation between the total number of medical terms preferred (range, 0-10) and Rapid Estimate of Adult Literacy in Medicine scores (range, 0-66). RESULTS: Most patients (62%) had low health literacy, which was strongly correlated with their understanding of PCa terms (r = 0.526; p < .001). Poor comprehension of many PCa terms established the need to use alternative language for GU function (only 20% knew the word incontinence). There was a statistically significant positive association between the number of medical terms preferred and health literacy (r = 0.358; p < .001). A majority of patients (91%) preferred a mixture of medical and colloquial terms. CONCLUSIONS: Tailoring communications with colloquial terms for GU function was preferred by most patients regardless of health literacy.

CBCT-based synthetic CT image generation using a diffusion model for CBCT-guided lung radiotherapy.

BACKGROUND: Although cone beam computed tomography (CBCT) has lower resolution compared to planning CTs (pCT), its lower dose, higher high-contrast resolution, and shorter scanning time support its widespread use in clinical applications, especially in ensuring accurate patient positioning during the image-guided radiation therapy (IGRT) process. PURPOSE: While CBCT is critical to IGRT, CBCT image quality can be compromised by severe stripe and scattering artifacts. Tumor movement secondary to respiratory motion also decreases CBCT resolution. In order to improve the image quality of CBCT, we propose a Lung Diffusion Model (L-DM) framework. METHODS: Our proposed algorithm is based on a conditional diffusion model trained on pCT and deformed CBCT (dCBCT) image pairs to synthesize lung CT images from dCBCT images and benefit CBCT-based radiotherapy. dCBCT images were used as the constraint for the L-DM. The image quality and Hounsfield unit (HU) values of the synthetic CTs (sCT) images generated by the proposed L-DM were compared to three selected mainstream generation models. RESULTS: We verified our model in both an institutional lung cancer dataset and a selected public dataset. Our L-DM showed significant improvement in the four metrics of mean absolute error (MAE), peak signal-to-noise ratio (PSNR), normalized cross-correlation (NCC), and structural similarity index measure (SSIM). In our institutional dataset, our proposed L-DM decreased the MAE from 101.47 to 37.87 HU and increased the PSNR from 24.97 to 29.89 dB, the NCC from 0.81 to 0.97, and the SSIM from 0.80 to 0.93. In the public dataset, our proposed L-DM decreased the MAE from 173.65 to 58.95 HU, while increasing the PSNR, NCC, and SSIM from 13.07 to 24.05 dB, 0.68 to 0.94, and 0.41 to 0.88, respectively. CONCLUSIONS: The proposed L-DM significantly improved sCT image quality compared to the pre-correction CBCT and three mainstream generative models. Our model can benefit CBCT-based IGRT and other potential clinical applications as it increases the HU accuracy and decreases the artifacts from input CBCT images.

Biochemical Relapse-Free Survival in Postprostatectomy Patients Receiving 18F-Fluciclovine-Guided Prostate Bed-Only Radiation: Post Hoc Analysis of a Prospective Randomized Trial.

