Heather A. Jacene

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first‐line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium‐177 (177Lu)–Dotatate in patients with advanced, progressive, somatostatin‐receptor–positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well‐differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu‐Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long‐acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu‐Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression‐free survival. Secondary end points included the objective response rate, overall survival, safety, and the side‐effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data‐cutoff date for the primary analysis, the estimated rate of progression‐free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu‐Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu‐Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu‐Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu‐Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu‐Dotatate resulted in markedly longer progression‐free survival and a significantly higher response rate than high‐dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu‐Dotatate group. (Funded by Advanced Accelerator Applications; NETTER‐1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011‐005049‐11.)

[18F]Fluorodeoxyglucose Positron Emission Tomography Correlates With Akt Pathway Activity but Is Not Predictive of Clinical Outcome During mTOR Inhibitor Therapy

PURPOSE Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models. PATIENTS AND METHODS Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1. RESULTS Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression. CONCLUSION FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.

CT Hounsfield Units of Brown Adipose Tissue Increase with Activation: Preclinical and Clinical Studies

Brown adipose tissue (BAT) densities assessed as CT Hounsfield units (HUs) were evaluated in a rodent model and in patients to determine whether HUs changed in relation to BAT activity. Methods: Serial 18F-FDG PET/CT was performed on rats under both room temperature control conditions and after 4 h of cold-stimulation, which is known to activate BAT. The maximum standardized uptake values and CT HUs of BAT were measured, and tissues were examined in the laboratory. Image records from cancer patients who underwent PET/CT were reviewed, and 23 patients were identified who displayed both high and low 18F-FDG uptake into BAT on serial 18F-FDG PET/CT scans. The maximum standardized uptake values and CT HUs of BAT were compared in these scans. Results: The mean (±SD) CT HUs of cold-activated BAT (−12.4 ± 22.4) were significantly higher than those (−27.9 ± 9.6) of the controls in the rat model. The CT HUs of BAT (−71.6 ± 18.0) in the patients with high 18F-FDG uptake were significantly higher than those (−104.4 ± 16.8) of the patients with low 18F-FDG uptake . A decrease in relative lipid content is seen in activated BAT in rats on histology. Conclusion: The CT HUs of BAT increased in activated conditions in both animals and patients, likely because of lipid consumption by activated BAT.

Assessment of the Incremental Value of Recombinant Thyrotropin Stimulation before 2-[18F]-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography/Computed Tomography Imaging to Localize Residual Differentiated Thyroid Cancer

PURPOSE The purpose of the study was to assess prospectively the impact of recombinant human TSH (rhTSH) administration on positron emission tomography (PET)/computed tomography (CT) imaging in differentiated thyroid cancer patients who, after primary treatment, had a suppressed or stimulated serum thyroglobulin greater than 10 ng/ml and no radioactive iodine uptake consistent with thyroid cancer on a whole body scan. PATIENTS AND METHODS PET/CT was performed before (basal PET) and 24-48 h after rhTSH administration (rhTSH-PET) in 63 patients (52 papillary and 11 follicular thyroid cancers). Images were blindly analyzed by two readers. The proposed treatment plan was prospectively assessed before basal PET, after basal PET, and again after rhTSH-PET. RESULTS A total of 108 lesions were detected in 48 organs in 30 patients. rhTSH-PET was significantly more sensitive than basal PET for the detection of lesions (95 vs. 81%; P = 0.001) and tended to be more sensitive for the detection of involved organs (94 vs. 79%; P = 0.054). However, basal PET and rhTSH-PET did not have significantly different sensitivity for detecting patients with any lesions (49 vs. 54%; P = 0.42). Changes in treatment management plan occurred in 19% of the patients after basal PET. Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in eight patients, among whom only four were true-positive on pathology (6%). CONCLUSION The use of rhTSH for 2-[18F]-fluoro-2-deoxy-D-glucose-PET/CT significantly increased the number of lesions detected, but the numbers of patients in whom any lesion was detected were no different between basal and rhTSH-stimulated PET/CT scans. Treatment changes due to true positive lesions occurred in 6% of cases.

