Krithika Suresh

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

Predictors of severe long-term toxicity after re-irradiation for head and neck cancer

OBJECTIVE To identify predictive factors of severe long-term toxicity after re-irradiation of recurrent/persistent or second-primary head and neck cancer. METHODS Outcomes and treatment plans of patients who underwent modern IMRT based re-irradiation to the head and neck from 2008-2015 were reviewed. Co-variables including demographic, clinical and oncologic factors, as well as interval to re-irradiation and re-irradiated planning tumor volume (PTV) were analyzed as predictors of developing severe (CTCAE grade⩾3) long-term toxicity with death as a competing risk. RESULTS A total of 66 patients who met inclusion criteria were eligible for analysis. A median re-irradiation dose of 70Gy was delivered at a median of 37.5months after initial radiotherapy. Re-irradiation followed surgical resection in 25 (38%) patients, and concurrent chemotherapy was delivered to 41 (62%) patients. Median follow-up after re-irradiation was 23months and median overall survival was 22months (predicted 2year overall survival 49%). Of the 60 patients who survived longer than 3months after re-irradiation, 16 (25%) patients experienced severe long-term toxicity, with the majority (12 of 16) being feeding tube -dependent dysphagia. In multivariable analysis, shorter intervals to re-irradiation (<20months) and larger re-irradiated PTVs (>100cm(3)) were independent predictors of developing severe long-term toxicity. Patients with longer disease-free intervals and smaller PTVs had a 94% probability of being free of severe toxicity at two years. CONCLUSION Selection of patients with longer re-irradiation intervals and requiring smaller re-irradiated PTVs can independently predict avoidance of severe long-term toxicity.

Intermediate Endpoints After Postprostatectomy Radiotherapy: 5-Year Distant Metastasis to Predict Overall Survival

BACKGROUND Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. OBJECTIVE To identify a potential ICE for men receiving PORT. DESIGN, SETTING, AND PARTICIPANTS We performed an institutional review board-approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination. RESULTS AND LIMITATIONS OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45-3.71; p<0.001), DM (HR 6.52, 95% CI 4.20-10.1; p<0.001), and CRPC (HR 2.47, 95% CI 1.56-3.92; p<0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. CONCLUSIONS While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. PATIENT SUMMARY We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival.

A prediction model for colon cancer surveillance data.

Dynamic prediction models make use of patient-specific longitudinal data to update individualized survival probability predictions based on current and past information. Colonoscopy (COL) and fecal occult blood test (FOBT) results were collected from two Australian surveillance studies on individuals characterized as high-risk based on a personal or family history of colorectal cancer. Motivated by a Poisson process, this paper proposes a generalized nonlinear model with a complementary log-log link as a dynamic prediction tool that produces individualized probabilities for the risk of developing advanced adenoma or colorectal cancer (AAC). This model allows predicted risk to depend on a patients baseline characteristics and time-dependent covariates. Information on the dates and results of COLs and FOBTs were incorporated using time-dependent covariates that contributed to patient risk of AAC for a specified period following the test result. These covariates serve to update a persons risk as additional COL, and FOBT test information becomes available. Model selection was conducted systematically through the comparison of Akaike information criterion. Goodness-of-fit was assessed with the use of calibration plots to compare the predicted probability of event occurrence with the proportion of events observed. Abnormal COL results were found to significantly increase risk of AAC for 1 year following the test. Positive FOBTs were found to significantly increase the risk of AAC for 3 months following the result. The covariates that incorporated the updated test results were of greater significance and had a larger effect on risk than the baseline variables.

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.