A Prospective Phase I/II Clinical Trial of High-Dose Proton Therapy for Chordomas and Chondrosarcomas.

Purpose: The purpose of this study was to evaluate the feasibility and safety of dose-escalated proton beam therapy for treating chordomas and chondrosarcomas of the skull base and spine. Methods: A prospective cohort of 54 patients (42 with chordomas and 12 with chondrosarcomas) was enrolled between 2010 and 2018. The primary endpoints were feasibility and <20% rate of acute grade ≥3 toxicity, and secondary endpoints included cancer-specific outcomes and toxicities. Patients were followed with magnetic resonance imaging or computed tomography at 3-month intervals. Proton beam therapy was delivered with doses up to 79.2 Gy using protons only, combination protons/intensity modulated radiation therapy (IMRT), or IMRT only. Results: Feasibility endpoints were met, with only 2 out of 54 patient radiation therapy plans failing to meet dosimetric constraints with protons, and 4 out of 54 experiencing a delay or treatment break >5 days, none for toxicities related to treatment. There were no grade 4 acute toxicities and 1 grade 3 acute toxicity (sensory neuropathy). The only 2 grade 3 late toxicities recorded, osteoradionecrosis and intranasal carotid blowout (mild and not emergently treated), occurred in a single patient. We report overall survival as 83% at 5 years, with local failure-free survival and progression-free survival rates of 72% and 68%, respectively. Five patients developed distant disease, and among the 9/54 patients who died, 4 deaths were not attributed to treatment or recurrence. Conclusions: Our findings suggest that high-dose proton therapy alone or in combination with IMRT is a safe and effective treatment option for chordomas and chondrosarcomas of the skull base and spine.

Locoregional Control Benefit of a Tumor Bed Boost for Ductal Carcinoma In Situ.

Purpose: Radiation therapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces invasive and in situ recurrences. Whereas landmark studies suggest that a tumor bed boost improves local control for invasive breast cancer, the benefit in DCIS remains less certain. We evaluated outcomes of patients with DCIS treated with or without a boost. Methods and Materials: The study cohort comprised patients with DCIS who underwent BCS at our institution from 2004 to 2018. Clinicopathologic features, treatment parameters, and outcomes were ascertained from medical records. Patient and tumor characteristics were evaluated relative to outcomes using univariable and multivariable Cox models. Recurrence-free survival (RFS) estimates were generated using the Kaplan-Meier method. Results: We identified 1675 patients who underwent BCS for DCIS (median age, 56 years; interquartile range, 49-64 years). Boost RT was used in 1146 cases (68%) and hormone therapy in 536 (32%). At a median follow-up of 4.2 years (interquartile range, 1.4-7.0 years), we observed 61 locoregional recurrence events (56 local, 5 regional) and 21 deaths. Univariable logistic regression demonstrated that boost RT was more common among younger patients (P < .001) with positive or close margins (P < .001) and with larger tumors (P < .001) of higher grade (P = .025). The 10-year RFS rate was 88.8% among those receiving a boost and 84.3% among those without a boost (P = .3), and neither univariable nor multivariable analyses revealed an association between boost RT and locoregional recurrence. Conclusions: Among patients with DCIS who underwent BCS, use of a tumor bed boost was not associated with locoregional recurrence or RFS. Despite a preponderance of adverse features among the boost cohort, outcomes were similar to those of patients not receiving a boost, suggesting that a boost may mitigate risk of recurrence among patients with high-risk features. Ongoing studies will elucidate the extent to which a tumor bed boost influences disease control rates.

Radiation Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma: What Is the Right Regimen for Palliation?

