Roslyn J. Francis

Early Prediction of Response to Chemotherapy and Survival in Malignant Pleural Mesothelioma Using a Novel Semiautomated 3-Dimensional Volume-Based Analysis of Serial 18F-FDG PET Scans

The aim of chemotherapy for mesothelioma is to palliate symptoms and improve survival. Measuring response using CT is challenging because of the circumferential tumor growth pattern. This study aims to evaluate the role of serial 18F-FDG PET in the assessment of response to chemotherapy in patients with mesothelioma. Methods: Patients were prospectively recruited and underwent both 18F-FDG PET and conventional radiological response assessment before and after 1 cycle of chemotherapy. Quantitative volume-based 18F-FDG PET analysis was performed to obtain the total glycolytic volume (TGV) of the tumor. Survival outcomes were measured. Results: Twenty-three patients were suitable for both radiological and 18F-FDG PET analysis, of whom 20 had CT measurable disease. After 1 cycle of chemotherapy, 7 patients attained a partial response and 13 had stable disease on CT assessment by modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In the 7 patients with radiological partial response, the median TGV on quantitative PET analysis fell to 30% of baseline (range, 11%–71%). After 1 cycle of chemotherapy, Cox regression analysis demonstrated a statistically significant relationship between a fall in TGV and improved patient survival (P = 0.015). Neither a reduction in the maximum standardized uptake value (P = 0.097) nor CT (P = 0.131) demonstrated a statistically significant association with patient survival. Conclusion: Semiquantitative 18F-FDG PET using the volume-based parameter of TGV is feasible in mesothelioma and may predict response to chemotherapy and patient survival after 1 cycle of treatment. Therefore, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients. This technology may also be useful in the assessment of new systemic treatments for mesothelioma.

A Novel Prognostic Model for Malignant Mesothelioma Incorporating Quantitative FDG-PET Imaging with Clinical Parameters

Purpose: Existing prognostic systems for malignant pleural mesothelioma do not incorporate imaging information. We aimed to identify the contribution of quantitative fluorodeoxyglucose positron emission tomography (FDG-PET) analysis to other prognostic variables in this disease. Experimental Design: Patients with malignant pleural mesothelioma underwent helical thoracoabdominal computed tomography and FDG-PET scans at baseline. Patients were treated as clinically indicated and followed for survival. FDG-PET variables derived included total glycolytic volume, a composite of tumor volume and glycolytic activity. Results: Ninety-three patients were accrued from 2003 to 2006. Of 89 eligible assessable patients, 28 had undergone pleurodesis before enrolment. Seventeen patients remained alive at analysis; median survival is 15.4 months. On univariate analysis, significant prognostic factors were: total glycolytic volume on FDG-PET (P = 0.003), sarcomatoid histology (P < 0.0005), weight loss (P = 0.031), computed tomography stage (P = 0.015), and European Organization for Research and Treatment of Cancer good prognostic score (P = 0.049). In patients with epithelioid or biphasic histology, baseline total glycolytic volume remained predictive of survival in patients with (P = 0.01) or without (P = 0.018) previous pleurodesis. In multivariate analysis, no variable other than histology contributed to the model in patients with sarcomatoid histology; total glycolytic volume and weight loss contributed to the models in patients with nonsarcomatoid histology. computed tomography–assessed tumor-node-metastasis stage did not contribute to the model. A nomogram, which incorporates quantitative PET parameters and pleurodesis into prognostic information, is presented. Conclusions: Sarcomatoid histology remains the strongest prognostic factor. In patients with non sarcomatoid disease, volumetric FDG-PET parameters are more predictive of survival than tumor-node-metastasis staging, suggesting that tumor volume and glycolytic activity may be more important determinants of prognosis in malignant pleural mesothelioma than anatomic extent of disease. Clin Cancer Res; 16(8); 2409–17. ©2010 AACR.

