The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR-positive metastatic breast cancer who had received ≥2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 mg) was administered once intravenously (i.v.). Blood was collected for biochemistry/hematology testing and pharmacokinetic and immunogenicity analyses at selected times post injection (p.i.). Whole body planar images were acquired at 1, 4-6, 24 and 72 h p.i. and SPECT images at 24 and/or 72 h p.i. Macrodosimetry (MIRD) for the whole body and organs was estimated using OLINDA. Correlative radiological imaging was obtained at baseline, 1 and 3 months and then 6 monthly. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE)v2.0. Sixteen patients, median age 47 yr (range, 35-59), received (111)In-DTPA-hEGF as follows: 357-434 MBq (7), 754-805 MBq (3), 1,241-1,527 MBq (3) and 2,030-2,290 MBq (3). Fifteen were evaluable for toxicity. The commonest adverse events (AE) were flushing, chills, nausea, and vomiting occurring during or immediately p.i. One patient experienced Grade 3 thrombocytopenia (attributed to bone marrow infiltration by cancer). There were no other Grade 3 or 4 AEs. Maximum tolerated dose was not reached. Clear accumulation of radiopharmaceutical in at least one known site of disease was observed in 47% of patients. (111)In-DTPA-hEGF was cleared biexponentially from the blood with α-phase T½ of 0.16 ± 0.03 h and β-phase T½ of 9.41 ± 1.93 h. (111)In-DTPA-hEGF was not immunogenic. The mean radiation dose estimates in mGy/MBq for whole body, liver, kidneys, spleen and thyroid were 0.08, 0.86, 0.74, 0.37 and 0.30, respectively. No objective antitumor responses were observed at the doses studied. In summary, administered amounts of up to 2,290 MBq (0.25 mg) of (111)In-DTPA-hEGF were well tolerated as a single i.v. injection.

6049 Background: The clinical utility of PET/CT in patients with suspected cancer recurrence remains unclear. The aim of this multi-center, prospective, comparative effectiveness study is to assess the impact of PET/CT on clinical management of patients with suspected cancer recurrence. Methods: Patients were eligible if cancer recurrence (non-small cell lung, breast, head and neck, ovarian, esophageal, Hodgkin’s or non-Hodgkin’s lymphoma) was clinically suspected, and if conventional imaging (e.g. X-ray, ultrasound, CT, or MRI) was non-diagnostic. As a pre-requisite to PET/CT booking, clinicians were asked at enrolment to indicate their planned management if PET/CT were not available. Patients then underwent 18FDG-PET/CT. Clinicians were then asked to indicate their management plan based on PET/CT findings. Patients were followed up once at 3 months. The primary outcome was change in planned management after PET/CT and was assessed independently and in duplicate by external outcome adjudicators using all available source documents. Results: 101 patients (mean age 64 y, 45% male, median 1.3 y since last treatment) were enrolled from 4 centers in Ontario, Canada between April 2009 and June 2011. Distribution of tumor types was: non-small cell lung (55%), breast (19%), ovarian (10%), esophageal (6%), lymphoma (6%), head and neck (4%). 8 patients did not complete the study (non-adherence to protocol, 2; death, 5; disease progression prior to PET/CT, 1), of whom 2 did not receive PET/CT. PET/CT changed planned management in 52 (53%) patients (Table). At 3 months, planned management was carried out in 46/52 (88%) patients. Conclusions: In patients with suspected cancer recurrence, PET/CT changes planned management from non-treatment to treatment for approximately 1 in every 3 patients (“number needed to scan” = 3) and contributes importantly to clinical management. [Table: see text]