PURPOSE: Whole-pelvis (WP) radiation therapy (radiation) improved biochemical relapse-free survival (bRFS) compared with prostate bed (PB)-only radiation in the Radiation Therapy Oncology Group 0534, but was performed in an era prior to positron emission tomography (PET) staging. Separately, 18F-fluciclovine PET/CT-guided postprostatectomy radiation improved 3-year bRFS versus radiation guided by conventional imaging alone. We hypothesized that patients who were changed from WP to PB-only radiation after PET would have bRFS that was: (a) no higher than patients initially planned for PB-only radiation; and (b) lower than patients planned for WP radiation without PET guidance. METHODS AND MATERIALS: We conducted a post hoc analysis of a prospective, randomized trial comparing conventional (arm 1) versus PET-guided (arm 2) postprostatectomy radiation. In arm 2, pre-PET treatment field decisions were recorded and post-PET fields were defined per protocol; pathologic node negative (pN0) without pelvic or extrapelvic PET uptake received PB-only radiation. Three-year bRFS was compared in patients planned for WP with change to PB-only radiation (arm 2 [WP:PB]) vs arm 2 patients planned for PB-only with final radiation to PB-only (arm 2 [PB:PB]) and arm 1 pN0 patients treated with WP radiation (arm 1 [WP]) using the Z test and log-rank test. Demographics were compared using the chi-square test, Fisher exact test, or analysis of variance, as appropriate. RESULTS: We identified 10 arm 2 (WP:PB), 31 arm 2 (PB:PB) and 11 arm 1 (WP) patients. Androgen deprivation was used in 50.0% of arm 2 (WP:PB) and 3.2% of arm 2 (PB:PB) patients, P < .01. Median preradiation prostate-specific antigen was higher in arm 2 (WP:PB) vs arm 2 (PB:PB) patients (0.4 vs 0.2 ng/mL, P = .03); however, there were no significant differences in T stage, Gleason score, or margin positivity. Three-year bRFS was 80% in arm 2 (WP:PB) vs 87.4% in arm 2 (PB:PB), P = .47, respectively. Arm 1(WP) patients had significantly worse 3-year (23%) bRFS vs arm 2 (WP:PB), P < .01. CONCLUSIONS: Patients initially planned for WP radiation with field decision change to PB-only radiation after PET showed (1) no significant difference in 3-year bRFS compared with patients initially planned for PB-only radiation; and (2) improved bRFS compared with patients receiving WP radiation without PET guidance. PET-guided volume de-escalation in selected patients may be 1 approach to mitigating toxicity without compromising outcomes.

Patterns of Undertreatment and Overtreatment in Adjuvant Radiotherapy for Early-Stage Endometrial Cancer Based on Molecular Classification.

The quality improvement study examines the use of risk-adaptive adjuvant radiotherapy in women with non­mismatch repair deficiency endometrial cancer.

Safety and efficacy of durvalumab after concurrent chemoradiation in Black patients with locally advanced non-small cell lung cancer.

BACKGROUND: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard-of-care in patients with stage III or unresectable non-small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real-world evaluation of the PACIFIC regimen in these patients. METHODS: This single-institution, multi-site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021. Overall survival (OS), progression-free survival (PFS), and grade ≥3 pneumonitis-free survival (PNFS) were compared between Black and non-Black patients using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 105 patients with a median follow-up of 22.8 months (interquartile range, 11.3-37.3 months) were identified for analysis, including 57 Black (54.3%) and 48 (45.7%) non-Black patients. The mean radiation prescription dose was higher among Black patients (61.5 ± 2.9 Gy vs. 60.5 ± 1.9 Gy; p = .031), but other treatment characteristics were balanced between groups. The median OS (not-reached vs. 39.7 months; p = .379) and PFS (31.6 months vs. 19.3 months; p = .332) were not statistically different between groups. Eight (14.0%) Black patients discontinued durvalumab due to toxicity compared to 13 (27.1%) non-Black patients (p = .096). The grade ≥3 pneumonitis rate was similar between Black and non-Black patients (12.3% vs. 12.5%; p = .973), and there was no significant difference in time to grade ≥3 PNFS (p = .904). Three (5.3%) Black patients and one (2.1%) non-Black patient developed grade 5 pneumonitis. CONCLUSIONS: The efficacy and tolerability of consolidative durvalumab after chemoradiation appears to be comparable between Black and non-Black patients.

Impact of 18 F-Fluciclovine PET/CT Findings on Failure-Free Survival in Biochemical Recurrence of Prostate Cancer Following Salvage Radiation Therapy.