Purpose: To report objective response rates (ORR), time to local failure (TTLF), and overall survival (OS) among patients with relapsed or refractory diffuse large B-cell lymphoma after salvage- or palliative-intent radiation therapy (RT) and to investigate whether outcomes differed with conventional versus hypofractionated (≥2.5 Gy/fraction) RT. Methods and Materials: A single-institution observational cohort study was performed for patients who completed a course of RT for relapsed or refractory diffuse large B-cell lymphoma between January 1, 2008, and April 1, 2020. Predictors of ORR, TTLF, and OS were calculated using univariable and multivariable regression models. The Kaplan-Meier method was used to estimate TTLF and OS, and log-rank analysis was used to compare outcomes. Equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/ß of 10. Results: One-hundred and sixty-nine patients were treated with 205 RT courses (73 [36%] salvage, 132 [64%] palliative), and hypofractionated RT was used in 100 RT courses (49%). Median RT dose was 30 Gy (range, 8-60 Gy). ORR was 60% for the total cohort (53% and 69% for palliative and salvage cohorts, respectively). Over a median follow-up time of 4 months, median OS in all patients was 5 months (3 and 22 months for palliative and salvage cohorts, respectively). No statistically significant differences in ORR, TTLF, and OS were observed with hypofractionation compared with conventional fractionation. EQD2 ≥35 Gy was associated with improved ORR (odds ratio, 3.79 [1.19-12.03]; P = .024) and prolonged TTLF (0.39 [0.18-0.87]; P = .022), while double-hit receptor status (8.18 [1.08-62.05]; P = .042), cell of origin (3.87 [1.17-8.74]; P = .0012), and bulky disease (≥7.5 cm; 2.12 [1.18-3.81]; P = .012) were associated with inferior TTLF. In the palliative-only cohort, a low-dose regimen of 8 Gy in 2 fractions was associated with similar ORR compared with other fractionation schema but trended towards inferior TTLF (P = .36). Conclusions: Hypofractionation is not associated with differences in disease outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma, while higher RT dose (EQD2 ≥35 Gy) may improve ORR and TTLF. Future work is warranted to elucidate the ideal dose and fractionation schema for such patients who will likely also undergo novel systemic agents and cellular therapies.

Preclinical models of radiation-induced cardiac toxicity: Potential mechanisms and biomarkers.

Radiation therapy (RT) is an important modality in cancer treatment with >50% of cancer patients undergoing RT for curative or palliative intent. In patients with breast, lung, and esophageal cancer, as well as mediastinal malignancies, incidental RT dose to heart or vascular structures has been linked to the development of Radiation-Induced Heart Disease (RIHD) which manifests as ischemic heart disease, cardiomyopathy, cardiac dysfunction, and heart failure. Despite the remarkable progress in the delivery of radiotherapy treatment, off-target cardiac toxicities are unavoidable. One of the best-studied pathological consequences of incidental exposure of the heart to RT is collagen deposition and fibrosis, leading to the development of radiation-induced myocardial fibrosis (RIMF). However, the pathogenesis of RIMF is still largely unknown. Moreover, there are no available clinical approaches to reverse RIMF once it occurs and it continues to impair the quality of life of long-term cancer survivors. Hence, there is an increasing need for more clinically relevant preclinical models to elucidate the molecular and cellular mechanisms involved in the development of RIMF. This review offers an insight into the existing preclinical models to study RIHD and the suggested mechanisms of RIMF, as well as available multi-modality treatments and outcomes. Moreover, we summarize the valuable detection methods of RIHD/RIMF, and the clinical use of sensitive radiographic and circulating biomarkers.

Radiomic Phenotypes for Improving Early Prediction of Survival in Stage III Non-Small Cell Lung Cancer Adenocarcinoma after Chemoradiation.

We evaluate radiomic phenotypes derived from CT scans as early predictors of overall survival (OS) after chemoradiation in stage III primary lung adenocarcinoma. We retrospectively analyzed 110 thoracic CT scans acquired between April 2012-October 2018. Patients received a median radiation dose of 66.6 Gy at 1.8 Gy/fraction delivered with proton (55.5%) and photon (44.5%) beam treatment, as well as concurrent chemotherapy (89%) with carboplatin-based (55.5%) and cisplatin-based (36.4%) doublets. A total of 56 death events were recorded. Using manual tumor segmentations, 107 radiomic features were extracted. Feature harmonization using ComBat was performed to mitigate image heterogeneity due to the presence or lack of intravenous contrast material and variability in CT scanner vendors. A binary radiomic phenotype to predict OS was derived through the unsupervised hierarchical clustering of the first principal components explaining 85% of the variance of the radiomic features. C-scores and likelihood ratio tests (LRT) were used to compare the performance of a baseline Cox model based on ECOG status and age, with a model integrating the radiomic phenotype with such clinical predictors. The model integrating the radiomic phenotype (C-score = 0.69, 95% CI = (0.62, 0.77)) significantly improved (p<0.005) upon the baseline model (C-score = 0.65, CI = (0.57, 0.73)). Our results suggest that harmonized radiomic phenotypes can significantly improve OS prediction in stage III NSCLC after chemoradiation.

