Stephen G. Chun

Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: A secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

Isolated central nervous system progression on Crizotinib: An Achilles heel of non-small cell lung cancer with EML4-ALK translocation?

Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in this subset of NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.

Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer

Combined targeting of distinct cellular signaling mechanisms may improve the efficacy and reduce the toxicity of therapy in pancreatic cancer. Histone deacetylases (HDACs) control cellular functions through epigenetic modulation, and HDACs inhibitors suppress cell growth in pancreatic adenocarcinoma. The Hedgehog (Hh) pathway regulates the development of the pancreas, and aberrant Hh signaling promotes the initiation and progression of pancreatic neoplasia. We hypothesize that HDACs and the Hh pathway cooperatively interact to regulate cellular proliferation of the exocrine pancreas. A combination of the HDAC inhibitor SAHA and the Smoothened antagonist SANT-1 was evaluated for their ability to suppress growth of the Gemcitabine-resistant pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3. The combination of SAHA and SANT-1 supra-additively suppressed cellular proliferation and colony formation. Flow cytometric and immunohistochemical analyses indicated that enhanced induction of apoptotic cell death, cell cycle arrest in G0/G1 phase, and ductal epithelial differentiation are involved. Cell death was associated with nuclear localization of survivin, increased bax expression, and activation of caspases 3 and 7. Consistent with the cell cycle arrest and cytodifferentiation, the cyclin-dependent kinase inhibitors p21waf and p27kip1 were upregulated, and cyclin D1 down-regulated. The potentiated anti-proliferative effect by the combination of SAHA and SANT-1 may involve cooperative suppression of the Hh pathway activity, as shown by the up-regulation of HHIP by SAHA, and enhanced repression of of Ptc-1 mRNA expression. In summary, we have developed a molecular target-based therapeutic approach that overcomes chemoresistance in pancreatic cancer cells by chemically inhibiting HDACs and Hh signaling in combination.

Aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy

Purpose High-risk prostate cancer (PC) has poor outcomes due to therapeutic resistance to conventional treatments, which include prostatectomy, radiation, and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in PC patients. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC. Materials and Methods Analysis was performed on 74 high-risk PC patients who were treated with radiotherapy from 2005 to 2008 at UT Southwestern. Of these patients, 43 were on AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were analyzed. Results Median follow-up was 56.6 mo for all patients. For patients taking any AC compared with no AC, there was improved FFBF at 5 years of 80% vs. 62% (P = 0.003), and for aspirin the FFBF was 84% vs. 65% (P = 0.008). Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7%, P = 0.039). On subset analysis of patients with Gleason score (GS) 9–10 histology, aspirin resulted in improved 5-year OS (88% vs. 37%, P = 0.032), which remained significant on multivariable analysis (P < 0.05). Conclusions AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with GS 9–10, who are most likely to experience mortality from PC. This hypothesis-generating result suggests AC use may represent an opportunity to augment current therapy.

Werner syndrome as a hereditary risk factor for exocrine pancreatic cancer: Potential role of WRN in pancreatic tumorigenesis and patient-tailored therapy

Advanced age is considered a risk factor of pancreatic cancer, but this relationship at the molecular and genetic level remains unclear. We present a clinical case series focusing on an association between pancreatic adenocarcinoma and Werner syndrome (WS) that is an autosomal recessive genetic disorder characterized by accelerated aging and cancer predisposition, and caused by loss-of-function mutations in the WS RecQ helicase gene (WRN). Although pancreatic adenocarcinoma mostly occurs in a sporadic fashion, a minority of cases occurs in the context of susceptible individuals with hereditary syndromes. While WS has not been previously recognized as a risk factor for developing malignant tumors of the exocrine pancreas, the clinicopathologic features of three reported patients suggest a contributory role of WRN deficiency in pancreatic carcinogenesis. Molecular genetic analyses support the role of WRN as a tumor suppressor gene, although recent evidence reveals that WRN can alternatively promote oncogenicity depending on the molecular context. Based upon the clinico-pathologic features of these patients and the role of WRN in experimental models, we propose that its loss-of-function predisposes the development of pancreatic adenocarcinoma through epigenetic silencing or loss-of-heterozygosity of WRN. To test this hypothesis, we are investigating the mechanistic role of WRN in pancreatic cancer models including a pancreatic adenocarcinoma cell line generated from a human with WS. These studies are expected to provide new insight into the relationship between aging and pancreatic tumorigenesis, and facilitate development of novel strategies for patient-tailored interventions in this deadly malignancy.

