Efficacy and Safety of Dose-Escalated Alectinib in Patients With Metastatic ALK-Positive NSCLC and Central Nervous System Relapse on Standard-Dose Alectinib

Introduction: Central nervous system (CNS) metastases remain a common challenge in patients with ALK-positive NSCLC. We previously reported reinduction of CNS responses using dose-intensified alectinib in two patients with CNS progression on standard-dose alectinib. Nevertheless, this strategy has not been assessed in larger cohorts. Methods: Patients were eligible for this retrospective study if they had metastatic ALK-positive NSCLC with CNS relapse on alectinib 600 mg twice daily dosing and subsequently received escalated dosing (900 mg twice daily) of alectinib. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Results: Among 27 patients, median duration of dose-escalated alectinib was 7.7 months (95% confidence interval [CI]: 4.8–10.9), with median overall time-to-progression (TTP) of 7.1 months (95% CI: 4.4–9.6). Among 25 CNS response-assessable patients, CNS objective response rate was 12.0% (95% CI: 2.5–31.2) and CNS disease control rate was 92.0% (95% CI: 74.0–99.0), with median CNS duration of disease control of 5.3 months (95% CI: 3.4–8.3) and median CNS TTP of 7.1 months (95% CI: 4.4–9.6). Among four patients with measurable CNS disease at baseline, three experienced a best intracranial response of stable disease and one experienced intracranial partial response with CNS TTP ranging from 4.1 to 7.7 months. No patient required drug discontinuation due to treatment-related adverse event or experienced grade 3 or higher treatment-related adverse events. Conclusions: Dose-intensified alectinib was found to have tolerability and activity in patients with ALK-positive NSCLC who experienced CNS relapse on standard-dose alectinib and represents one clinically viable strategy for this population

Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas

Purpose: To conduct phase 1 and 2 trials with photon intensity modulated radiation therapy and intensity modulated proton therapy (IMPT) arms to selectively escalate the retroperitoneal sarcoma preoperative radiation dose to tumor volume (clinical target volume [CTV] 2) that is judged to be at a high risk for positive margins and aim to reduce local recurrence. We report on the IMPT study arm in phase 1. Methods and materials: Patients aged ≥18 years with primary or locally recurrent retroperitoneal sarcoma were treated with preoperative IMPT, 50.4 GyRBE in 28 fractions, to CTV1 (gross tumor volume and adjacent tissues at risk of subclinical disease) with a simultaneous integrated boost to CTV2 to doses of 60.2, 61.6, and 63.0 GyRBE in 28 fractions of 2.15, 2.20, and 2.25 GyRBE, respectively. The primary objective of the phase 1 study was to determine the maximum tolerated dose to CTV2, which will be further tested in the phase 2 study. Results: Eleven patients showed increasing IMPT dose levels without acute dose limiting toxicities that prevented dose escalation to maximum tolerated dose. Acute toxicity was generally mild with no radiation interruptions. No unexpected perioperative morbidity was noted. Eight months postoperatively, one patient developed hydronephrosis that was treated by stent with ureter dissected off tumor and received 57.5 GyRBE. Retained ureter(s) was (were) subsequently constrained to 50.4 GyRBE without further problem. With an 18-month median follow-up, there were no local recurrences. Conclusions: IMPT dose escalation to CTV2 to 63 GyRBE was achieved without acute dose limiting toxicities. The phase 2 study of IMPT will accrue patients to that dose. Parallel intensity modulated radiation therapy phase 1 arm is currently accruing at the initial dose level. Ureters that undergo a high dose radiation and/or surgery are at risk for late hydro-ureter. Future studies will constrain retained ureters to 50.4 GyRBE to avoid ureteral stricture

Analysis of patient outcomes following proton radiation therapy for retinoblastoma

Purpose: Proton radiation therapy (PRT) is used to treat patients with retinoblastoma (RB) and has the potential to minimize exposure of normal tissue to radiation and thus decrease the risk of toxicity and second malignancies. However, comprehensive analyses of long-term patient outcomes are not available. Methods and materials: Patients with RB who were treated with PRT at our institution between 1986 and 2012 were invited to participate in a study that was designed to assess long-term outcomes. Patients who were enrolled in the study underwent a comprehensive analysis that included oncologic, ophthalmic, endocrine, cephalometric, and quality of life (QOL) assessments. Results: A total of 12 patients were enrolled in this study. The average length of follow-up was 12.9 years (range, 4.8-22.2 years). All study patients had bilateral disease, and the disease and visual outcomes were similar to the outcomes for all patients with RB who were treated with PRT over the same time period at our institution. An analysis of endocrine-related test results revealed no growth abnormalities or hormonal deficiencies across the cohort. Magnetic resonance imaging scans and external cephalometry showed that PRT was associated with less facial hypoplasia than enucleation. Patient and parent-proxy QOL assessments revealed that treatment for RB did not appear to severely affect long-term QOL. Conclusions: In addition to providing an opportunity for long-term disease control and functional eye preservation, PRT does not appear to be associated with unexpected late visual, endocrine, or QOL effects in this cohort of patients with RB