Yusuf Menda

Response Assessment of Aggressive Non-Hodgkin’s Lymphoma by Integrated International Workshop Criteria and Fluorine-18–Fluorodeoxyglucose Positron Emission Tomography

PURPOSE To determine whether a response classification based on integration of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. RESULTS By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. CONCLUSION Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.

90Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide

PURPOSE Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.

Can FDG-PET reduce the need for mediastinoscopy in potentially resectable nonsmall cell lung cancer?

BACKGROUND Few fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) nonsmall cell lung cancer (NSCLC) trials have had sufficient patients to adequately evaluate PET for mediastinal staging. We question whether once PET is performed, is mediastinoscopy necessary? METHODS We performed a 5-year retrospective analysis of operable patients with known or suspicious NSCLC. Standard PET techniques were used. Inclusion criteria were (1) surgical mediastinal nodal sampling by mediastinoscopy within 31 days of the PET and (2) definitive diagnosis. RESULTS There were 237 patients who met the evaluation criteria; ninety-nine patients with NSCLC and 138 with suspicious lesions (137 men and 100 women; aged 20 to 88 years). The PETs were performed from 0 to 29 days before mediastinoscopy (median, 7 days). The standardized uptake value for the primary lesion was 0 to 24.6 (7.9+/-5.0). Nine primary lesions had no FDG uptake (1 benign, 8 NSCLCs). Seventy-one patients (31%) had mediastinal PET positive disease, and 44 patients (19%) had histologic positive mediastinal disease; N2 41 patients (17%) and N3 9 patients (4%). In 6 patients (3%), the initial frozen sections were negative, but PET positivity encouraged further biopsies that were positive for cancer. The PET sensitivity was 82%, specificity 82%, accuracy 82%, negative predictive value 95%, and positive predictive value was 51%. All primary lesions with a standardized uptake value less than 2.5 and a negative mediastinal PET were negative histologically (n = 29). Logistic regression analysis resulted in 100% specificity for PET in this group. CONCLUSIONS In NSCLC PET may reduce the necessity for mediastinoscopy when the primary lesion standardized uptake value is less than 2.5 and the mediastinum is PET negative. Accepting this approach in our patient population, the need for mediastinoscopy would have been reduced by 12%.

Clinical Significance of Postradiotherapy [18F]-Fluorodeoxyglucose Positron Emission Tomography Imaging in Management of Head-and-Neck Cancer—A Long-Term Outcome Report

PURPOSE To determine the accuracy and prognostic significance of post-treatment [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) in head-and-neck squamous cell carcinoma after radiotherapy (RT). METHODS AND MATERIALS This was a retrospective study of 188 patients with head-and-neck squamous cell carcinoma who had undergone FDG-PET within 12 months after completing RT. All living patients had >/=1 year of follow-up after FDG-PET. All patients had undergone intensity-modulated RT, 128 with definitive and 60 with postoperative intensity-modulated RT. RESULTS For all patients, the median follow-up after RT completion was 32.6 months and after FDG-PET was 29.2 months. For the neck, 171 patients had negative FDG-PET findings. Of these results, two were falsely negative. Seventeen patients had positive FDG-PET findings, of which 12 were true-positive findings. The sensitivity, specificity, positive predictive value, and negative predictive value for FDG-PET in the assessment of the treatment response in the neck was 86%, 97%, 71%, and 99%, respectively. For the primary site, 151 patients had negative FDG-PET findings, of which two were falsely negative. Thirty-seven patients had positive FDG-PET findings, of which 12 were true-positive findings. The sensitivity, specificity, positive predictive value, and negative predictive value for FDG-PET in the assessment of the treatment response in the primary site was 86%, 86%, 32.4%, and 98.7%, respectively. Patients with positive post-RT PET findings had significantly worse 3-year overall survival and disease-free survival. CONCLUSION The results of our study have shown that the findings of post-RT FDG-PET have a high negative predictive value and are a significant prognostic factor. It can provide guidance for the management of head-and-neck cancer after definitive treatment.

Pathology and FDG PET correlation of residual lymph nodes in head and neck cancer after radiation treatment

Background:This study determines if postradiotherapy [18F]fluorodeoxyglucose positron emission tomography (FDG PET) can predict the pathology status of residual cervical lymph nodes in patients undergoing definitive radiotherapy for head and neck squamous cell carcinoma (HNSCC). Methods:Patients with stage N2 or higher HNSCC underwent PET and CT imaging after definitive radiotherapy. Patients with radiographically persistent lymphadenopathy underwent either neck dissection or fine needle aspiration (FNA) of the lymph nodes under ultrasound guidance. PET scan results were correlated with the pathologic findings of the residual lymphadenopathy. Results:Twenty-four hemi-necks in 23 patients with residual lymphadenopathy had neck dissection or FNA. The pathology correlated strongly with the post-RT FDG PET studies. All patients with a negative post-RT FDG PET and those with a maximum standardized uptake value (SUVmax) of less than 3.0 in the post-RT FDG PET were found to be free from residual viable tumor. Using a SUVmax of less than 3.0 as the criterion for a negative FDG PET study, the sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 84.2%, 62.5%, and 100%, respectively. Conclusions:A negative post-RT FDG PET is very predictive of negative pathology in the residual lymph node after definitive radiotherapy for advanced HNSCC. A prospective clinical trial is warranted to determine if neck dissection can be withheld in these patients.

