Zabi Wardak

Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic Non–Small-Cell Lung Cancer

PURPOSE Patients with stage IV non-small-cell lung cancer (NSCLC) who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in original sites of gross disease. Cytoreduction with stereotactic body radiation therapy (SBRT) may help systemic agents delay relapse. PATIENTS AND METHODS Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression. After erlotinib commencement, SBRT with equipotent fractionation was delivered to all sites of disease. PFS, OS, and other end points were evaluated. RESULTS Twenty-four patients (13 men and 11 women) with a median age of 67 years (range, 56-86 years) were enrolled with median follow-up of 11.6 months. All patients had progressed through platinum-based chemotherapy. A total of 52 sites were treated with 16 of 24 patients receiving SBRT to more than one site. Lung parenchyma was most often irradiated. Median PFS was 14.7 months, and median OS was 20.4 months. Most patients progressed in new distant sites with only three of 47 measurable lesions recurring within the SBRT field. Two grade 3 toxicities were radiation related. Zero of 13 patients tested were positive for an EGFR mutation. CONCLUSION Use of SBRT with erlotinib for unselected patients with stage IV NSCLC as a second- or subsequent line therapy resulted in dramatic changes in patterns of failure, was well tolerated, and resulted in high PFS and OS, substantially greater than historical values for patients who only received systemic agents.

Consolidative Radiotherapy for Limited Metastatic Non–Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial

Importance Patterns-of-failure studies suggest that in metastatic non–small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. Objective To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non–progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). Design, Setting, and Participants This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. Interventions Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. Main Outcomes and Measures The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. Results A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy–alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy–alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. Conclusions and Relevance Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. Trial Registration clinicaltrials.gov Identifier: NCT02045446

Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

PURPOSE Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. METHODS AND MATERIALS Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. RESULTS Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥ 3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥ 3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥ 3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P = .24). The median overall survival was 6 months with no significant differences between dose levels (P = .59). CONCLUSIONS Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.

An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types

MOTIVATION Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. RESULTS We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. AVAILABILITY AND IMPLEMENTATION The code is available at: http://www.taehyunlab.org CONTACT jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Automatic metastatic brain tumor segmentation for stereotactic radiosurgery applications.

The objective of this study is to develop an automatic segmentation strategy for efficient and accurate metastatic brain tumor delineation on contrast-enhanced T1-weighted (T1c) magnetic resonance images (MRI) for stereotactic radiosurgery (SRS) applications. The proposed four-step automatic brain metastases segmentation strategy is comprised of pre-processing, initial contouring, contour evolution, and contour triage. First, T1c brain images are preprocessed to remove the skull. Second, an initial tumor contour is created using a multi-scaled adaptive threshold-based bounding box and a super-voxel clustering technique. Third, the initial contours are evolved to the tumor boundary using a regional active contour technique. Fourth, all detected false-positive contours are removed with geometric characterization. The segmentation process was validated on a realistic virtual phantom containing Gaussian or Rician noise. For each type of noise distribution, five different noise levels were tested. Twenty-one cases from the multimodal brain tumor image segmentation (BRATS) challenge dataset and fifteen clinical metastases cases were also included in validation. Segmentation performance was quantified by the Dice coefficient (DC), normalized mutual information (NMI), structural similarity (SSIM), Hausdorff distance (HD), mean value of surface-to-surface distance (MSSD) and standard deviation of surface-to-surface distance (SDSSD). In the numerical phantom study, the evaluation yielded a DC of 0.98  ±  0.01, an NMI of 0.97  ±  0.01, an SSIM of 0.999  ±  0.001, an HD of 2.2  ±  0.8 mm, an MSSD of 0.1  ±  0.1 mm, and an SDSSD of 0.3  ±  0.1 mm. The validation on the BRATS data resulted in a DC of 0.89  ±  0.08, which outperform the BRATS challenge algorithms. Evaluation on clinical datasets gave a DC of 0.86  ±  0.09, an NMI of 0.80  ±  0.11, an SSIM of 0.999  ±  0.001, an HD of 8.8  ±  12.6 mm, an MSSD of 1.5  ±  3.2 mm, and an SDSSD of 1.8  ±  3.4 mm when comparing to the physician drawn ground truth. The result indicated that the developed automatic segmentation strategy yielded accurate brain tumor delineation and presented as a useful clinical tool for SRS applications.