Implementation of FDG-PET/CT imaging methodology for quantification of inflammatory response in patients with locally advanced non-small cell lung cancer: results from the ACRIN 6668/RTOG 0235 trial.

We measured changes in 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) images in the lung parenchyma to quantify the degree of lung inflammation in patients with locally advanced non-small cell lung cancer (NSCLC) who received radiotherapy (RT). The goal of this study was to demonstrate successful implementation of this imaging methodology on NSCLC patients and to report quantitative statistics between pre-RT and post-RT. Seventy-one patients with NSCLC underwent FDG-PET/CT imaging before and after RT in a prospective study (ACRIN 6668/RTOG 0235). Comparisons between pre-RT and post-RT PET/CT were conducted for partial volume corrected (PVC)-mean standardized uptake value (SUVmean), PVC-global lung parenchymal glycolysis (GLPG), and lung volume for both ipsilateral and contralateral lungs using the nonparametric Wilcoxon signed-rank test. Regression modeling was conducted to associate clinical characteristics with post-RT PET/CT parameters. There was a significant increase in average SUVmean and GLPG of the ipsilateral lung (relative change 40% and 20%) between pre-RT and post-RT PET/CT scans (P<0.0001 and P=0.004). Absolute increases in PVC-SUVmean and PVC-GLPG were more pronounced (ΔPVC-SUVmean 0.32 versus ΔSUVmean 0.28; ΔPVC-GLPG 463.34 cc versus ΔGLPG 352.90 cc) and highly significant (P<0.0001). In contrast, the contralateral lung demonstrated no significant difference between pre-RT to post-RT in either GLPG (P=0.12) or SUVmean (P=0.18). The only clinical feature significantly associated with post-RT PET/CT parameters was clinical staging. Our study demonstrated inflammatory response in the ipsilateral lung of NSCLC patients treated with photon RT, suggesting that PET/CT parameters may serve as biomarkers for radiation pneumonitis (RP).

Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer.

INTRODUCTION: Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition. METHODS: We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging. RESULTS: Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8-40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months. CONCLUSIONS: The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer.

A Novel Mouse Model of Radiation-Induced Cardiac Injury Reveals Biological and Radiological Biomarkers of Cardiac Dysfunction with Potential Clinical Relevance.

PURPOSE: Radiation-induced cardiotoxicity is a significant concern in thoracic oncology patients. However, the basis for this disease pathology is not well characterized. We developed a novel mouse model of radiation-induced cardiotoxicity to investigate pathophysiologic mechanisms and identify clinically targetable biomarkers of cardiac injury. EXPERIMENTAL DESIGN: Single radiation doses of 20, 40, or 60 Gy were delivered to the cardiac apex of female C57BL/6 mice ages 9-11 weeks, with or without adjacent lung tissue, using conformal radiotherapy. Cardiac tissue was harvested up to 24 weeks post-radiotherapy for histologic analysis. Echocardiography and Technetium-99m sestamibi single photon emission computed tomography (SPECT) at 8 and 16 weeks post-radiotherapy were implemented to evaluate myocardial function and perfusion. Mouse cardiac tissue and mouse and human plasma were harvested for biochemical studies. RESULTS: Histopathologically, radiotherapy resulted in perivascular fibrosis 8 and 24 (P < 0.05) weeks post-radiotherapy. Apical perfusion deficits on SPECT and systolic and diastolic dysfunction on echocardiography 8 and 16 weeks post-radiotherapy were also observed (P < 0.05). Irradiated cardiac tissue and plasma showed significant increases in placental growth factor (PlGF), IL6, and TNFα compared with nonradiated matched controls, with greater increases in cardiac cytokine levels when radiotherapy involved lung. Human plasma showed increased PlGF (P = 0.021) and TNFα (P = 0.036) levels after thoracic radiotherapy. PlGF levels demonstrated a strong correlation (r = 0.89, P = 0.0001) with mean heart dose. CONCLUSIONS: We developed and characterized a pathophysiologically relevant mouse model of radiation-induced cardiotoxicity involving in situ irradiation of the cardiac apex. The model can be used to integrate radiomic and biochemical markers of cardiotoxicity to inform early therapeutic intervention and human translational studies.