Serum Soluble Mesothelin Concentrations in Malignant Pleural Mesothelioma: Relationship to Tumor Volume, Clinical Stage and Changes in Tumor Burden

Purpose: To examine the clinical utility of soluble mesothelin in patients with malignant pleural mesothelioma. Experimental Design: A total of 97 patients (female: 11; male: 86) were prospectively enrolled, longitudinal serum samples collected, and mesothelin concentrations determined. Baseline mesothelin levels were analyzed relative to tumor stage, presence of metastatic disease, the positron emission tomography (PET) parameters maximum standardized uptake value, tumor volume, total glycolytic volume, and survival. Changes in mesothelin level were correlated to objective response to chemotherapy, as assessed radiologically and by PET imaging, and with patient survival. Results: Baseline mesothelin levels greater than 5 nmol/L were a significant negative prognostic indicator (HR = 2.25; 95% CI, 1.20–4.21) and correlated with tumor stage and volume. In 55 patients who received chemotherapy, change in mesothelin correlated with radiological response (χ2 = 11.32; P = 0.023) and change in metabolically active tumor volume (r = 0.58; P < 0.01). Median survival for patients with a reduction in mesothelin following chemotherapy (19 months) was significantly longer than for patients with increased mesothelin (5 months; P < 0.001). Conclusion: These findings show the potential value of changes in mesothelin levels for prognostication and monitoring of treatment response in mesothelioma. Clin Cancer Res; 17(5); 1181–9. ©2010 AACR.

Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres

BackgroundCoincidence imaging of low-abundance yttrium-90 (90Y) internal pair production by positron emission tomography with integrated computed tomography (PET/CT) achieves high-resolution imaging of post-radioembolization microsphere biodistribution. Part 2 analyzes tumor and non-target tissue dose-response by 90Y PET quantification and evaluates the accuracy of tumor 99mTc macroaggregated albumin (MAA) single-photon emission computed tomography with integrated CT (SPECT/CT) predictive dosimetry.MethodsRetrospective dose quantification of 90Y resin microspheres was performed on the same 23-patient data set in part 1. Phantom studies were performed to assure quantitative accuracy of our time-of-flight lutetium-yttrium-oxyorthosilicate system. Dose-responses were analyzed using 90Y dose-volume histograms (DVHs) by PET voxel dosimetry or mean absorbed doses by Medical Internal Radiation Dose macrodosimetry, correlated to follow-up imaging or clinical findings. Intended tumor mean doses by predictive dosimetry were compared to doses by 90Y PET.ResultsPhantom studies demonstrated near-perfect detector linearity and high tumor quantitative accuracy. For hepatocellular carcinomas, complete responses were generally achieved at D70 > 100 Gy (D70, minimum dose to 70% tumor volume), whereas incomplete responses were generally at D70 < 100 Gy; smaller tumors (<80 cm3) achieved D70 > 100 Gy more easily than larger tumors. There was complete response in a cholangiocarcinoma at D70 90 Gy and partial response in an adrenal gastrointestinal stromal tumor metastasis at D70 53 Gy. In two patients, a mean dose of 18 Gy to the stomach was asymptomatic, 49 Gy caused gastritis, 65 Gy caused ulceration, and 53 Gy caused duodenitis. In one patient, a bilateral kidney mean dose of 9 Gy (V20 8%) did not cause clinically relevant nephrotoxicity. Under near-ideal dosimetric conditions, there was excellent correlation between intended tumor mean doses by predictive dosimetry and those by 90Y PET, with a low median relative error of +3.8% (95% confidence interval, -1.2% to +13.2%).ConclusionsTumor and non-target tissue absorbed dose quantification by 90Y PET is accurate and yields radiobiologically meaningful dose-response information to guide adjuvant or mitigative action. Tumor 99mTc MAA SPECT/CT predictive dosimetry is feasible. 90Y DVHs may guide future techniques in predictive dosimetry.

A phase I study of single administration of antibody-directed enzyme prodrug therapy with the recombinant anti-carcinoembryonic antigen antibody-enzyme fusion protein MFECP1 and a bis-iodo phenol mustard prodrug

Purpose: Antibody-directed enzyme prodrug therapy is a two-stage treatment whereby a tumor-targeted antibody-enzyme complex localizes in tumor for selective conversion of prodrug. The purpose of this study was to establish optimal variables for single administration of MFECP1, a recombinant antibody-enzyme fusion protein of an anti–carcinoembryonic antigen single-chain Fv antibody and the bacterial enzyme carboxypeptidase G2 followed by a bis-iodo phenol mustard prodrug. MFECP1 is manufactured in mannosylated form to facilitate normal tissue elimination. Experimental Design: Pharmacokinetic, biodistribution, and tumor localization studies were used to test the hypothesis that MFECP1 localizes in tumor and clears from normal tissue via the liver. Firstly, safety of MFECP1 and a blood concentration of MFECP1 that would avoid systemic prodrug activation were tested. Secondly, dose escalation of prodrug was done. Thirdly, the dose of MFECP1 and timing of prodrug administration were optimized. Results: MFECP1 was safe and well tolerated, cleared rapidly via the liver, and was less immunogenic than previously used products. Eighty-fold dose escalation from the starting dose of prodrug was carried out before dose-limiting toxicity occurred. Confirmation of the presence of enzyme in tumor and DNA interstrand cross-links indicating prodrug activation were obtained for the optimal dose and time point. A total of 28 of 31 patients was evaluable for response, the best response being a 10% reduction of tumor diameter, and 11 of 28 patients had stable disease. Conclusions: Optimal conditions for effective therapy were established. A study testing repeat treatment is currently being undertaken.