NQO1-Mediated tumor-selective lethality and radiosensitization for head and neck cancer

Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of IR. Immunohistochemical staining and Western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs expressed elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependent tumor cell lethality, increased ROS, TUNEL-positive cells, DNA damage, NAD+, and ATP consumption, and resulted in significant antitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap–induced radiosensitization. Mol Cancer Ther; 15(7); 1757–67. ©2016 AACR.

A Retrospective Analysis of Tumor Volumetric Responses to Five-Fraction Stereotactic Radiotherapy for Paragangliomas of the Head and Neck (Glomus Tumors)

Background: Skull base paragangliomas (SBP) are locally expansile tumors that can be treated with stereotactic radiotherapy with favorable results. This report describes the results of 31 patients with SBP treated with CyberKnife radiotherapy delivering a total dose of 25 Gray in five fractions. Methods: All patients treated with five-fraction CyberKnife radiotherapy at a single institution were identified between 2007 and 2013. Tumor volumetric analyses were performed to assess responses to radiotherapy. Results: Median follow-up was 24 months with a range of 4-78 months. Local control and overall survival were 100%. Of the 20 patients who presented with tinnitus, 12 reported improvement (60%), of whom 6 reported complete resolution. There was a 37.3% reduction in tumor volume among all patients (p = 0.16). On subset analysis of patients with ≥24 months of follow-up, tumor volume decreased 49% (p = 0.01). The rate of grade 1-2 toxicity was 19%, with no grade 3 or worse toxicity. Conclusion: A five-fraction CyberKnife-based stereotactic radiotherapy approach is safe and efficacious for the management for patients with SBP. Our findings suggest the potential use of this strategy as a definitive or salvage treatment option for SBP.

Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

Summary Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish. We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited the expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity.

SBRT for early-stage glottic larynx cancer-Initial clinical outcomes from a phase i clinical trial

Purpose To confirm safety and feasibility of hypofractionated SBRT for early-stage glottic laryngeal cancer. Methods Twenty consecutive patients with cTis-T2N0M0 carcinoma of glottic larynx were enrolled. Patients entered dose-fractionation cohorts of incrementally shorter bio-equivalent schedules starting with 50 Gy in 15 fractions (fx), followed by 45 Gy/10 fx and, finally, 42.5 Gy/5 fx. Maximum combined CTV-PTV expansion was limited to 5 mm. Patients were treated on a Model G5 Cyberknife (Accuray, Sunnyvale, CA). Results Median follow-up is 13.4 months (range: 5.6–24.6 months), with 12 patients followed for at least one year. Maximum acute toxicity consisted of grade 2 hoarseness and dysphagia. Maximum chronic toxicity was seen in one patient treated with 45 Gy/10 fx who continued to smoke >1 pack/day and ultimately required protective tracheostomy. At 1-year follow-up, estimated local disease free survival for the full cohort was 82%. Overall survival is 100% at last follow-up. Conclusions We were able to reduce equipotent total fractions of SBRT from 15 to 5 without exceeding protocol-defined acute/subacute toxicity limits. With limited follow-up, disease control appears comparable to standard treatment. We continue to enroll to the 42.5 Gy/5 fx cohort and follow patients for late toxicity. Trial registration ClinicalTrials.gov NCT01984502

Prophylactic Cranial Irradiation for Extensive Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) has a high predilection for metastasizing to the brain after chemotherapy. This has been blamed on the blood-brain barrier, which prevents chemotherapy from penetrating into the brain, thus creating a sanctuary site. It has been estimated that up to three quarters of patients with SCLC will eventually develop brain metastases. This led investigators to administer prophylactic cranial irradiation (PCI) to decrease this risk. Several trials were performed in patients with SCLC after initial therapy (chemotherapy with or without thoracic radiotherapy) that compared the outcomes of PCI versus no PCI. Early trials generally found that PCI significantly decreased the risk of brain metastases but did not significantly improve survival. These trials were re-evaluated in two larger meta-analyses that included patients with either limited-stage SCLC or extensive-stage SCLC (ESCLC). Both meta-analyses reported that PCI significantly decreased brain metastases and improved survival in patients who had a complete response following initial therapy. These studies were performed before the advent of modern imaging with computed tomography or magnetic resonance imaging (MRI). There have been two modern trials of PCI versus no PCI in patients with ESCLC and both found that PCI decreases brain metastases. The first did not include brain MRI before registration and found that PCI improved survival, whereas the second study did include MRI before registration and at frequent intervals thereafter. That trial found that PCI did not confer a survival advantage. This review will examine the evidence and provide recommendations regarding the role of PCI for patients with ESCLC.