OBJECTIVE:The purpose of this study was to compare FDG PET/CT and contrast-enhanced 64-MDCT of the chest, abdomen, and pelvis in the detection of tumor recurrence in patients with colorectal cancer and an elevated level of carcinoembryonic antigen (CEA).MATERIALS AND METHODS:A retrospective analysis included 50 patients (31 men, 19 women; mean age, 61 years; range, 28-89 years) with 55 clinical events of elevated or increasing CEA level who underwent FDG PET/CT and MDCT for suspected tumor recurrence.RESULTS:Recurrent or metastatic disease was found in 36 of 55 events (65.5%) of elevated CEA. Fifty-four of 61 tumor sites suspected as tumor recurrence with any imaging technique were found to be local recurrence or metastatic colorectal cancer at final analysis. The other seven sites were one separate malignant tumor (small lymphocytic lymphoma) and six benign lesions. Diagnosis was based on histopathologic findings (n = 27) or clinical and imaging findings (n = 35) during a median follow-up period of 12 months (range, 6-31 months). One site of tumor recurrence was missed prospectively at both MDCT and PET/CT. On an event-based analysis, the sensitivity of PET/CT and MDCT was 97.3% and 70.3% (p = 0.002); the specificity of both techniques was 94.4% (p = 1.0). In a tumor site-based analysis, the sensitivities of PET/CT and MDCT were 98.1% and 66.7% (p < 0.0001), and the specificities were 75% and 62.5% (p = 0.56). Tumors correctly identified with PET/CT and missed with MDCT were local recurrence in the presacral space (n = 5), metastatic subcentimeter lymph nodes (n = 4), peritoneal deposits (n = 3), and recurrences at the periphery of radiofrequency ablated metastatic lesions of the liver (n = 2) and in the abdominal wall (n = 1), liver (n = 1), and uterine cervix (n = 1).CONCLUSION:FDG PET/CT has higher sensitivity than MDCT in the identification of sites of recurrent and metastatic disease in patients with colorectal cancer and an elevated CEA level. The two techniques appear to have similar specificity.

Background and purpose: Distant metastases are the dominant mode of failure after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). The primary study objective was to evaluate if the maximum standardized uptake value (SUVmax) on pre-treatment FDG-PET/CT predicted clinical outcomes. Secondary objectives were to correlate 3-month post-SBRT SUVmax and change in SUVmax with outcomes.Materials and methods: Consecutive patients with medically inoperable early-stage NSCLG and an FDG-PET/CT scan before (n = 82) and 3 months after (n = 62) SBRT.Results: Median follow up was 2 years. On univariate analysis baseline SUVmax predicted for distant failure (p = 0.0096), relapse free survival (RFS) (p = 0.037) and local failure (p = 0.044). On multivariate analysis baseline SUVmax predicted for RFS (p = 0.037). Baseline SUVmax of above 5 was the most statistically significant cut off point for predicting distant failure (p = 0.0002). Baseline SUVmax >= 4.75 (median) was correlated with a higher risk of distant failure (p = 0.012) and poorer RFS (p = 0.04). Patients with a post-SBRT SUVmax >= 2 and a reduction of <2.55 had a significantly higher rate of distant failure.Conclusions: Pre-SBRT SUVmax on FDG-PET/CT correlated most strongly with distant failure. A cut off of >= 5 was the most significant. Post-SBRT SUVmax >= 2 and a reduction of <2.55 were associated with a higher risk of distant failure. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 104 (2012) 62-66

The early response of lung tumours to stereotactic radiotherapy was prospectively evaluated with 18F-fluorodeoxyglucose positron emission tomography-computed tomography. Three months after treatment, the maximum standardised uptake value and the tumour diameter fell by 64 and 30%, respectively. This imaging strategy therefore remains under ongoing evaluation with the aim of identifying predictive and prognostic factors.

CONTEXT Paragangliomas are tumors that develop from extraadrenal chromaffin cells. Approximately 20% of paragangliomas are malignant, and surgical resection is considered the primary treatment when possible. The optimal systemic treatment for advanced disease is undefined, due in part to lack of effective agents. Here we report our experience suggesting that sunitinib is an effective agent in this malignancy. SETTING AND PATIENTS Three patients with metastatic paraganglioma were treated with sunitinib at the Princess Margaret Hospital. Limited analyses of tumor tissue and germline DNA were available. INTERVENTION Sunitinib at a standard dose (50 mg daily, 4 wk on, 2 wk off) was titrated to patient tolerance. RESULTS One patient has achieved a near complete response, and two patients demonstrated partial responses. Two patients demonstrated germline defects suggesting a pseudo-hypoxic drive to the tumor whereas the third demonstrated immunohistochemical evidence of this phenomenon. CONCLUSIONS Sunitinib appears to be an active agent in this malignancy based on this limited cohort, with an understandable mechanism of action similar to that described in other hypoxia-driven tumors. A single arm phase 2 trial is underway.