Adrenal insufficiency after stereotactic body radiation therapy for bilateral adrenal metastases

The adrenal (suprarenal) glands are paired retroperitoneal organs that consist of 2 functionally discrete regions with distinct embryologic and physiological functions, the adrenal cortex and the adrenal medulla. The adrenal cortex is composed of 3 zones: the zona glomerulosa, the zona fasiculata, and zona reticularis, which release aldosterone, cortisol, and sex steroids, respectively. Given the vital function of the adrenal glands, a rich vascular supply provides a fertile environment for trapping and growth of hematogenous metastases. Surgery is the standard of care for resectable adrenal metastases, but stereotactic body radiation therapy (SBRT) is increasingly being used as an alternative ablative technique, with high rates of local control.1 Unilateral metastases predominate, with the incidence of bilateral adrenal metastases ranging between 4% and 20% in surgical and SBRT series.2-4

Molecular pathways and potential therapeutic targets in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common primary brain malignancy. The current standard of therapy consists of surgical resection followed by concurrent chemoradiotherapy with temozolomide. Despite steady advances in all therapeutic modalities, clinical improvements have been slow and the prognosis remains poor. Utilizing powerful large-scale molecular techniques, several key pathways implicated in gliomagenesis have recently been identified and confirmed. These represent potential therapeutic targets, and by developing novel methods to specifically manipulate these pathways, we may achieve a meaningful and substantial improvement in the way we treat GBM. Here, we present and discuss the current status of research into the molecular pathways and potential therapeutic targets in GBM.

Molecular Subtypes of Anaplastic Gliomas Identified with Somatic-Mutation and Pathway Based Gene Signature

Purpose Anaplastic gliomas constitute heterogeneous population with variable outcomes and no consensus on therapeutic approach. Molecular profiling may provide prognostication beyond clinical and pathologic factors and help guide treatment decisions. Experimental Design The Cancer Genome Atlas (TCGA) was utilized to derive a 39-gene low grade glioma-specific gene signature. Consensus clustering based on expression of the signature identified subgroups for 176 patients with anaplastic glioma from TCGA. Overall survival (OS) was analyzed for each subgroup. A total of 68 patients from Repository for Molecular Brain Neoplasia Data (REMBRANDT) were used as an independent validation dataset. Results Consensus clustering separated the TCGA group into two distinct cohorts. The OS was significantly different between two subgroups, 20 vs. 67 months (p<0.001). On univariate analysis, the molecular subgroup, age, KPS, IDH1/2 mutation, 1p19q-co-deletion, chemotherapy, and use of both chemotherapy and radiation-therapy were significantly associated with OS. On multivariable analysis, the molecular subgroup remained significant with HR of 2.6 (p=.047, 95%CI [1.01-6.68]). In an independent validation with REMBRANDT, consensus clustering based on the signature successfully identified similarly poor prognostic subgroup with median survival of 14 months and concordance of expression patterns in 21 of the genes. Conclusion Expression patterns of the 39 gene stratified anaplastic gliomas into two distinct subgroups with substantially different OS. This molecular prognostication was validated in an external dataset. Utilization of molecular subgroup, in addition to known prognostic factors may help define those requiring aggressive therapeutic intervention. Characteristic genes within the poor prognostic group may represent potential targets for therapeutic intensification. Source code and dataset used in this work is available for reviewers at: https://www.taehyunlab.org/ntripath Importance of the study Despite the revolution of tailored therapy, anaplastic gliomas represent a category of tumors without clear treatment recommendations. While current prognostic factors help guide therapy recommendations, further refinement with the addition of molecular markers can help physicians with treatment recommendations. In this study, we developed a 39 gene prognostic gene signature by utilizing Pan-Cancer TCGA mutation profiles of over 5,000 patients across 19 different TCGA cancer types to stratify patients with anaplastic gliomas. We performed consensus clustering based on gene expression profiles of our 39-gene signature without any consideration of clinical factors or outcomes to TCGA anaplastic gliomas patients as well as an independent dataset and successfully identified two molecular subgroups with distinct clinical outcome. We found that subgroups have remarkably different survivals with a clear poor prognostic group. Furthermore, the poor prognostic group showed significant benefits for aggressive multimodality therapy, justifying the use of intensive therapy based on molecular stratification.

