Andrew Quon

Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas

The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma.

Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

PURPOSE Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. METHODS AND MATERIALS A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). CONCLUSION SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.

Non–Small Cell Lung Cancer: Identifying Prognostic Imaging Biomarkers by Leveraging Public Gene Expression Microarray Data—Methods and Preliminary Results

PURPOSE To identify prognostic imaging biomarkers in non-small cell lung cancer (NSCLC) by means of a radiogenomics strategy that integrates gene expression and medical images in patients for whom survival outcomes are not available by leveraging survival data in public gene expression data sets. MATERIALS AND METHODS A radiogenomics strategy for associating image features with clusters of coexpressed genes (metagenes) was defined. First, a radiogenomics correlation map is created for a pairwise association between image features and metagenes. Next, predictive models of metagenes are built in terms of image features by using sparse linear regression. Similarly, predictive models of image features are built in terms of metagenes. Finally, the prognostic significance of the predicted image features are evaluated in a public gene expression data set with survival outcomes. This radiogenomics strategy was applied to a cohort of 26 patients with NSCLC for whom gene expression and 180 image features from computed tomography (CT) and positron emission tomography (PET)/CT were available. RESULTS There were 243 statistically significant pairwise correlations between image features and metagenes of NSCLC. Metagenes were predicted in terms of image features with an accuracy of 59%-83%. One hundred fourteen of 180 CT image features and the PET standardized uptake value were predicted in terms of metagenes with an accuracy of 65%-86%. When the predicted image features were mapped to a public gene expression data set with survival outcomes, tumor size, edge shape, and sharpness ranked highest for prognostic significance. CONCLUSION This radiogenomics strategy for identifying imaging biomarkers may enable a more rapid evaluation of novel imaging modalities, thereby accelerating their translation to personalized medicine.

Metabolic Tumor Volume Predicts for Recurrence and Death in Head and Neck Cancer

PURPOSE To evaluate the prognostic value of metabolic tumor volume measured on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and other clinical factors in patients treated for locally advanced head-and-neck cancer (HNC) at a single institution. MATERIALS AND METHODS Between March 2003 and August 2007, 85 patients received positron emission tomography (PET)/computed tomography-guided chemoradiotherapy for HNC. Metabolically active tumor regions were delineated on pretreatment PET scans semiautomatically using custom software. We evaluated the relationship of (18)F-fluorodeoxyglucose-PET maximum standardized uptake value (SUV) and total metabolic tumor volume (MTV) with disease-free survival (DFS) and overall survival (OS). RESULTS Mean follow-up for surviving patients was 20.4 months. The estimated 2-year locoregional control, DFS, and OS for the group were 88.0%, 69.5%, and 78.4%, respectively. The median time to first failure was 9.8 months among the 16 patients with relapse. An increase in MTV of 17.4 mL (difference between the 75th and 25th percentiles) was significantly associated with an increased hazard of first event (recurrence or death) (1.9-fold, p < 0.001), even after controlling for Karnofsky performance status (KPS) (1.8-fold, p = 0.001), and of death (2.1-fold, p < 0.001). We did not find a significant relationship of maximum SUV, stage, or other clinical factors with DFS or OS. CONCLUSIONS Metabolic tumor volume is an adverse prognostic factor for disease recurrence and death in HNC. MTV retained significance after controlling for KPS, the only other significant adverse prognostic factor found in this cohort. MTV is a direct measure of tumor burden and is a potentially valuable tool for risk stratification and guiding treatment in future studies.

FDG-PET and Beyond: Molecular Breast Cancer Imaging

Positron emission tomography (PET) scanning has gained widespread acceptance for the diagnosis, staging, and management of a variety of malignancies, including breast cancer. This has heralded an exciting new era of molecular imaging research of which using FDG as the primary PET tracer is only the beginning. The fundamental strength of PET over conventional imaging is the ability to convey functional information that even the most exquisitely detailed anatomic image cannot provide. As the standard PET radiotracer in current clinical use, FDG is a glucose analog that is taken up by cells in proportion to their rate of glucose metabolism. The increased glycolytic rate and glucose avidity of malignant cells in comparison to normal tissue is the basis of the ability of FDG-PET imaging to accurately differentiate cancer from benign tissue irregardless of morphology. The level or intensity of FDG uptake on PET is semiquantified and reported as the standardized uptake value (SUV). A multitude of new PET tracers are under development, many of which are aimed at targeting cellular processes that are more specific than glucose metabolism. In relation to breast cancer, these tracers include thymidine analogs such as [F-18]fluoro-L-thymidine (FLT) that target DNA replication as a measure of cell proliferation, annexin V derivatives that evaluate apoptosis, estrogen receptor (ER) tracers such as 16 -[F-18]fluoroestradiol-17 (FES), and engineered antibody fragments that directly target HER-2/neu receptors. In addition to new tracers, scanner technology is also rapidly evolving. Chief among these is the advent of the dual modality PET/CT scanner, which at the very least increases patient convenience by permitting PET and computed tomography (CT) imaging in a single appointment. But perhaps more importantly, initial studies indicate that the sum of the two modalities is better than either used separately and also may be an extremely useful tool in preradiation therapy planning. Other new scanning devices are also being developed, including small gantry PET scanners designed specifically for breast imaging, and handheld PET probes for direct intraoperative localization of tracer-avid tumor foci.