Purpose: Optimal target delineation threshold values for positron emission tomography (PET) and computed tomography (CT) radiotherapy planning is controversial. In this present study, different PET CT threshold values were used for target delineation and then compared pathologically.Methods and Materials: A total of 31 non small-cell lung cancer patients underwent PET CT before surgery. The maximal diameter (MD) of the pathologic primary tumor was obtained. The CT-based gross tumor volumes (GTV(CT)) were delineated for CT window-level thresholds at 1,600 and 300 Hounsfield units (HU) (GTV(CT1)); 1,600 and 400 (GTV(CT2)); 1,600 and 450 HU (GTV(CT3)); 1,600 and 690 HU (GTV(CT4)); 1,200 and 700 HU (GTV(CT5)); 900 and -450 HU (GTV(CT6)); and 700 and -450 HU (GTV(CT7)). The PET-based GTVs (GTV(PET)) were autocontoured at 29% (GTV(20)), 39% (GTV(30)), 40% (GTV(40)), 45% (GTV(45)), 50% (GTV(50)), and 55% (GTV(55)) of the maximal intensity level. The MD of each image-based GTV in three-dimensional orientation was determined. The MD of the GTV(PET) and GTV(CT) were compared with the pathologically determined MD.Results: The median MD of the GTV(CT) changed from 2.89 (GTV(CT2)) to 4.46 (GTV(CT7)) as the CT thresholds were varied. The correlation coefficient of the GTV(CT) compared with the pathologically determined MD ranged from 0.76 to 0.87. The correlation coefficient of the GTV(CT1), was the best (r = 0.87). The median MD of GTV(PET) changed from 5.72cm to 2.67cm as the PET thresholds increased. The correlation coefficient of the GTV(PET) compared with the pathologic finding ranged from 0.51 to 0.77. The correlation coefficient of GTV(50) was the best (r = 0.77).Conclusion: Compared with the MD of GTV(PET), the MD of GTV(CT) had better correlation with the pathologic MD. The GTV(CT) and GTV(50) had the best correlation with the pathologic results. (C) 2010 Elsevier Inc.

To evaluate the safety, pharmacokinetics, tumour and normal tissue distribution and radiation dosimetry of 111In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical for EGFR-positive cancer, in a Phase I trial involving breast cancer patients with metastatic disease. Sixteen patients received 111In-DTPA-hEGF by slow i.v. infusion as follows: 357-434 MBq (7 patients), 754-805 MBq (3), 1241-1527 MBq (3) and 2030-2290 MBq (3). Clinical biochemistry/hematology testing was performed at 1, 2, and 6 weeks and 3 and 6 months. Blood samples were obtained up to 72 h p.i. for pharmacokinetics. Whole body planar images were obtained at 1, 4-6, 24, and 72 h p.i. and SPECT at 24 and/or 72 h. Correlative radiological imaging was obtained prior to study entry and at 3 and 6 months. Toxicity was scored using NCICTCv2. Macrodosimetry (MIRD) estimates were calculated for the whole body and normal tissues. All patients (median age 47 years; range, 35-59 years) had EGFR-positive metastatic breast cancer and had received 2-10 prior regimens of systemic treatment. The most common adverse effects were facial flushing (16), nausea (16), and vomiting (6) at the time, or immediately after 111In-DTPA-hEGF administration. One patient had a transient drop in b.p. that did not require specific treatment. No Grade 3 or 4 adverse events were observed. 111In-DTPA-hEGF was cleared bioexponentially from the blood with an alpha-phase t1/2 of 0.16 ± 0.03 h and a beta-phase t1/2 of 9.41 ± 1.93 h. The volume of distribution of the central compartment (V1) was 0.459 ± 0.107 L/kg and at steady-state (Vss) was 2.644 ± 0.730 L/kg. The clearance (CL) was 0.267 ± 0.062 L/h/kg. The 24 h urinary excretion of radioactivity was 16.05 ± 2.45% (mean ± SEM). 111In-DTPA-hEGF was accumulated by the liver (30-40%), kidneys (10-15%), spleen (1.5-2%) and thyroid (<1%). The mean radiation dose estimates for the first 9 patients (cGy/37 MBq) were whole body (0.89), liver (5.30), kidneys (7.73), spleen (2.31), and thyroid (0.79). There were no treatment-related changes in RBC, WBC, platelets or serum AST/ALT or creatinine. No antitumor responses were observed. 111In-DTPA-hEGF (up to 2290 MBq, 0.25 mg) was administered without serious adverse events. A multi-dose Phase I trial of 111In-DTPA-hEGF is planned in patients with NSCLC, head and neck, and breast cancers.

