This trial design also provides a rare opportunity to derive information about the drug response to untreated clinical lung cancer. Typical lung cancer drugs are initially evaluated for disease activity in the setting of clinical cohorts that have already failed one or more types of chemotherapy. Drug candidates must be used for many years in heavily pretreated patients before these agents will ever be evaluated in the setting of early lung cancer. Developing a strategy to accelerate this process is critically important and complements new strategies for drug development proposed by the US Food and Drug Administration (FDA).
The window-of-opportunity trial design also allows for direct comparison of analogs for targeted drug development using efficient, new randomized design strategies. Finally, window trials could also be used to define optimal drug dosing for a new agent by virtue of the serial tumor tissue sampling protocols built into this type of study. Molecular analysis sampling tumor tissue before and after drug exposure can be used to determine if known downstream molecular signaling is blocked as expected by the doses of drug used in the trial.
An important accomplishment of this Workshop series was the reported completion of a neoadjuvant window-of-opportunity trial by Dr. Nasser Altorki of Cornell University Medical Center. Dr. Altorki outlined the rationale for this new clinical trial approach in evaluating new targeted therapeutics in untreated, primary lung cancer and discussed the completion of a multicenter, neoadjuvant, window-of-opportunity trial performed in collaboration with GlaxoSmithKline. This trial evaluated the effect of a dual-kinase, vascular endothelial growth factor inhibitor (pazopanib) on tumor volume as measured by high-resolution spiral CT images performed before and after a brief preoperative course of the orally administered agent. In this trial, the drug was well tolerated and did not interfere with curative surgical management.
Workshop participants suggested that the systematic molecular analysis of preoperative biopsies and resected tumor tissue will define what drug targets are present in which types of tumors and how often. The molecular analysis done in parallel with the imaging should establish which downstream signaling pathways are affected by the drug exposure and suggest logical targets for subsequent combination drug therapy.
Shortly after the Workshop, Dr. Altorki presented the neoadjuvant trial results with pazopanib at the American Society of Clinical Oncology (ASCO) annual meeting. In this 26-patient evaluation, evidence of tumor volume reduction was seen on spiral CT of the chest in 82% of the patients receiving a 2- to 3-week course of pazopanib. Only modest drug side effects were reported in this trial. The preliminary results of the biologic monitoring of tumor response from the specimens obtained in the course of this study paralleled the pattern of response seen on the imaging endpoints of the trial.
Areas of Progress in Thoracic Image-Processing and Validation Ricardo Avila, of Kitware, Inc, gave an overview of lung cancer and COPD image analysis methods and discussed progress in image-processing over the past year. This overview included a proposal for a minimum recommendation of CT acquisition parameters for future lung cancer clinical trials. He also discussed the development of an infrastructure to support an open database of patient-donated CT scans. The patient advocacy group, Lung Cancer Alliance, had completed a pilot project named “Give-A-Scan” with a small group of patients. In this project, patients donate their own CT scan data and provide basic clinical outcome data. The project received 6.2 GB of CT scan data from 15 donors, including 10 cases of lung cancer. The pilot project will be followed up with a larger project over the next year.
Mr. Avila next discussed a recommendation from last year’s Workshop to create an open source set of reference methods for measuring tumor size. He announced that a consortium of federal and OSA funding had been committed to support the development of an open source lesion-sizing tool. Another recommendation from last year’s Workshop was to establish a method to measure the progress of investigators working on CT lesion-sizing methods. In response, the National Institute of Standards and Technology (NIST) developed an algorithm validation matrix called BioChange 2008 at the Workshop. To address the final recommendation of last year’s Workshop, Kitware developed a mailing list and wiki for constant communication throughout the year. This has been a functional resource for the past 10 months.
Dr. Charles Fenimore of NIST announced the BioChange 2008 project and described efforts to precisely measure the performance of software methods that quantify the size of lesions in CT scans. Dr. Fenimore provided the goals and rationale for the project and summarized early results associated with the acceptance of benchmarking data from a number of institutions.
Subsequently, Dr. Lutz Guendel of Siemens, Dr. Michael Lee of Phillips, and Dr. Anthony Reeves of Cornell University provided additional results and feedback. Each presenter reviewed the challenges in evaluating lesion-sizing performance, and all reported on the critical need for a larger collection of phantom and clinical images.