The efficacy and safety of definitive concurrent chemoradiotherapy for non-operable esophageal cancer.

OBJECTIVE: To report outcomes and toxicity in patients who received definitive concurrent chemoradiation (DCCRT) for non-operable esophageal cancer (EC) in the modern era, and to identify markers of overall and disease-free survival (OS/DFS). METHODS: We conducted a retrospective cohort study of patients with unresectable EC who received DCCRT at our institution between 1/2008 and 1/2019. Descriptive statistics were used to report disease-control outcomes and CTCAE v4.0-5.0 toxicities. Univariable and multivariable Cox regression, and stepwise regression were used to identify associations with survival. RESULTS: At a median follow-up of 19.5 months, 130 patients with adenocarcinoma (AC) (62%) or squamous cell carcinoma (SCC) (38%) were evaluable (Stage II-III: 92%). Patients received carboplatin/paclitaxel (75%) or fluorouracil-based (25%) concurrent chemotherapy. Median total RT dose was 50.4 Gy (range, 44.7-71.4 Gy) delivered in 28 fractions (24-35). Locoregional and distant recurrence occurred in 30% and 35% of AC, and 24% and 33% of SCC, respectively. Median OS and DFS were 22.9 and 10.7 months in AC, and 25.7 and 20.2 months in SCC, respectively. On stepwise regression, tumor stage, feeding tube during DCCRT, and change in primary tumor PET/CT SUVmax were significantly associated with OS and DFS. Most severe toxicities were acute grade 4 hematologic cytopenia (6%) and radiation dermatitis (1%). Most common acute grade 3 toxicities were hematologic cytopenia (35%), dysphagia (23%), and anorexia (19%). CONCLUSIONS: Treatment of non-operable EC with DCCRT has acceptable toxicity and can provide multi-year disease control for some patients, even in AC. Continued follow-up and investigation in large studies would be useful.

18F-Fluciclovine PET/CT in Therapeutic Decision Making for Prostate Cancer: A Large Single-Center Practice-Based Analysis.

METHODS: We carried out a retrospective cohort study of patients with BR after primary treatment of PC who received imaging with 18F-fluciclovine PET/CT at our institution between January 2010 and January 2019. PET/CT results were compared with biopsy, conventional imaging results, and/or response to PC therapy. 18F-Fluciclovine PET/CT performance statistics and effects on treatment planning were calculated. RESULTS: A total of 328 patients with a median age of 71 years (range, 47-90 years) and median serum prostate-specific antigen level of 1.6 ng/mL (0.02-186.7 ng/mL) were included. Three hundred thirty-six 18F-fluciclovine PET/CT scans were analyzed and classified as positive (65%), negative (25%), or equivocal (10%) based on radiology reports. Sensitivity was 93% (95% confidence interval, 86%-96%) and specificity was 63% (95% confidence interval, 45%-77%). Of patients with known management recommendations post-PET/CT, scan results changed or influenced pre-PET/CT management plans in 73%, and 58% of recommendations involved treatment modality decisions. Overall, 82% of patients' actual management was concordant with post-PET/CT recommendations. Of evaluable patients, 116 (35%) had some form of post-PET radiotherapy included in their care plans, with 95% receiving radiotherapy at a PET-avid target. CONCLUSIONS: In the largest single-institutional cohort to date, 18F-fluciclovine PET/CT showed value in the workup of PC in the setting of BR, with noteworthy influence over clinical management decisions. Further studies are needed to evaluate whether PET/CT-based changes in management are associated with improved outcomes.

18F-FDG-PET/CT in the quantification of photon radiation therapy-induced vasculitis.

