L. Bazzi

Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer.

Purpose Radiation therapy is a critical component in the care of patients with non-small-cell lung cancer (NSCLC), yet cardiac injury after treatment is a significant concern. Therefore, we wished to elucidate the incidence of cardiac events and their relationship to radiation dose to the heart. Patients and Materials Study eligibility criteria included patients with stage II to III NSCLC treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013. All cardiac events were reviewed and graded per Common Terminology Criteria for Adverse Events (v4.03). The primary end point was the development of a grade ≥ 3 cardiac event. Results In all, 125 patients met eligibility criteria; median follow-up was 51 months for surviving patients. Median prescription dose was 70 Gy, 84% received concurrent chemotherapy, and 27% had pre-existing cardiac disease. Nineteen patients had a grade ≥ 3 cardiac event at a median of 11 months (interquartile range, 6 to 24 months), and 24-month cumulative incidence was 11% (95% CI, 5% to 16%). On multivariable analysis (MVA), pre-existing cardiac disease (hazard ratio [HR], 2.96; 95% CI, 1.07 to 8.21; P = .04) and mean heart dose (HR, 1.07/Gy; 95% CI, 1.02 to 1.13/Gy; P = .01) were significantly associated with grade ≥ 3 cardiac events. Analyzed as time-dependent variables on MVA analysis, both disease progression (HR, 2.15; 95% CI, 1.54 to 3.00) and grade ≥ 3 cardiac events (HR, 1.76; 95% CI, 1.04 to 2.99) were associated with decreased overall survival. However, disease progression (n = 71) was more common than grade ≥ 3 cardiac events (n = 19). Conclusion The 24-month cumulative incidence of grade ≥ 3 cardiac events exceeded 10% among patients with locally advanced NSCLC treated with definitive radiation. Pre-existing cardiac disease and higher mean heart dose were significantly associated with higher cardiac event rates. Caution should be used with cardiac dose to minimize risk of radiation-associated injury. However, cardiac risks should be balanced against tumor control, given the unfavorable prognosis associated with disease progression.

Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage: A Phase 2 Clinical Trial

Importance Patients with preexisting liver dysfunction could benefit the most from personalized therapy for liver tumors to balance maximal tumor control and minimal risk of liver failure. We designed an individualized adaptive trial testing the hypothesis that adapting treatment based on change in liver function could optimize the therapeutic index for each patient. Objective To characterize the safety and efficacy of individualized adaptive stereotactic body radiotherapy (SRBT) for liver tumors in patients who have preexisting liver dysfunction. Design, Setting, and Participants From 2010 to 2014, 90 patients with intrahepatic cancer treated with prior liver-directed therapy were enrolled in this large phase 2, single-arm, clinical trial at an academic medical center. All patients had at least 1 year of potential follow-up. Interventions Using indocyanine green retention at 15 minutes (ICGR15) as a direct biomarker of liver function and a Bayesian adaptive model, planned SBRT was individually modified midway through the course of therapy to maintain liver function after the complete course. Main Outcomes and Measures The primary outcome was local control; the secondary outcome was safety and overall survival. Results Patients were 34 to 85 years of age, and 70% (63) were male. Ninety patients (69 [77%] with hepatocellular carcinoma, 4 [4%] with intrahepatic cholangiocarcinoma, and 17 [19%] with metastatic) received treatment to 116 tumors. Sixty-two patients (69%) had cirrhosis, 21 (23%) were Child-Pugh (CP) grade B. The median tumor size was 3 cm; 16 patients (18%) had portal vein involvement. Sixty-two (69%) received all 5 fractions (47 full dose, 15 dose-reduced owing to rising ICGR15). Treatment was well tolerated, with a lower than expected complication rate without adaptation: 6 (7%) experienced a 2-point decline in CP 6 months post-SBRT. The 1- and 2-year local control rates were 99% (95% CI, 97%-100%) and 95% (95% CI, 91%-99%), respectively. Conclusions and Relevance We demonstrated that the treatment strategy of individualized adaptive therapy based on a direct biomarker of liver function can be used to achieve both high rates of local control and a high degree of safety without sacrificing either. Individualized adaptive radiotherapy may represent a new treatment paradigm in which dose is based on individual, rather than population-based, tolerance to treatment. Trial Registration clinicaltrials.gov Identifier: NCT01522937