PURPOSE: We aimed to evaluate the impact of 18 F-fluciclovine PET/CT imaging on failure-free survival (FFS) post-salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence. METHODS: Seventy-nine patients were recruited in a phase 2/3 clinical trial to undergo 18 F-fluciclovine PET/CT before SRT for PCa. Four patients with extrapelvic disease were excluded. All patients were followed up at regular intervals up to 48 months. Treatment failure was defined as a serum prostate-specific antigen level of ≥0.2 ng/mL above the nadir after SRT, confirmed with an additional measurement, requiring systemic treatment or clinical progression. Failure-free survival was computed and compared between patients grouped according to 18 F-fluciclovine PET/CT imaging findings. RESULTS: Eighty percent (60/75) of patients had a positive finding on 18 F-fluciclovine PET/CT, of which 56.7% (34/60) had prostate bed-only uptake, whereas 43.3% (26/60) had pelvic nodal ± bed uptake. Following SRT, disease failure was detected in 36% (27/75) of patients. There was a significant difference in FFS between patients who had a positive versus negative scan (62.3% vs 92.9% [ P < 0.001] at 36 months and 59.4% vs 92.9% [ P < 0.001] at 48 months). Similarly, there was a significant difference in FFS between patients with uptake in pelvic nodes ± bed versus prostate bed only at 36 months (49.8% vs 70.7%; P = 0.003) and at 48 months (49.8% vs 65.6%; P = 0.040). Failure-free survival was also significantly higher in patients with either negative PET/CT or prostate bed-only disease versus those with pelvic nodal ± prostate bed disease at 36 (78% vs 49.8%, P < 0.001) and 48 months (74.4% vs 49.8%, P < 0.001). CONCLUSIONS: Findings on pre-SRT 18 F-fluciclovine PET/CT imaging, even when acted upon to optimize the treatment decisions and treatment planning, are predictive of post-SRT FFS in men who experience PCa recurrence after radical prostatectomy. A negative 18 F-fluciclovine PET/CT is most predictive of a lower risk of failure, whereas the presence of pelvic nodal recurrence portends a higher risk of SRT failure.

Differences in Failure-Free Survival After Salvage Radiotherapy Guided by Conventional Imaging Versus 18F-Fluciclovine PET/CT in Postprostatectomy Patients: A Post Hoc Substratification Analysis of the EMPIRE-1 Trial.

The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement 1) trial reported a survival advantage in recurrent prostate cancer salvage radiotherapy (SRT) guided by 18F-fluciclovine PET/CT versus conventional imaging. We performed a post hoc analysis of the EMPIRE-1 cohort stratified by protocol-specified criteria, comparing failure-free survival (FFS) between study arms. Methods: EMPIRE-1 randomized patients to SRT planning via either conventional imaging only (bone scanning plus abdominopelvic CT or MRI) (arm A) or conventional imaging plus 18F-fluciclovine PET/CT (arm B). Randomization was stratified by prostate-specific antigen (PSA) level (<2.0 vs. ≥ 2.0 ng/mL), adverse pathology, and androgen-deprivation therapy (ADT) intent. We subdivided patients in each arm using the randomization stratification criteria and compared FFS between patient subgroups across study arms. Results: Eighty-one and 76 patients received per-protocol SRT in study arms A and B, respectively. The median follow-up was 3.5 y (95% CI, 3.0-4.0). FFS was 63.0% and 51.2% at 36 and 48 mo, respectively, in arm A and 75.5% at both 36 and 48 mo in arm B. Among patients with a PSA of less than 2 ng/mL (mean, 0.42 ± 0.42 ng/mL), significantly higher FFS was seen in arm B than arm A at 36 mo (83.2% [95% CI, 70.0-91.0] vs. 66.5% [95% CI, 51.6-77.8], P < 0.001) and 48 mo (83.2% [95% CI, 70.0-91.0] vs. 56.2% [95% CI, 40.5-69.2], P < 0.001). No significant difference in FFS between study arms in patients with a PSA of at least 2 ng/mL was observed. Among patients with adverse pathology, significantly higher FFS was seen in arm B than arm A at 48 mo (68.9% [95% CI, 52.1-80.8] vs. 42.8% [95% CI, 26.2-58.3], P < 0.001) though not at the 36-mo follow-up. FFS was higher in patients without adverse pathology in arm B versus arm A (90.2% [95% CI, 65.9-97.5] vs. 73.1% [95% CI, 42.9-89.0], P = 0.006) at both 36 and 48 mo. Patients in whom ADT was intended in arm B had higher FFS than those in arm A, with the difference reaching statistical significance at 48 mo (65.2% [95% CI, 40.3-81.7] vs. 29.1 [95% CI, 6.5-57.2], P < 0.001). Patients without ADT intent in arm B had significantly higher FFS than patients in arm A at 36 mo (80.7% [95% CI, 64.9-90.0] vs. 68.0% [95% CI, 51.1-80.2]) and 48 mo (80.7% [95% CI, 64.9-90.0] vs. 58.6% [95% CI, 41.0-72.6]). Conclusion: The survival advantage due to the addition of 18F-fluciclovine PET/CT to SRT planning is maintained regardless of the presence of adverse pathology or ADT intent. Including 18F-fluciclovine PET/CT to SRT leads to survival benefits in patients with a PSA of less than 2 ng/mL but not in patients with a PSA of 2 ng/mL or higher.