To evaluate changes in FDG-PET uptake in patients treated with SBRT for early stage (T1-2N0M0) NSCLC. 30 patients (31 lesions) with FDG PET/CT imaging pre-SBRT and 3 months (m) post-SBRT were evaluated. All lesions were T1 (n = 24) or T2 (n = 7). Median follow-up was 6.1m. Treatment schedules were 48 Gy/4fr (n = 16, typically T1 near organs at risk), 54 or 60 Gy/3fr (n = 11), and 60 Gy/8fr (n = 3) or 50 Gy/10fr (n = 1) for lesions near critical structures. Patients were imaged with the Siemens Biograph 2 PET/CT scanner, 60 minutes after injection of 18F-FDG (5MBq/kg). CT scan was performed for attenuation correction and co-registration, with thoracic images acquired at end-expiration. FDG-PET uptake is reported as the maximum standardized uptake value (SUVmax), defined as the maximum activity in the selected region (MBq/ml)/(injected dose [MBq]/body weight [kg]). The SUVmax was obtained with the MDStation (Thinking Systems), using regions of interest over the volume of the lesion. The anatomic response on CT is defined by RECIST criteria. Data are presented using descriptive statistics. Pre-SBRT, the baseline median SUVmax was 5.8 (mean 6.2, range 1-14.7) and longest diameter 2.2 cm (2.4 cm, 1-4.5 cm). 3 months post-SBRT, the median and mean reduction in SUVmax for all 31 lesions was 64 and 62% respectively (T1 = 64 and 62%, T2 = 64% and 63%). The median reduction in SUVmax with 48 Gy/4fr and 54 or 60 Gy/3fr was 64% (mean 68 and 57%, respectively). 30/31 (97%) lesions exhibited a fall in SUVmax. 97% of 3m SUVmax readings were <4 (baseline = 26%) and 58% <2 (baseline = 6%); 29% fell by >80%. 1 lesion increased from SUVmax 1 to 1.5 (CT-stable at 3m). At 3m, 15 lesions were CT-stable (median reduction SUVmax 60%) and 16 had responded (13 partial and 3 complete, median reduction SUVmax 77%). The difference in percentage reduction of SUVmax between these groups was not significant (Mann-Whitney). Of 24 lesions with a CT scan 6m post-SBRT a further 3 had become complete responders (33-83% SUVmax reduction at 3m); 1 had progressed (58% reduction in SUVmax and partial CT response at 3m) and 4 (17%) were non-evaluable due to treatment-induced lung changes. Large reductions in SUVmax are seen soon after SBRT for T1-2 NSCLC, making FDG PET a potential candidate for predicting response. The CT response evolves over time and an accurate assessment of the performance of FDG PET will require larger patient numbers and longer follow-up. Treatment-induced lung changes can prevent evaluation by conventional CT. The optimal paradigm for response evaluation in thoracic SBRT remains to be defined.

The objective of this study is to study the changes in FDG uptake in lung tumors and surrounding tissue over the course of radiation treatment to facilitate further research in FDG PET CT as a feasible tool for adaptive radiotherapy. Patients were prospectively enrolled on an REB approved protocol. Each patient had FDG-PET/CT studies performed before radiation, during radiation (after 2-4 weeks), and again after 8 weeks following treatment. CT defined tumor volumes, PET based maximum SUV's, and PET defined tumor volumes based on a SUV of greater than 2.5 are contoured. Metabolic and radiographic tumor responses are then analyzed. 15 patients with small-cell and non-small-cell lung cancer receiving both palliative (3 patients) and radical radiotherapy (12 patients) with or without chemotherapy have completed all 3 (before, during, and after) scans and are included in this analysis. The median pre-radiotherapy, during radiotherapy, and post radiotherapy SUV was 14.6 (range 4.97 - 30.41), 10.8 (range 3.0 - 27.3), and 6.8 (range 3.0 - 14.0), respectively. This corresponds to a decrease to 74% during radiotherapy and 47% post radiotherapy. The corresponding median CTV volume in exhale was 102.7 cc, 73.5 cc, and 33.7 cc respectively. The median tumor volume defined by a SUV of 2.5 was 108.3 cc, 59.8 cc, and 13.8 cc respectively. There were 8 metabolic responders and 1 metabolic progression by week 4 of radiotherapy by EORTC criteria. 14 out of the 15 patients responded at the post radiotherapy scan and 1 patient progressed. 3 of the 15 patients were small cell histology and all responded after 3 weeks of radiotherapy. Among the 8 early responders, SUVs decreased to a median of 60.6% initially (range 22.6%- 70.6%), then decreased to a median of 38.7% (range 18.4%-73.8%) on the post radiotherapy scan with 2 patients having a slight increase in their SUVs. No cases of radiation induced metabolic uptake in surrounding tissue were observed during radiotherapy. However, this occurred in a total of 6 cases post radiotherapy. There is a large variation in tumor SUV and metabolic responses between individual patients. In early responding patients, there is an initial large decrease in the maximal SUV during radiotherapy followed by a more gradual decrease in maximal SUV. Interpretation of FDG PET CT during treatment is not affected by metabolic uptake in surrounding tissue. The utility of FDG PET CT as a tool for adaptive radiotherapy in lung cancer should be further investigated.