Lower Incidence of Esophagitis in the Elderly Undergoing Definitive Radiation Therapy for Lung Cancer

Introduction: Most patients with lung cancer are elderly and poorly represented in randomized clinical trials. They are often undertreated because of concerns about their ability to tolerate aggressive treatment. We tested the hypothesis that elderly patients undergoing definitive lung radiation might tolerate treatment differently than younger patients. Methods: A total of 125 patients who underwent definitive lung radiotherapy were identified from a prospective institutional database (University of Michigan cohort). Logistic regression modeling was performed to assess the impact of age on esophagitis grade 2 or higher or grade 2 or higher and pneumonitis grade 3 or higher or grade 2 or higher, with adjustment for esophageal and lung dose, respectively, as well as for chemotherapy utilization, smoking status, and performance status. The analysis was validated in a large cohort of 691 patients from the Michigan Radiation Oncology Quality Consortium registry, an independent statewide prospective database. Results: In the University of Michigan cohort, multivariable regression models revealed a significant inverse correlation between age and rate of esophagitis for both toxicity levels, (adjusted OR = 0.93 for both models and 95% confidence intervals of 0.88–0.98 and 0.87–0.99), with areas under the curve of 0.747 and 0.721, respectively, demonstrating good fit. This same association was noted in the Michigan Radiation Oncology Quality Consortium cohort. There was no significant association between age and pneumonitis. Conclusions: There is a lower incidence of esophagitis with increasing age even after adjustment for use of chemotherapy. This is a novel finding in thoracic oncology. No age dependence was noted for pulmonary toxicity. The elderly are able to tolerate definitive thoracic radiation well and should be offered this option when clinically warranted.

Using Indocyanine Green Extraction to Predict Liver Function After Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

PURPOSE To test the hypothesis that mid-treatment measures of the retention of indocyanine green after 15 minutes (ICGR15) would improve the prediction of posttreatment liver function in the setting of hepatocellular carcinoma. METHODS AND MATERIALS Between 2006 and 2015, 144 patients with hepatocellular carcinoma received 175 courses of stereotactic body radiation therapy (SBRT). Patient data, such as age, sex, portal vein thrombosis, cirrhosis, Child-Pugh (CP) score, prior liver-directed therapies, and liver function tests, including albumin-bilirubin (ALBI) and ICG clearance, and dosimetric data, such as tumor volume and radiation dose, were collected. Toxicity was evaluated as a 2-point increase in CP score or a change in ALBI score at 3 months from start of SBRT. Logistic or linear regression was used to build toxicity prediction models based on patient and tumor characteristics and ICG clearance variables. Performance of the models for the binary CP outcome was summarized using area under the curve and receive operating characteristic curves. Likelihood ratio tests were used to evaluate whether the model fit improved after incorporating the ICG variable information. RESULTS In multivariable analysis age, baseline ICGR15, and change in ICGR15 were associated with toxicity defined by increased CP score. For the continuous ALBI outcome, being female, having cirrhosis, and increasing radiation dose were associated with increased toxicity. When incorporating ICGR15 into these models, an increase in ICGR15 from baseline to mid-treatment was most consistently significantly associated with an increase in toxicity. CONCLUSIONS Incorporation of ICGR15 variables significantly improves the prediction of post-SBRT liver function. The use of ICGR15 can facilitate the delivery of the maximum safe dose of radiation for patients with hepatocellular carcinoma and has the potential to improve uncomplicated tumor control and survival.