Evaluation of various corrections to the standardized uptake value for diagnosis of pulmonary malignancy.

Objective Standard uptake values (SUVs) are widely used for quantifying the uptake of 18F-fluorodeoxyglucose (18F-FDG) in tumours. The objective of this study was to evaluate the accuracy of SUVs for malignancy in lung nodules/masses and to analyse the effects of tumour size, blood glucose levels and different body weight corrections on SUV. Methods One hundred and twenty-seven patients with suspicious lung lesions imaged with 18F-FDG positron emission tomography (PET) were studied retrospectively. Pathology results were used to establish lesion diagnosis in all cases. SUVs based on maximum pixel values were obtained by placing regions of interest around the focus of abnormal 18F-FDG uptake in the lungs. The SUVs were calculated using the following normalizations: body weight (BW), lean body weight (LBW), scaled body surface area (BSA), blood glucose level (Glu) and tumour size (Tsize). Receivers operating characteristic (ROC) curves were generated to compare the accuracy of different methods of SUV calculation. Results The areas under the ROC curves for SUVBW, SUVBW+Glu, SUVLBW, SUVLBW+Glu, SUVBSA, SUVBSA+Glu and SUVBW+Tsize were 0.915, 0.912, 0.911, 0.912, 0.916, 0.909 and 0.864, respectively. Conclusion The accuracy of SUV analysis for malignancy in lung nodules/masses is not improved by correction for blood glucose or tumour size or by normalizing for body surface area or lean body weight instead of body weight.

Radiopeptide Imaging and Therapy in the United States

Radiolabeled peptides targeted against receptors on the cell surface have been shown to be remarkably specific and effective in the diagnosis and therapy of malignant disease. Much of the early work in this field took place outside the United States, but in recent years the research effort within the United States has accelerated. Most of the initial studies in the United States focused on somatostatin receptor ligands. 111In-pentetreotide was approved in 1994 and has been used extensively in the diagnosis and management of a wide variety of neuroendocrine tumors, particularly carcinoid. This work was extended to 99mTc-labeled analogs, and the most successful, 99mTc-depreotide, was approved in 1999. This agent was found to be accurate in the diagnosis of lung cancer, but it was not particularly successful because it was supplanted by 18F-FDG imaging with positron tomography. More recently, studies with 68Ga-labeled somatostatin analogs were initiated in the United States. This effort was delayed relative to that in other parts of the world because of difficulty in obtaining the necessary generators and regulatory uncertainty, both of which are less of a problem currently. Several ligands are being developed to image melanoma through targeting of the melanocyte-stimulating hormone receptor. Other ligands are being developed to use the arginine-glycine-aspartate oligopeptide to target angiogenesis and to use bombesin analogs to target the gastrin-releasing peptide receptor for the diagnosis and potential therapy of prostate cancer. Peptide dimers that target 2 receptors simultaneously are also being constructed, potentially increasing the selectivity of the approach significantly. Radiopeptide therapy has been explored with these ligands, initially with high-dose 111In-pentetreotide. This step has been followed by U.S. participation in several trials with 90Y-, 177Lu-, and 188Re-labeled analogs. Some of these agents are now available clinically outside the United States, and it is important to design and conduct the appropriate trials so that this therapy can be offered within the United States.

Single photon emission computed tomography (SPECT) should be routinely performed for the detection of parathyroid abnormalities utilizing technetium-99m sestamibi parathyroid scintigraphy.