A Phase II Study of Intermittent Sunitinib Malate as Second-Line Therapy in Progressive Malignant Pleural Mesothelioma

Introduction: There is no accepted second-line therapy for patients with advanced malignant pleural mesothelioma (MPM), whose disease has progressed after first-line chemotherapy. The multitargeted tyrosine kinase inhibitor sunitinib malate targets several pathways overexpressed in mesothelioma. This phase II study assessed objective response to sunitinib and correlative biomarkers in patients with progressive pretreated MPM. Methods: Eligible patients had confirmed MPM, radiological progression after chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 1, and measurable disease. Patients received oral sunitinib 50 mg daily for 28 of every 42 days. The primary endpoint was objective radiological response. Patients without prior pleurodesis had fluorodeoxyglucose positron emission tomographic response assessed by total glycolytic volume criteria. Correlative biomarkers included serum mesothelin, vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, sVEGFR-2, sVEGFR-3, and s-kit. Results: Fifty-three patients received sunitinib between July 2006 and December 2009; 51 were assessable for response. Patients received a median of two cycles (range, 1–12); 40% required dose reduction. Fatigue was the most prominent toxicity. Six patients (12%) had a confirmed radiological partial response, 34 (65%) had stable disease, and 11 (22%) had progressive disease as best response. Six of 20 patients had a decrease in fluorodeoxyglucose positron emission tomographic total glycolytic volume of 15% or more. Median overall survival was 6.1 months, and median time to progression was 3.5 months. Correlative biomarkers did not predict treatment response. Conclusions: Sunitinib has activity in a subset of patients with pretreated MPM. Consideration should be given to different treatment schedules and examination of other biomarkers for further study of sunitinib in MPM.

Interventional therapies for malignant pleural effusions: The present and the future

The approach to management of malignant pleural effusions (MPE) has changed over the past few decades. The key goals of MPE management are to relieve patient symptoms using the least invasive means and in the most cost‐effective manner. There is now a realization that patient‐reported outcome measures should be the primary goal of MPE treatment, and this now is the focus in most clinical trials. Efforts to minimize patient morbidity are complemented by development of less invasive treatments that have mostly replaced the more aggressive surgical approaches of the past. Therapeutic thoracentesis is simple, effective and generally safe, although its benefits may only be temporary. Pleurodesis is the conventional and for a long time the only definitive therapy available. However, the efficacy and safety of talc pleurodesis has been challenged. Indwelling pleural catheter (IPC) drainage is increasingly accepted worldwide and represents a new concept to improve symptoms without necessarily generating pleural symphysis. Recent studies support the effectiveness of IPC treatment and provide reassurance regarding its safety. An unprecedented number of clinical trials are now underway to improve various aspects of MPE care. However, choosing an optimal intervention for MPE in an individual patient remains a challenge due to our limited understanding of the underlying pathophysiology of breathlessness in MPE and a lack of predictors of survival and pleurodesis outcome. This review provides an overview of common pleural interventional procedures used for MPE management, controversies and limitations of current practice, and areas of research most needed to improve practice in future.

Imaging in pleural mesothelioma: A review of Imaging Research Presented at the 9th International Meeting of the International Mesothelioma Interest Group