Radiation therapy (RT) is an important component of care for head and neck cancers (HNC). Photon RT vasculitis is a complication of incidental dose delivery to nearby vascular structures. However, optimal methods for early diagnosis are not clearly established. The aim of this study was to evaluate 18F-FDG-PET/CT in detecting radiation-induced vasculitis of the left common carotid (LCC) and the arch of the aorta (AoA) in patients treated for HNC. 18F-FDG-PET/CT scans obtained before RT (Pre-RT) and 3 months after RT (Post-RT) were retrospectively reviewed in 30 HNC patients (25 males, 5 females; average age 57.9±8.1 years) treated with photon RT. All subjects underwent 18F-FDG-PET/CT imaging 60 minutes after 5.0 MBq/kg 18F-FDG injection. Average standard uptake values (Avg SUVmean) of the LCC and AoA were obtained by global assessment. A two-tailed paired t-test was used to assess the difference in Avg SUVmean between pre- and post-RT imaging. Subjects demonstrated significant increased Avg SUVmean within the LCC post-RT (pre = 1.42, post = 1.65, P<0.001), with a mean increase of 0.23 SUV. Similarly, subjects exhibited higher 18F-FDG uptake in the AoA post-RT (pre = 1.44, post = 1.69, P<0.01), with a mean increase of 0.23 SUV. 18F-FDG-PET/CT may be used to detect and quantify photon RT vasculitis in HNC patients. Further investigation is warranted to evaluate the clinical implications of this pathology and the role for alternative treatment strategies in minimizing tissue toxicity.

Evolving Role of Novel Quantitative PET Techniques to Detect Radiation-Induced Complications.

Radiation-induced normal tissue toxicities vary in terms of pathophysiologic determinants and timing of disease development, and they are influenced by the dose and radiation volume the critical organs receive, and the radiosensitivity of normal tissues and their baseline rate of cell turnover. Radiation-induced lung injury is dose limiting for the treatment of lung and thoracic cancers and can lead to fibrosis and potentially fatal pneumonitis. This article focuses on pulmonary and cardiovascular complications of radiation therapy and discusses how PET-based novel quantitative techniques can be used to detect these events earlier than current imaging modalities or clinical presentation allow.

The efficacy and safety of hypofractionated radiotherapy with concurrent anti-HER-2 therapy following breast-conserving therapy for breast cancer.

The purpose of this study was to report rates and severities of radiation-related toxicities and analyze disease-control outcomes in patients who have received hypofractionated whole breast radiation (HF) with concurrent trastuzumab with or without pertuzumab. We conducted a retrospective cohort study including women with stage I-III HER2-positive breast cancer who received HF at the University of Pennsylvania between 1/2005 and 5/2018 with concurrent trastuzumab with or without pertuzumab. Fractionation was 266 cGy daily to a total dose of 4256 cGy with or without a sequential tumor bed boost. Eighty patients were included in the cohort with a median follow-up time of 21.44 months. There was one grade 3 acute toxicity (fatigue) and no grade 3 late toxicities. 91% and 25% of patients experienced grade 1-2 acute and late skin reactions, respectively. An excellent-good cosmetic outcome was reported by 74% and 95% of patients and physicians, respectively. No patients experienced tumor recurrences, and the only death was due to a secondary cause. These results suggest that hypofractionated whole breast radiation administered concurrently with anti-HER-2 therapies is efficacious and has acceptable toxicity in early-stage breast cancer patients treated with lumpectomy. Continued follow-up is warranted to evaluate long-term outcomes.

Precision Cardio-Oncology.

Modern oncologic therapies and care have resulted in a growing population of cancer survivors with comorbid, chronic health conditions. As an example, many survivors have an increased risk of cardiovascular complications secondary to cardiotoxic systemic and radiation therapies. In response, the field of cardio-oncology has emerged as an integral component of oncologic patient care, committed to the early diagnosis and treatment of adverse cardiac events. However, as current clinical management of cancer therapy-related cardiovascular disease remains limited by a lack of phenotypic data, implementation of precision medicine approaches has become a focal point for deep phenotyping strategies. In particular, -omics approaches (a field of study in biology ending in -omic, such as genomics, proteomics, or metabolomics) have shown enormous potential in identifying sensitive biomarkers of cardiovascular disease, applying sophisticated, pattern-revealing technologies to growing databases of biologic molecules. Moreover, the use of -omics to inform radiologic strategies may add a dimension to future clinical practices. In this review, we present a paradigm for a precision medicine approach to the care of cardiotoxin-exposed cancer patients. We discuss the role of current imaging techniques; demonstrate how -omics can advance our understanding of disease phenotypes; and describe how molecular imaging can be integrated to personalize surveillance and therapeutics, ultimately reducing cardiovascular morbidity and mortality in cancer patients and survivors.