Rationale: The current procedure guideline for performing dual-phase (DP) parathyroid scintigraphy, using technetium-99m sestamibi (Tc-99m MIBI) does not mandate the use of single photon emission computed tomography (SPECT) imaging for the detection of parathyroid adenoma (PA) or hyperplasia (PH). The aim of our study was to determine whether DP SPECT (DPS) is significantly superior to DP planar (DPP) imaging in the detection of these abnormalities, justifying its routine use with Tc-99m MIBI parathyroid scintigraphy. Methods: Thirty-six consecutive patients with biochemically-proven hyperparathyroidism who subsequently underwent surgical evaluation were studied. All patients underwent early and delayed planar and SPECT imaging at 15 and 90 minutes postinjection of 1.11 GBq (30 mCi) of Tc-99m MIBI. The sensitivity and false-positive rate of DPP and DPS Tc-99m MIBI scintigraphy were compared by retrospectively and blindly interpreting the images and comparing the results with surgical findings. Results: All 36 patients were shown to have either 1 PA (n=27), 2 PAs (n=1), or PH (n=8). Overall, 29 adenomas and 24 hyperplastic glands were found at surgery. On a per patient basis, the sensitivity for the detection of PA or PH for DPP was 42% (15/36) compared with 67% (24/36) for DPS (P = 0.03). For the detection of PAs, the sensitivity of DPP was 54% (15/28) versus 79% (22/28) for DPS (P = 0.05), whereas for the detection of PH, the sensitivities were 0% (0/8) for DPP versus 25% (2/8) for DPS (P = 0.13). There were 2 false-positive scans using DPP versus only 1 false-positive scan with DPS, resulting in false-positive rates of 7% and 4%, respectively. The combination of DPP and DPS did not add any advantage in detecting either PA or PH compared with DPS alone. Conclusions: DPS is significantly more sensitive, and at least as specific, compared with DPP in detecting parathyroid abnormalities in patients with primary hyperparathyroidism and should, therefore, be routinely used when DP Tc-99m MIBI is used in this setting. An algorithm for best utilization of this technique to determine the appropriate surgical approach in patients with primary hyperparathyroidism is presented.

Phase I Trial of 90Y-DOTATOC Therapy in Children and Young Adults with Refractory Solid Tumors That Express Somatostatin Receptors

The purpose of this study was to conduct a phase I trial of 90Y-DOTATOC to determine the dose-toxicity profile in children and young adults with somatostatin receptor–positive tumors. Methods: A 3 × 3 design was used to determine the highest tolerable dose of 90Y-DOTATOC, with administered activities of 1.11, 1.48, and 1.85 GBq/m2/cycle given in 3 cycles at 6-wk intervals. An amino acid infusion was coadministered with the radiopharmaceutical for renal protection. Eligibility criteria included an age of 2–25 y, progressive disease, a positive lesion on 111In-diethylenetriaminepentaacetic acid-D-Phe1-octreotide scanning, a glomerular filtration rate of 80 mL/min/1.73 m2 or more, bone marrow cellularity of 40% or more or stored autologous hematopoietic stem cells, 60% or more on the Lansky Play Scale, and informed consent. Results: Seventeen subjects (age, 2–24 y) received at least 1 dose of 90Y-DOTATOC; diagnoses included neuroblastoma, embryonal and astrocytic brain tumors, paraganglioma, multiple endocrine neoplasia IIB, and neuroendocrine tumors. No dose-limiting toxicities and no individual dose reductions due to renal or hematologic toxicity were noted. No complete responses were observed; 2 subjects experienced partial response, 5 had minor responses, 6 experienced stable disease, 2 had progressive disease, and 2 withdrew. Conclusion: Peptide receptor radionuclide therapy with 90Y-DOTATOC is safe in children and young adults and demonstrated a 12% partial response plus 29% minor response rate in patients with somatostatin receptor–positive tumors. No dose-limiting toxicities were observed. The recommended phase II dosing is 3 cycles of 1.85 GBq/m2/dose of 90Y-DOTATOC coadministered with amino acids.

A methodology for incorporating functional bone marrow sparing in IMRT planning for pelvic radiation therapy.

BACKGROUND AND PURPOSE The purpose of this study was to design a radiation therapy treatment planning approach that would spare hematopoietically active bone marrow using [(18)F]FLT PET imaging. MATERIALS AND METHODS We have developed an IMRT planning methodology to incorporate functional PET imaging using [(18)F]FLT scans. Plans were generated for two simulated cervical cancer patients, where pelvic active bone marrow regions were incorporated as avoidance regions based on the ranges: SUV4 ≥ 4; 4>SUV3 ≥ 3; and 3 > SUV2 ≥ 2. Dose objectives were set to reduce bone marrow volume that received 10 (V(10)) and 20 (V(20))Gy. RESULTS Active bone marrow regions identified by [(18)F]FLT with an SUV ≥ 2, SUV ≥ 3, and SUV ≥ 4 represented an average of 43.0%, 15.3%, and 5.8%, respectively of the total osseous pelvis for the two cases studied. Improved dose-volume histograms for all identified bone marrow SUV volumes and decreases in V(10), and V(20) were achieved without clinically significant changes to PTV or OAR doses. CONCLUSIONS Incorporation of [(18)F]FLT PET in IMRT planning provides a methodology to reduce radiation dose to active bone marrow without compromising PTV or OAR dose objectives in pelvic malignancies.