Incidence and predictors of toxicity in the management of vulvar squamous cell carcinoma treated with radiation therapy.

Purpose/Objective: Given the rarity of vulvar cancer, data on the incidence of acute and late severe toxicity and patients' symptom burden from radiotherapy (RT) are lacking. Materials/Methods: This multi-center, single-institution study included patients with vulvar squamous cell carcinoma treated with curative intent RT between 2009 and 2020. Treatment-related acute and late grade ≥ 3 toxicities and late patient subjective symptoms (PSS) were recorded. Results: Forty-two patients with predominantly stage III/IV disease (n = 25, 59.5 %) were treated with either definitive (n = 25, 59.5 %) or adjuvant (n = 17, 40.5 %) external beam RT to a median dose of 64 Gy and 59.4 Gy, respectively. Five patients received a brachytherapy boost with a median total dose of 84.3 Gy in 2 Gy-equivalent dose (EQD2). Intensity-modulated RT was used in 37 (88.1 %) of patients, and 25 patients (59.5 %) received concurrent chemotherapy. Median follow-up was 27 months. Acute grade ≥ 3 toxicity occurred in 17 patients (40.5 %), including 13 (31.0 %) acute grade 3 skin events. No factors, including total RT dose (p = 0.951), were associated with acute skin toxicity. Eleven (27.5 %) patients developed late grade ≥ 3 toxicity events, including 10 (23.8 %) late grade ≥ 3 skin toxicity events. Patients with late grade ≥ 3 skin toxicity had a higher mean body-mass index (33.0 vs 28.2 kg/m2; p = 0.009). Common late PSS included vaginal pain (n = 15, 35.7 %), skin fibrosis (n = 10, 23.8 %), and requirement of long-term opiates (n = 12, 28.6 %). Conclusion: RT for vulvar cancer is associated with considerable rates of severe acute and late toxicity and PSS burden. Larger studies are needed to identify risk factors, explore toxicity mitigation strategies, and assess patient-reported outcomes.

Impact of radiation dose to the immune cells in unresectable or stage III non-small cell lung cancer in the durvalumab era.

BACKGROUND/PURPOSE: Higher estimated radiation doses to immune cells (EDIC) have correlated with worse overall survival (OS) in patients with locally-advanced non-small cell lung cancer (NSCLC) prior to the PACIFIC trial, which established consolidative durvalumab as standard-of-care. Here, we examine the prognostic impact of EDIC in the durvalumab era. MATERIALS/METHODS: This single-institution, multi-center study included patients with unresectable stage II/III NSCLC treated with chemoradiation followed by durvalumab. Associations between EDIC [analyzed continuously and categorically (≤6 Gy vs > 6 Gy)] and OS, progression-free survival (PFS), and locoregional control (LRC) were evaluated by Kaplan-Meier and Cox proportional methods. RESULTS: 100 patients were included with median follow-up of 23.7 months. The EDIC > 6 Gy group had a significantly greater percentage of stage IIIB/IIIC disease (76.0 % vs 32.6 %; p < 0.001) and larger tumor volumes (170 cc vs 42 cc; p < 0.001). There were no differences in early durvalumab discontinuation from toxicity (24.1 % vs 15.2 %; p = 0.27). Median OS was shorter among the EDIC > 6 Gy group (29.6 months vs not reached; p < 0.001). On multivariate analysis, EDIC > 6 Gy correlated with worse OS (HR: 4.15, 95 %CI: 1.52-11.33; p = 0.006), PFS (HR: 3.79; 95 %CI: 1.80-8.0; p < 0.001), and LRC (HR: 2.66, 95 %CI: 1.15-6.18; p = 0.023). Analyzed as a continuous variable, higher EDIC was associated with worse OS (HR: 1.34; 95 %CI: 1.16-1.57; p < 0.001), PFS (HR: 1.52; 95 %CI: 1.29-1.79; p < 0.001), and LRC (HR: 1.34, 95 %CI: 1.13-1.60; p = 0.007). CONCLUSIONS: In the immunotherapy era, EDIC is an independent predictor of OS and disease control in locally advanced NSCLC, warranting investigation into techniques to reduce dose to the immune compartment.