SINGLE-FRACTION STEREOTACTIC BODY RADIATION THERAPY AND SEQUENTIAL GEMCITABINE FOR THE TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER

PURPOSE This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year. CONCLUSION Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.

Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study

Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET(+) interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: kappa statistic = 0.445 using ECOG criteria, and kappa statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924 [corrected].

18Fluorodeoxyglucose PET Is Prognostic of Progression-Free and Overall Survival in Locally Advanced Pancreas Cancer Treated With Stereotactic Radiotherapy

PURPOSE This study analyzed the prognostic value of positron emission tomography (PET) for locally advanced pancreas cancer patients undergoing stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS Fifty-five previously untreated, unresectable pancreas cancer patients received a single fraction of 25-Gy SBRT sequentially with gemcitabine-based chemotherapy. On the preradiation PET-CT, the tumor was contoured and the maximum standardized uptake value (SUVmax) and metabolic tumor burden (MTB) were calculated using an in-house software application. High-SUVmax and low-SUVmax subgroups were created by categorizing patients above or below the median SUVmax. The analysis was repeated to form high-MTB and low-MTB subgroups as well as clinically relevant subgroups with SUVmax values of <5, 5-10, or >10. Multivariate analysis analyzing SUVmax, MTB, age, chemotherapy cycles, and pretreatment carbohydrate antigen (CA)19-9 was performed. RESULTS For the entire population, median survival was 12.7 months. Median survival was 9.8 vs.15.3 months for the high- and low- SUVmax subgroups (p <0.01). Similarly, median survival was 10.1 vs. 18.0 months for the high MTB and low MTB subgroups (p <0.01). When clinical SUVmax cutoffs were used, median survival was 6.4 months in those with SUVmax >10, 9.5 months with SUVmax 5.0-10.0, and 17.7 months in those with SUVmax <5 (p <0.01). On multivariate analysis, clinical SUVmax was an independent predictor for overall survival (p = 0.03) and progression-free survival (p = 0.03). CONCLUSION PET scan parameters can predict for length of survival in locally advanced pancreas cancer patients.

Performance of 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography and Integrated PET/CT in Restaged Breast Cancer Patients

PurposeThis study was conducted to compare the clinical stage derived from 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) positron emission tomography (PET) to that of integrated PET/computed tomography (CT) in restaged breast cancer patients.ProceduresFifty-eight female patients (age range 29–80 years, mean age ±SD, 53.3 ± 11.7 years) underwent PET/CT restaging for breast cancer. Two experienced nuclear medicine physicians interpreted PET images. A radiologist was added for reading PET/CT studies. A patient-based analysis was performed. Histopathological findings, correlative imaging studies, changes in number, size, and hypermetabolic activity of suspicious lesions and/or patient outcome served as standard of reference for determining the diagnostic accuracy of both modalities.ResultsPET staged 79.3% (46/58) of the patients correctly, overstaged seven (12.1%), and understaged five patients (8.6%). Integrated PET/CT staged 89.7% (52/58) of the patients correctly, overstaged four (6.9%), and understaged two patients (3.4%). The staging accuracy of PET/CT was not significantly better than that of PET alone (p = 0.059). Lesions exhibiting mild hypermetabolic activity, benign inflammatory lesions, and physiological variants largely explained incorrect PET findings.ConclusionIntegrated PET/CT only marginally improves the restaging accuracy over PET alone (p = 0.059) in breast cancer patients.

Novel Strategy for a Cocktail 18F-Fluoride and 18F-FDG PET/CT Scan for Evaluation of Malignancy: Results of the Pilot-Phase Study

18F-FDG PET/CT is used for detecting cancer and monitoring cancer response to therapy. However, because of the variable rates of glucose metabolism, not all cancers are identified reliably. Sodium 18F was previously used for bone imaging and can be used as a PET/CT skeletal tracer. The combined administration of 18F and 18F-FDG in a single PET/CT study for cancer detection has not been reported to date. Methods: This is a prospective pilot study (November 2007–November 2008) of 14 patients with proven malignancy (6 sarcoma, 3 prostate cancer, 2 breast cancer, 1 colon cancer, 1 lung cancer, and 1 malignant paraganglioma) who underwent separate 18F PET/CT and 18F-FDG PET/CT and combined 18F/18F-FDG PET/CT scans for the evaluation of malignancy (a total of 3 scans each). There were 11 men and 3 women (age range, 19–75 y; average, 50.4 y). Results: Interpretation of the combined 18F/18F-FDG PET/CT scans compared favorably with that of the 18F-FDG PET/CT (no lesions missed) and the 18F PET/CT scans (only 1 skull lesion seen on an 18F PET/CT scan was missed on the corresponding combined scan). Through image processing, the combined 18F/18F-FDG scan yielded results for bone radiotracer uptake comparable to those of the 18F PET/CT scan performed separately. Conclusion: Our pilot-phase prospective trial demonstrates that the combined 18F/18F-FDG administration followed by a single PET/CT scan is feasible for cancer detection. This combined method opens the possibility for improved patient care and reduction in health care costs.