Stereotactic Body Radiation Therapy (SBRT) or Alternative Fractionation Schedules

The use of hypofractionated regimens for the treatment of tumors with radiation has come full circle. After the discovery of X-rays and their utilization for cancer treatment, the initial fractionation schemes were primarily hypofractionated in nature. However, due to technical limitations and associated toxicities, more protracted fractionated regimens eventually became the foundation for modern radiation therapy. With the advance of imaging and radiation delivery systems, interest in more hypofractionated approaches was revived. Stereotactic ablative radiation therapy (SABR; also referred as stereotactic body radiation therapy, SBRT) is the most abbreviated form of hypofractionation, typically utilizing 1–5 fractions for treatment. Its strengths include high rates of tumor control via a convenient, noninvasive outpatient procedure. Toxicities related to high, ablative radiation doses still are a potential concern; however, recent clinical trials for a variety of tumor sites have shown good outcomes in properly selected patients. This chapter will discuss the potential for SBRT/SABR to improve the therapeutic response. The use of SBRT/SABR regimens to treat lesions within the lung, liver, spine, and prostate will be reviewed. Due to more mature data in regard to the safety and efficacy, cost-effectiveness of the treatment, and potential for immunomodulatory effects, SBRT/SABR has become more wildly utilized in cancer treatment.

Multistage stereotactic radiosurgery for large cerebral arteriovenous malformations using the Gamma Knife platform

Purpose: Radiosurgery is an established technique to treat cerebral arteriovenous malformations (AVMs). Obliteration of larger AVMs (> 10–15 cm3 or diameter > 3 cm) in a single session is challenging with current radiosurgery platforms due to toxicity. We present a novel technique of multistage stereotactic radiosurgery (SRS) for large intracranial arteriovenous malformations (AVM) using the Gamma Knife system. Materials/Methods: Eighteen patients with large (> 10–15 cm3 or diameter > 3 cm) AVMs, which were previously treated using a staged SRS technique on the Cyberknife platform, were retrospectively selected for this study. The AVMs were contoured and divided into 3–8 subtargets to be treated sequentially in a staged approach at half to 4 week intervals. The prescription dose ranged from 15 Gy to 20 Gy, depending on the subtarget number, volume, and location. Gamma Knife plans using multiple collimator settings were generated and optimized. The coordinates of each shot from the initial plan covering the total AVM target were extracted based on their relative positions within the frame system. The shots were regrouped based on their location with respect to the subtarget contours to generate subplans for each stage. The delivery time of each shot for a subtarget was decay corrected with 60Co for staging the treatment course to generate the same dose distribution as that planned for the total AVM target. Conformality indices and dose–volume analysis were performed to evaluate treatment plans. Results: With the shot redistribution technique, the composite dose for the multistaged treatment of multiple subtargets is equivalent to the initial plan for total AVM target. Gamma Knife plans resulted in an average PTV coverage of 96.3 ± 0.9% and a PITV of 1.23 ± 0.1. The resulting Conformality indices, V12Gy and R50 dose spillage values were 0.76 ± 0.05, 3.4 ± 1.8, and 3.1 ± 0.5 respectively. Conclusion: The Gamma Knife system can deliver a multistaged conformal dose to treat large AVMs when correcting for translational setup errors of each shot at each staged treatment.