Randomized Trial of Conventional Versus Conventional Plus Fluciclovine (18F) Positron Emission Tomography/Computed Tomography-Guided Postprostatectomy Radiation Therapy for Prostate Cancer: Volumetric and Patient-Reported Analyses of Toxic Effects.

PURPOSE: Postprostatectomy radiation therapy planning with fluciclovine (18F) positron emission tomography (PET)/computed tomography has demonstrated improved disease-free survival over conventional only (computed tomography- or magnetic resonance imaging-based) treatment planning. We hypothesized that incorporating PET would result in larger clinical target volumes (CTVs) without increasing patient-reported toxic effects. METHODS AND MATERIALS: From 2012 to 2019, 165 postprostatectomy patients with detectable prostate-specific antigen were randomized (arm 1 [no PET]: 82; arm 2 [PET]: 83). Prostate bed target volumes with (CTV1: 45.0-50.4 Gy/1.8 Gy) or without (CTV2/CTV: 64.8-70.2 Gy/1.8 Gy) pelvic nodes, as well as organ-at-risk doses, were compared pre- versus post-PET (arm 2) using the paired t test and between arms using the t test. Patient-reported outcomes used International Prostate Symptom Score and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP). Univariate and multivariable analyses were performed and linear mixed models were fitted. RESULTS: Median follow-up of the whole cohort was 3.52 years. All patients had baseline patient-reported outcomes, 1 patient in arm 1 and 3 patients in arm 2 withdrew, and 4 arm 2 patients had extrapelvic uptake on PET with radiotherapy aborted, leaving 81 (arm 1) and 76 patients (arm 2) for analysis of toxic effects. Mean CTV1 (427.6 vs 452.2 mL; P = .462, arm 1 vs arm 2) and CTV2/CTV (137.18 vs 134.2 mL; P = .669) were similar before PET incorporation. CTV1 (454.57 vs 461.33 mL; P = .003) and CTV2/CTV (134.14 vs 135.61 mL; P < .001) were modestly larger after PET incorporation. Although V40 Gy (P = .402 and P = .522 for rectum and bladder, respectively) and V65 Gy (P = .157 and P = .182 for rectum and bladder, respectively) were not significantly different pre- versus post-PET, penile bulb dose significantly increased post-PET (P < .001 for both V40 Gy and V65 Gy). On univariate and multivariable analyses, arm was not significant for any EPIC-CP subdomain. International Prostate Symptom Score and EPIC-CP linear mixed models were not significantly different between arms. CONCLUSIONS: Despite larger CTVs after incorporation of fluciclovine (18F) PET, we found no significant difference in patient-reported toxic effects with long-term follow-up.

Bone Marrow Suppression during Postoperative Radiation for Bladder Cancer and Comparative Benefit of Proton Therapy-Phase 2 Trial Secondary Analysis.