2010 Objectives: To compare the precision of intra-patient tumor SUV measurements in FDG PET scans performed twice within a short time interval. Methods: Six patients with gastrointestinal cancer underwent 2 baseline FDG PET/CT scans, performed within a 5-day interval. All patients followed the same pre-scan prep routine. Patient height and weight was measured prior to each scan and the lean body mass (LBM) was calculated and entered in the Siemens Biograph PET/CT software. An angiocatheter was inserted in the arm, blood glucose measured, and 5 MBq/kg (body weight) FDG ± 10% injected. All scans were acquired with the same parameters and were initiated within 1.5 hours post injection, with each patient’s two injection-to-scan intervals varying by no more than 13 minutes. All scans were reconstructed using 2 iterations/8 subsets and a 5mm Gaussian filter. A target lesion was selected by the interpreting physician with a minimum size of 2 cm in any dimension. 2-D regions of interest were drawn on central axial slices of each lesion and the SUV mean and maximum pixel determined. Results: [table]A paired t-test showed that there is no significant difference between the two scan sets for both mean (p=0.435) and max pixel SUVs (p=0.377). Linear regression analysis showed the values of both mean and max pixel first and second measurements were highly correlated (R2=0.98) with a slope not significantly different from 1 (p

Objective: To determine whether varicocele is associated with retention of sperm cytoplasmic droplets in infertile men.Design: Retrospective study.Setting: University infertility clinic.Patient(s): Nonazoospermic men with idiopathic (n = 69) and varicocele-associated infertility (n = 73), and 20 fertile controls presenting for vasectomy.Intervention(s): None.Main Outcome Measures(s): Standard semen parameters and percentage of spermatozoa with cytoplasmic droplets on Papanicolaou smears.Result(s): No statistically significant differences were found between the fertile and infertile groups with respect to semen volume. Fertile controls had significantly greater mean percent sperm motility and normal morphology than infertile men. The mean percentage of sperm with residual cytoplasm was statistically significantly different in all three groups. Infertile men with varicocele had the highest percentage of sperm with cytoplasmic droplets, the next highest level being in men with idiopathic infertility and the lowest level in fertile controls (11.7 +/- 1.0, 8.1 +/- 0.9 and 3.2 +/- 0.4%, respectively, P<.0001).Conclusion(s): Our data show that idiopathic and even moreso, varicocele-related male infertility are conditions associated with impaired disposal of residual sperm cytoplasm by the testis and/or epididymis. These data provide a possible mechanism for the observed semen abnormalities and reduced fertility potential associated with varicocele and idiopathic male infertility. (Fertil Steril(R) 2000,74:461-4. (C) 2000 by American Society for Reproductive Medicine.).

OBJECTIVES:To determine whether cigarette smoking is associated with the abnormal retention of residual sperm cytoplasm in infertile men. METHODS:Semen samples were obtained from 87 consecutive non-azoospermic men with idiopathic infertility (18 smokers and 69 nonsmokers) and from 20 men presenting for vasectomy (fertile controls). Standard semen parameters and the percentage of spermatozoa with residual cytoplasm (on Papanicolaou smears) were recorded. RESULTS:Subject age, semen volume, and sperm density, motility, and morphology were not significantly different between the two groups of infertile men. However, a significant difference was found in the mean +/- SEM percentages of sperm with cytoplasm droplets between smokers and nonsmokers (12.9% +/- 1.7% and 8.1% +/- 0.9%, respectively; P < 0.001). CONCLUSIONS:Our data suggest that cigarette smoking is associated with retention of sperm cytoplasmic droplets in infertile men, a morphologic characteristic associated with impaired sperm function.