Imaging of malignant pleural mesothelioma (MPM) poses many challenges for imaging specialists and clinicians due to the anatomic location and unique growth pattern of this tumor. Nevertheless, imaging in MPM plays a critical role in diagnosis, prognostication, prediction or measurement of response to therapy, and monitoring of disease recurrence after aggressive surgical management. Imaging-based studies presented at the 9th International Conference of the International Mesothelioma Interest Group (IMIG) in October 2008 sought to further define the current practice and future potential of imaging for the mesothelioma patient. The Imaging Session was dominated by presentations that addressed the use of fluorodeoxyglucose positron emission tomography (FDG-PET), a clear indication of the expanding role of this modality. These uses included FDG-PET imaging at the point of diagnosis, in prognostication, and in the assessment of response to chemotherapy. Often FDG-PET studies were combined with computed tomography (CT) scans in an attempt to overcome limitations associated with either imaging modality alone. At diagnosis, FDG-PET parameters had a high sensitivity and specificity for differentiation of benign from malignant pleural disease. The use of FDG-PET to extract quantitative features from metabolically active tumor volume was shown to be a significant factor in the prediction of patient survival. The prognostic value of FDG-PET was not confounded by prior talc pleurodesis, despite the inflammatory response associated with the procedure. Metabolic response based on FDG-PET was found to be significantly correlated with progression-free survival. CT-based assessment of mesothelioma was determined to be inconsistent with spherical-model-based criteria so that changes in tumor area, a presumably more complete assessment of tumor burden, exhibited a 46% concordance rate with changes in linear measurements.

Detection of hypoxia with 18F-fluoromisonidazole (18F-FMISO) PET/CT in suspected or proven pancreatic cancer.

Purpose of the Report Pancreatic carcinoma is known to demonstrate molecular features of hypoxia. The aim of this prospective pilot study is to analyze the hypoxia agent fluoromisonidazole (FMISO) using PET/CT in pancreatic carcinoma and to compare FMISO activity with glucose metabolism reflected by FDG. Patients and Methods Ten patients with pancreatic carcinoma underwent FMISO and FDG PET scans. FMISO and FDG PET/CT scans were analyzed by 2 PET physicians. Regions of interest drawn on the FDG images were transposed to the FMISO images after study coregistration. The FDG SUVmax was used to quantify metabolic activity and FMISO SUVmax and tumor-to-background (muscle) ratio to quantify hypoxia. Results Seven patients were diagnosed with pancreatic adenocarcinoma. The remaining patients had a neuroendocrine tumor, poorly differentiated/sarcomatoid carcinoma, and mucinous neoplasm. Visual analysis demonstrated increased FMISO activity in 2 pancreatic adenocarcinomas. All patients, however, had increased FDG activity at the tumor site. Mean FDG SUVmax was 6 (range: 3.8 to 9.5) compared to 2.3 for FMISO (range: 1 to 3.4). The 2 positive studies on visual analysis of FMISO did not correspond to the largest tumors, the studies with the highest FMISO or FDG SUVmax. There was no significant correlation between FMISO and FDG SUVmax values. Conclusions The hypoxia imaging agent, FMISO, demonstrates minimal activity in pancreatic tumors. If FMISO PET/CT is to be included in clinical trial protocols of hypoxia in pancreatic cancer, it would require correlation with other imaging modalities to localize the tumor and allow semiquantitative analysis.

Assessment of tumour response with 18 F-fluorodeoxyglucose positron emission tomography using three-dimensional measures compared to SUVmax—a phantom study

SUVmax is currently the most common semi-quantitative method of response assessment on FDG PET. By defining the tumour volume of interest (VOI), a measure of total glycolytic volume (TGV) may be obtained. We aimed to comprehensively examine, in a phantom setting, the accuracy of TGV in reflecting actual lesion activity and to compare TGV with SUVmax for response assessment. The algorithms for VOI generation from which TGV was derived included fixed threshold techniques at 50% of maximum (MAX50), 70% of maximum (MAX70), an adaptive threshold of 50% of (maximum + background)/2 (BM50) and a semi-automated iterative region-growing algorithm, GRAB. Comparison with both actual lesion activity and response scenarios was performed. SUVmax correlated poorly with actual lesion activity (r = 0.651) and change in lesion activity (r = 0.605). In a response matrix scenario SUVmax performed poorly when all scenarios were considered, but performed well when only clinically likely scenarios were included. The TGV derived using MAX50 and MAX70 algorithms performed poorly in evaluation of lesion change. The TGV derived from BM50 and GRAB algorithms however performed extremely well in correlation with actual lesion activity (r = 0.993 and r = 0.982, respectively), change in lesion activity (r = 0.972 and r = 0.963, respectively) and in the response scenario matrix. TGV(GRAB) demonstrated narrow confidence bands when modelled with actual lesion activity. Measures of TGV generated by iterative algorithms such as GRAB show potential for increased sensitivity of metabolic response monitoring compared to SUVmax, which may have important implications for improved patient care.