PURPOSE: For patients with high-risk bladder cancer (pT3+ or N+), local regional failure remains a challenge after chemotherapy and cystectomy. An ongoing prospective phase 2 trial (NCT01954173) is examining the role of postoperative photon radiation therapy for high-risk patients using volumetric modulated arc therapy. Proton beam therapy (PBT) may be beneficial in this setting to reduce hematologic toxicity. We evaluated for dosimetric relationships with pelvic bone marrow (PBM) and changes in hematologic counts before and after pelvic radiation therapy and explored the potential of PBT treatment plans to achieve reductions in PBM dose. MATERIALS AND METHODS: All enrolled patients were retrospectively analyzed after pelvic radiation per protocol with 50.4 to 55.8 Gy in 28 to 31 fractions. Comparative PBT plans were generated using pencil-beam scanning and a 3-beam multifield optimization technique. Changes in hematologic nadirs were assessed using paired t test. Correlation of mean nadirs and relative PBM dose levels were assessed using the Pearson correlation coefficient (CC). RESULTS: Eighteen patients with a median age of 70 were analyzed. Mean cell count values after radiation therapy decreased compared with preradiation therapy values for white blood cells (WBCs), absolute neutrophil count (ANC), absolute lymphocyte count (all P < .001), and platelets (P = .03). Increased mean PBM dose was associated with lower nadirs in WBC (Pearson CC -0.593, P = .02), ANC (Pearson CC -0.597, P = .02), and hemoglobin (Pearson CC -0.506, P = .046), whereas the PBM V30 to V40 correlated with lower WBC (Pearson CC -0.512 to -0.618, P < .05), and V20 to V30 correlated with lower ANC (Pearson CC -0.569 to -0.598, P < .04). Comparative proton therapy plans decreased the mean PBM dose from 26.5 Gy to 16.1 Gy (P < .001) and had significant reductions in the volume of PBM receiving doses from 5 to 40 Gy (P < .001). CONCLUSION: Increased PBM mean dose and V20 to V40 were associated with lower hematologic nadirs. PBT plans reduced PBM dose and may be a valuable strategy to reduce the risk of hematologic toxicity in these patients.

Definitive intensity modulated proton re-irradiation for lung cancer in the immunotherapy era.

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.

Influence of Timing Between Androgen Deprivation Therapy and External Beam Radiation Therapy in Patients With Localized, High-Risk Prostate Cancer.

PURPOSE: Treatment with long-term androgen deprivation therapy (ADT) and radiation therapy (RT) is the nonsurgical standard-of-care for patients with high- or very high-risk prostate cancer (HR-PC), but the optimal timing between ADT and RT initiation is unknown. We evaluate the influence of timing between ADT and RT on outcomes in patients with HR-PC using a large national cancer database. METHODS AND MATERIALS: Data for patients with clinical T1-T4 N0, M0, National Cancer Comprehensive Network HR-PC who were treated with definitive external RT (≥60 Gy) and ADT starting either before or within 14 days after RT start were extracted from the National Cancer Database (2004-2015). Patients were grouped on the basis of ADT initiation: (1) >11 weeks before RT, (2) 8 to 11weeks before RT, and (3) <8 weeks before RT. Kaplan-Meier, propensity score matching, and multivariable Cox proportional hazards were performed to evaluate overall survival (OS). RESULTS: With a median follow-up of 68.9 months, 37,606 patients with HR-PC were eligible for analysis: 13,346 (35.5%) with >11 weeks of neoadjuvant ADT, 11,456 (30.5%) with 8 to 11 weeks of neoadjuvant ADT; and 12,804 (34%) patients with <8 weeks of neoadjuvant ADT. The unadjusted 10-year OS rates for >11 weeks, 8 to 11 weeks, and <8 weeks neoadjuvant ADT groups were 49.9%, 51.2%, and 46.9%, respectively (P = .002). On multivariable and inverse probability of treatment weighting analyses, there was a significant OS advantage for patients in the 8 to 11 weeks neoadjuvant ADT group (adjusted hazard ratio 0.90; 95% confidence interval, 0.86-0.95; P < .001) but not the >11 weeks group. CONCLUSIONS: Neoadjuvant ADT initiation 8 to 11 weeks before RT is associated with significantly improved OS compared with shorter neoadjuvant ADT duration. Although prospective validation is warranted, this analysis is the largest retrospective study suggesting an influence of timing between ADT and RT initiation in HR-PC.

18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.

BACKGROUND: Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy. METHODS: In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants. FINDINGS: From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98-3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2-not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached-not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2-74·0) in the conventional imaging group versus 75·5% (95% CI 62·5-84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3-20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 [95% CI 1·06-3·93], p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 [46%] of 81 patients in the conventional imaging group and 31 [41%] of 76 in the PET group), and acute diarrhoea (11 [14%] in the conventional imaging group and 16 [21%] in the PET group). INTERPRETATION: Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study. FUNDING: National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.

