A. Brade

PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer

PURPOSE The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy. PATIENTS AND METHODS Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m(2) and cisplatin 50 mg/m(2) intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05. RESULTS Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period. CONCLUSION Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer.

Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma.

PURPOSE To report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS A prospective study of SBRT was developed for patients with CP B7 or B8 unresectable HCC, <10 cm. Selected ineligible patients (e.g. CP>B8, >10 cm) treated off-study from 2004 to July 2012 were also reviewed. Patients were excluded if they were treated as a bridge-to-liver-transplant. RESULTS 29 patients with CP B/C HCC were treated with SBRT (median dose 30 Gy in 6 fractions) from 2004 to December 2012. The majority had CP B7 liver function (69%) and portal vein tumor thrombosis (76%). The median survival was 7.9 months (95% CI: 2.8-15.1). Survival was significantly better in patients with CP=B7 and AFP≤4491 ng/mL. Of 16 evaluable patients, 63% had a decline in CP score by ≥2 points at 3 months. CONCLUSION SBRT is a treatment option for selected HCC patients with small HCCs and modestly impaired (CP B7) liver function.

Stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC): Is FDG-PET a predictor of outcome?

BACKGROUND AND PURPOSE Distant metastases are the dominant mode of failure after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). The primary study objective was to evaluate if the maximum standardized uptake value (SUV(max)) on pre-treatment FDG-PET/CT predicted clinical outcomes. Secondary objectives were to correlate 3-month post-SBRT SUV(max) and change in SUV(max) with outcomes. MATERIALS AND METHODS Consecutive patients with medically inoperable early-stage NSCLC and an FDG-PET/CT scan before (n=82) and 3 months after (n=62) SBRT. RESULTS Median follow up was 2 years. On univariate analysis baseline SUV(max) predicted for distant failure (p=0.0096), relapse free survival (RFS) (p=0.037) and local failure (p=0.044). On multivariate analysis baseline SUV(max) predicted for RFS (p=0.037). Baseline SUV(max) of above 5 was the most statistically significant cut off point for predicting distant failure (p=0.0002). Baseline SUV(max) ≥4.75 (median) was correlated with a higher risk of distant failure (p=0.012) and poorer RFS (p=0.04). Patients with a post-SBRT SUV(max) ≥2 and a reduction of <2.55 had a significantly higher rate of distant failure. CONCLUSIONS Pre-SBRT SUV(max) on FDG-PET/CT correlated most strongly with distant failure. A cut off of ≥5 was the most significant. Post-SBRT SUV(max) ≥2 and a reduction of <2.55 were associated with a higher risk of distant failure.

Heat-directed gene targeting of adenoviral vectors to tumor cells.

Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heat-directed gene-targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites (heat shock elements; HSE) found in the promoters of heat-inducible genes. Here we present a quantitative analysis of heat-inducible gene expression mediated by the wild-type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. β-Galactosidase (β-gal) expression was induced between 50- and 800-fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild-type hsp70b promoter (Ad.70b.βg) following treatment at 43°C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter (Ad.HSE.70b.βg) resulted in a 200- to 950-fold increase in β-gal expression under the same conditions, and also provided a 1–2°C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b.βg construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target β-gal gene expression following intratumoral injection of Ad.70b.βg. Adenoviral vectors incorporating heat-inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia. Cancer Gene Therapy (2000) 7, 1566–1574.

Practical Considerations Arising from the Implementation of Lung Stereotactic Body Radiation Therapy (SBRT) at a Comprehensive Cancer Center

Introduction: With the anticipation of improved outcomes, especially for patients with early-stage non-small cell lung cancer, stereotactic body radiation therapy (SBRT) has been rapidly introduced into the thoracic radiation oncology community. Although at first glance lung SBRT might seem methodologically similar to conventional radiotherapy, there are important differences in its execution that require particular consideration. The objective of this paper is to highlight these and other issues to contribute to the safe and effective diffusion of lung SBRT. We discuss practical challenges that have been encountered in the implementation of lung SBRT at a single, large institution and emphasize the importance of a systematic approach to the design of lung SBRT services. Methods: Specific technical and clinical components that were identified as being important during the development of lung SBRT at Princess Margaret Hospital are described. The clinical system that evolved from these is outlined. Results: Using this clinical framework the practical topics addressed include: patient assessment, simulation and treatment planning, tumor and organ at risk delineation, trial set up before treatment, on-line image-guidance, and patient follow-up. Conclusions: The potential gain in therapeutic ratio that is theoretically possible with lung SBRT can only be realized if the tumor is adequately irradiated and normal tissue spared. A discussion of the component parts of lung SBRT is presented. It is a complex process and specific challenges need to be overcome to effect the satisfactory transition of lung SBRT into routine practice.

A Phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis

Purpose: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies. Experimental Design: Patients were treated with veliparib (80–320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1–3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Results: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX–positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline). Conclusions: Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation. Clin Cancer Res; 21(1); 68–76. ©2014 AACR.

Scheduling of Radiation and Chemotherapy for Limited-Stage Small-Cell Lung Cancer: Repopulation As a Cause of Treatment Failure?

Themeta-analystcancastabroadnettogainstatisticalpower, possibly obtaining results clouded by the combining of heterogeneous trials, or can focus on more homogeneous data, thereby sacrificingpower.Inthisissue,DeRuysscheretal 1 havechosenthe latter approach to test the plausible hypothesis that initial chemotherapy or protracted radiotherapy can trigger repopulation of surviving cells in limited-stage small-cell lung cancer (LSCLC), thus decreasing the effectiveness of treatment. Repopulation of cells in critical normal tissues between individual dose fractions of either radiotherapy or chemotherapy is important for recovery or retention of normal organ function, thereby improving tolerance to treatment. Thus, a schedule of radiotherapy administered over 6 to 7 weeks leads to less normal tissuereactionthanasimilartotaldoseadministeredoverashorter time, and the kinetics of repopulation in the bone marrow allow repetitive scheduling of cycle-active chemotherapy at approximately 3-week intervals. However, repopulation of surviving tumor cells also occurs between dose fractions of either radiation or chemotherapy and effectively decreases tumor-cell kill (Fig 1). 2,3 There is evidence in several tumor types for an increase in the rate of repopulation during the latter part of a course of radiation treatment, which is an effect long recognized as a mechanism of clinicallysignificantresistancetotreatment. 4 Therearefewdataon the role of repopulation in the longer intervals between cycles of chemotherapy, but accelerating repopulation probably occurs and can lead to clinical resistance, even if there is no change in the inherent sensitivity of the cancer cells. 2

Phase II Trial of Palliative Radiotherapy for Hepatocellular Carcinoma and Liver Metastases

PURPOSE To evaluate the feasibility and response of liver radiotherapy (RT) in improving symptoms and quality of life in patients with hepatocellular carcinoma (HCC) or liver metastases (LM). PATIENTS AND METHODS Eligible patients had HCC or LM, unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were completed by patients at baseline and each follow-up. The primary outcome was the percentage of patients with a clinically significant change at 1 month in the BPI subscale of symptom on average in the past 24 hours. Secondary outcomes were improvement in other BPI subscales and at other time points, FACT-Hep and EORTC QLQ-C30 at each follow-up, and toxicity at 1 week. RESULTS Forty-one patients (30 men and 11 women) with HCC (n = 21) or LM (n = 20) were accrued. At 1 month, 48% had an improvement in symptom on average in the past 24 hours. Fifty-two percent of patients had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements in the FACT-G and hepatobiliary subscale were seen in 23% and 29% of patients, respectively, at 1 month. There were also improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. One patient developed grade 3 nausea at 1 week. CONCLUSION Improvements in symptoms were observed at 1 month in a substantial proportion of patients. A phase III study of palliative liver RT is planned. [Corrected]

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

PURPOSE To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). METHODS AND MATERIALS Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. RESULTS Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. CONCLUSIONS Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.

Radiation recall dermatitis triggered by multi-targeted tyrosine kinase inhibitors: Sunitinib and sorafenib

Small molecule tyrosine kinase inhibitors are rapidly being integrated into the management of cancer. This is the first report of sorafenib and sunitinib, both small molecule tyrosine kinase inhibitors of vascular endothelial growth factor and platelet-derived growth factor receptors, triggering radiation recall dermatitis. The pathophysiology of radiation recall is poorly understood, and several possible mechanisms have been proposed. The clinical presentations of these two cases were consistent with one hypothesized mechanism of radiation recall, an idiosyncratic drug hypersensitivity reaction.