Comparison of 90Y-Ibritumomab Tiuxetan and 131I-Tositumomab in Clinical Practice

We retrospectively evaluated our single-center clinical experience with 90Y-ibritumomab tiuxetan and 131I-tositumomab for therapy of refractory non-Hodgkins lymphoma (NHL). We evaluated the hypothesis that the patient-specific dosing regimen used with 131I-tositumomab results in less bone marrow toxicity than does the weight-based dosing regimen used with 90Y-ibritumomab tiuxetan. Methods: Thirty-eight patients (25 male and 13 female; median age, 64 y) received radioimmunotherapy for NHL (20 received 90Y-ibritumomab tiuxetan; 18 received 131I-tositumomab). Patient and disease characteristics were evaluated to determine whether any were prognostic indicators of short- or long-term clinical response. The 12-wk response rate and clinical and hematologic toxicities attributable to each therapy were assessed. The response rate at 12 wk was correlated with long-term overall survival. Results: Twenty-six patients received full-radiation-dose radioimmunotherapy and 12 received attenuated doses because of hematologic concerns. The 12-wk overall response rate for all patients was 47%, and the complete response rate was 13%. The 12-wk overall response rate did not significantly differ between the 90Y-ibritumomab tiuxetan and 131I-tositumomab groups. Responses at 12 wk were more frequent in patients with normal levels of serum lactate dehydrogenase, no bone marrow involvement, and International Prognostic Index scores of no more than 2 (P ≤ 0.04). Grade 3 or 4 thrombocytopenia occurred in 57% and 56% of patients treated with 90Y-ibritumomab tiuxetan and 131I-tositumomab, respectively. Grade 3 or 4 neutropenia was observed in 57% and 50%, respectively. The time to the absolute neutrophil count nadir was shorter for the 90Y-ibritumomab tiuxetan group than for the 131I-tositumomab group (36 ± 9 vs. 46 ± 14 d, P = 0.01). The mean percentage decline in platelet count after radioimmunotherapy was greater in the 90Y-ibritumomab tiuxetan group than in the 131I-tositumomab group (79% ± 17% vs. 63% ± 28%, P = 0.04). Overall survival was longer in responders than in nonresponders 12 wk after therapy (P ≤ 0.05). Conclusion: Both 90Y-ibritumomab tiuxetan and 131I-tositumomab were well tolerated. We observed response rates at the lower range of those reported in the literature, possibly because of referral bias, dose attenuation, and reasonably liberal acceptance criteria for a patient to receive therapy. Initial response assessments 12 wk after radioimmunotherapy predict longer-term response. 131I-tositumomab caused significantly less severe declines in platelet counts than did 90Y-ibritumomab tiuxetan and may be a more appropriate choice for patients with limited bone marrow reserve, but large, randomized, prospective trials are needed to better compare the performance of these 2 treatments.

Assessment of Interobserver Reproducibility in Quantitative 18F-FDG PET and CT Measurements of Tumor Response to Therapy

Our goal was to estimate and compare across different readers the reproducibility of the 18F-FDG PET standardized uptake value (SUV) and CT size measurements, and changes in those measurements, in malignant tumors before and after therapy. Methods: Fifty-two tumors in 25 patients were evaluated on 18F-FDG PET/CT scans. Maximum SUVs (SUVbw max) and CT size measurements were determined for each tumor independently on pre- and posttreatment scans by 8 different readers (4 PET, 4 CT) using routine nonautomated clinical methods. Percentage changes in SUVbw max and CT size between pre- and posttreatment scans were calculated. Interobserver reproducibility of SUVbw max, CT size, and changes in these values were described by intraclass correlation coefficients (ICCs) and estimates of variance. Results: The ICC was higher for the pretreatment, posttreatment, and percentage change in SUVbw max than the ICC for the longest CT size and the 2-dimensional CT size (before treatment, 0.93, 0.72, and 0.61, respectively; after treatment, 0.91, 0.85, and 0.45, respectively; and percentage change, 0.94, 0.70, and 0.33, respectively). The variability of SUVbw max was significantly lower than the variability of the longest CT size and the 2-dimensional CT size (mean ± SD before treatment, 6.3% ± 14.2%, 16.2% ± 17.8%, and 27.5% ± 26.7%, respectively, P ≤ 0.001; and after treatment, 18.4% ± 26.8%, 35.1% ± 47.5%, and 50.9% ± 51.4%, respectively, P ≤ 0.02). The variability of percentage change in SUVbw max (16.7% ± 36.2%) was significantly lower than that for percentage change in the longest CT size (156.3% ± 157.3%, P ≤ 0.0001) and the 2-dimensional CT size (178.4% ± 546.5%, P < 0.0001). Conclusion: The interobserver reproducibility of SUVbw max for both untreated and treated tumors and percentage change in SUVbw max are substantially higher than measurements of CT size and percentage change in CT size. Measurements of tumor metabolism by PET should be included in trials to assess response to therapy. Although PET reproducibility was high, the variability observed in analyses of identical image sets by 4 readers indicates that automated analytic tools to assess response might be helpful to further enhance reproducibility.

Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma

In classical Hodgkin lymphoma, circulating clonotypic malignant cells express CD20, which potentially explains the observed activity of rituximab. This multicenter phase 2 study investigated the combination of rituximab-ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for stage II-IV untreated classical Hodgkin lymphoma. A goal was to assess the behavior of circulating clonotypic B cells clinically. Of 49 evaluable patients, 69% had stage IIB-IV disease; 8% had CD20(+) Hodgkin and Reed-Sternberg cells. Rituximab-ABVD was generally well tolerated. Delivered relative dose intensity was 94% for AVD and 79% for bleomycin. After 6 cycles, 81% of patients were in complete remission. Only 8% received radiation therapy. The actuarial 3-year event-free and overall survival rates were 83% and 98%, respectively. EBV copy number in plasma fell dramatically during cycle 1 in patients with EBV(+) tumors. Persistence of detectable circulating clonotypic B cells was associated with a greater relapse frequency (P < .05). Rituximab-ABVD and clonotypic B cells warrant additional study in classical Hodgkin lymphoma.

Prediction of the Need for Surgical Intervention in Obstructive Crohn's Disease by 18F-FDG PET/CT

We preoperatively determined the accuracy of 18F-FDG PET/CT for differentiating fixed muscle hypertrophy and fibrotic stenoses from acute transmural inflammatory stenoses in patients with Crohns disease (CD) scheduled to undergo surgical resection for obstructive symptoms. Methods: Seventeen patients with known CD prospectively underwent 18F-FDG PET/CT before already-planned surgery for obstructive symptoms. Image interpretation was by consensus of 2 readers with knowledge of patient participation in the study but not of other clinical history. Lesions were qualitatively graded on a 5-point scale for the presence of increased 18F-FDG uptake consistent with active inflammation. Maximum lean standardized uptake value (SULmax) was determined for lesions scored 1 or more. Imaging results were compared with the pathologic grading of inflammation and predominant histopathologic subtype for each patients surgical specimen, whether mainly inflammation, fibrosis, or muscle hypertrophy. Results: Thirteen of the 17 patients underwent surgery (median, 28 d after PET/CT; range, 2–148 d), and 12 of these 13 had histopathologic correlation. Despite the predominant histopathologic subtype (inflammation, 5; fibrosis, 4; and muscle hypertrophy, 3), acute and chronic inflammation, fibrosis (median, 50%; range, 40%−90%), and muscle hypertrophy (median, 20-fold thickening; range, 9- to 40-fold thickening) were found in all patients. SULmax was significantly higher in severe than in mild-to-moderate chronic inflammation (8.2 ± 2.8 vs. 4.7 ± 2.5, P = 0.04). No patient with predominantly fibrosis or muscle hypertrophy (n = 7) had an SULmax greater than 8. Visually, 10 of 12 patients on PET/CT were considered to have active inflammation of the bowel. Conclusion: Patients with CD who undergo surgery for obstructive symptoms have histopathologically mixed findings of inflammation, fibrosis, and muscle hypertrophy. Qualitative PET interpretations were quite sensitive, but additional semiquantitative analyses using SULmax helped identify patients with active inflammation. This information may be beneficial for referring gastroenterologists considering medical therapy versus surgery for patients with CD who present with obstructive symptoms.

Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: A study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center

BACKGROUND Merkel cell carcinoma (MCC) is a rare and lethal cutaneous neuroendocrine carcinoma. Imaging is crucial for accurate staging, which remains a strong predictor of survival, as well as earlier detection of recurrence and progression, which are common despite aggressive management. There is no consensus on the role of initial and subsequent imaging for MCC. OBJECTIVE We sought to evaluate the use of 2-fluoro-[(18)F]-deoxy-2-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in the management of MCC. METHODS In all, 270 FDG-PET/CT studies were performed in 97 patients with pathology-proven MCC at the Dana-Farber/Brigham and Womens Cancer Center, Boston, Mass, from August 2003 to December 2010. RESULTS FDG-PET/CT scans were obtained as part of the initial (61 scans in 61 patients) and subsequent (209 scans in 79 patients) treatment strategies. MCCs were FDG-avid with a mean maximum standardized uptake value of primary lesions of 6.5 (range 1.3-12.9) and a mean maximum standardized uptake value of regional and distant metastases of 7.2 (range 1.5-9.9). FDG-PET/CT upstaged 16% of patients who underwent baseline scans. FDG-PET/CT studies showed that bone and bone-marrow metastases were more common than previously reported, and were often undetected by CT. LIMITATIONS Our study is limited by its retrospective design, and potential referral bias associated with a tertiary care center. CONCLUSIONS FDG-PET/CT performed as part of the initial management strategy tended to upstage patients with more advanced disease. FDG-PET/CT performed as part of the subsequent treatment strategy identified metastatic disease, particularly in bone/bone marrow, which was not seen on CT. FDG-PET/CT imaging is a valuable staging and restaging tool in MCC management.

Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors

PURPOSE Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. PATIENTS AND METHODS We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). RESULTS Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. CONCLUSION mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.