Small-Cell Carcinoma of the Prostate: Report of Outcomes of Localized Disease Using the National Cancer Database.

BACKGROUND: Small-cell carcinoma of the prostate (SCCP) is a rare but aggressive prostate cancer histology. We studied the reported comparative outcomes of the efficacy of radiotherapy (RT) versus surgery for nonmetastatic SCCP. METHODS: The National Cancer Database (NCDB) was queried for nonmetastatic disease diagnosed from 2004 to 2015 as SCCP (defined as having a component of SCCP) receiving a single definitive local control modality (RT or surgery). RESULTS: A total of 243 patients were included (177 RT and 66 surgery). A total of 142 patients received chemotherapy (CHT). Mean age was 68 years. One hundred forty patients had adenocarcinoma concurrently with the SCCP while 103 patients had pure histology. For pure histology, multivariable analysis (MVA) showed nonacademic facility, stage 4 disease, and poorly differentiated grade were associated with worse survival. On MVA, receipt of CHT (hazard ratio [HR] = 0.84, P = .644) or receipt of androgen deprivation therapy (HR = 0.88, P = .715) did not affect overall survival. Receipt of RT was nonsignificant compared to surgery (HR = 0.75, P = .475). For mixed histology, MVA showed receipt of CHT and prostate-specific antigen > 20 ng/mL were associated with worse survival. Receipt of androgen deprivation therapy (HR = 1.35, P = .414) did not affect overall survival. Receipt of RT was also nonsignificant compared to surgery (HR = 1.42, P = .344). CONCLUSION: RT and surgery for nonmetastatic SCCP yield comparable options as local therapies.

Overall Survival After Treatment of Localized Prostate Cancer With Proton Beam Therapy, External-Beam Photon Therapy, or Brachytherapy.

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.

Lung Stereotactic Body Radiation Therapy and Concurrent Immunotherapy: A Multicenter Safety and Toxicity Analysis.

PURPOSE: Radical treatment of metastases with stereotactic body radiation therapy (SBRT) is commonly implemented in patients receiving concurrent immune checkpoint inhibition (ICI), despite limited safety and toxicity data. The purpose of this study was to evaluate the safety and tolerability of lung SBRT with concurrent ICI. METHODS AND MATERIALS: Records from a single academic institution were reviewed to identify patients treated with lung SBRT and concurrent (within 30 days) ICI; a contemporaneous cohort receiving lung SBRT alone was included for reference. Treatment-related adverse effects occurring within 30 days (acute) and 180 days (subacute) of SBRT were evaluated. RESULTS: Our study included 117 patients; 54 received SBRT with concurrent ICI (56 courses, 69 target lesions), and 63 received SBRT alone (68 courses, 79 lesions). Median follow-up was 9.2 months in the SBRT + ICI cohort. Among the patients, 67.9% received ICI monotherapy, 17.9% ICI/chemotherapy, and 14.3% ICI/ICI combinations; 25% received ICI between SBRT fractions, and 42.9% received ICI both before and after SBRT. The risk of grade 3 pneumonitis was higher in the SBRT + ICI versus SBRT alone cohort (10.7% vs 0%, P < .01) and any-grade pneumonitis was similar (33.9% vs 27.9%, SBRT + ICI vs SBRT, P = .47). The risk of any-grade pneumonitis appeared elevated with ICI/ICI combinations (62.5% vs 29.2%). Receipt of ICI, planning treatment volume, and lobes involved in SBRT were linked to high-grade pneumonitis. Subacute grade 3+ adverse effects occurred in 26.8% of SBRT + ICI and 2.9% of SBRT-alone patients. CONCLUSIONS: Overall, concurrent lung SBRT + ICI is safe. Given the clinically meaningful risk of pneumonitis, closer monitoring should be considered for SBRT + ICI patients, especially those receiving radiation therapy with ICI/ICI combinations.

Health care disparities among octogenarians and nonagenarians with stage III lung cancer.

BACKGROUND: To the authors' knowledge, the practice patterns for patients aged more than 80 years with stage III non-small cell lung cancer (NSCLC) is not well known. The purpose of the current study was to investigate factors predictive of and the impact on overall survival (OS) after concurrent chemoradiation (CRT) among patients aged ≥80 years with American Joint Committee on Cancer stage III NSCLC in the National Cancer Data Base (NCDB). METHODS: In the NCDB, patients aged ≥80 years who were diagnosed with stage III NSCLC from 2004 to 2013 with complete treatment records were identified. Multivariable logistic regression and Cox proportional hazard models were generated and propensity score-matched analysis was used. RESULTS: A total of 12,641 patients met the entry criteria: 6018 (47.6%) had stage IIIA disease and 6623 (52.4%) had stage IIIB disease. The median age at the time of diagnosis was 83.0 years (range, 80-91 years). A total of 7921 patients (62.7%) received no therapy. Black race (odds ratio [OR], 1.23; 95% confidence interval [95% CI], 1.06-1.43) and living in a lower educated census tract of residence (OR, 1.20; 95% CI, 1.03-1.40) were found to be associated with not receiving care, whereas treatment at an academic center (OR, 0.80; 95% CI, 0.70-0.92) was associated with receiving cancer-directed therapy. Receipt of no treatment (hazard ratio [HR], 2.69; 95% CI, 2.57-2.82) or definitive radiation alone (HR, 1.15; 95% CI, 1.07-1.24) compared with CRT was associated with worse OS. On propensity score matching, not receiving CRT was found to be associated with worse OS (HR, 1.58; 95% CI, 1.44-1.72). CONCLUSIONS: In this NCDB analysis, approximately 62.7% of patients aged ≥80 years with stage III NSCLC received no cancer-directed care. Black race and living in a lower educated census tract were associated with not receiving cancer-directed care. OS was found to be improved in patients receiving CRT. Cancer 2018;124:775-84. © 2018 American Cancer Society.

Next-generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy.

BACKGROUND: Genetic aberrations are well characterized in lung adenocarcinomas (LACs) and clinical outcomes have been influenced by targeted therapies in the advanced setting. Stereotactic body radiotherapy (SBRT) is the standard-of-care therapy for patients with nonoperable, early-stage LAC, but to the authors' knowledge, no information is available regarding the impact of genomic changes in these patients. The current study sought to determine the frequency and clinical impact of genetic aberrations in this population. METHODS: Under an Institutional Review Board-approved protocol, the records of 242 consecutive patients with early-stage lung cancers were reviewed; inclusion criteria included LAC histology with an adequate tumor sample for the successful use of next-generation sequencing and fluorescence in situ hybridization testing. Univariate analysis was performed to identify factors associated with clinical outcomes. RESULTS: LAC samples from 98 of the 242 patients were reviewed (40.5%), of whom 45 patients (46.0%) had genetic testing. The following mutations were noted: KRAS in 20.0% of samples, BRAF in 2.2% of samples, SMAD family member 4 (SMAD4) in 4.4% of samples, epidermal growth factor receptor (EGFR) in 15.6% of samples, STK1 in 2.2% of samples, tumor protein 53 (TP53) in 15.6% of samples, and phosphatase and tensin homolog (PTEN) in 2.2% of samples. The following gene rearrangements were observed: anaplastic lymphoma kinase (ALK) in 8.9% of samples, RET in 2.2% of samples, and MET amplification in 17.8% of samples. The median total delivered SBRT dose was 50 grays (range, 48-60 grays) over a median of 5 fractions (range, 3-8 fractions). The KRAS mutation was associated with worse local control (odds ratio [OR], 3.64; P<.05). MET amplification was associated with worse regional (OR, 4.64; P<.05) and distant (OR, 3.73; P<.05) disease control. CONCLUSIONS: To the authors' knowledge, the current series is the first to quantify genetic mutations and their association with clinical outcomes in patients with early-stage LAC treated with SBRT. KRAS mutations were associated with worse local control and MET amplification was associated with worse regional and distant disease control, findings that need to be validated in a prospective setting. Cancer 2017;123:3681-3690. © 2017 American Cancer Society.