Jan Müller-Brand

Response, Survival, and Long-Term Toxicity After Therapy With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine Cancers

PURPOSE To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) in neuroendocrine cancers. PATIENTS AND METHODS In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [(90)Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface [(90)Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity. RESULTS Overall, 1,109 patients received 2,472 cycles of [(90)Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003). CONCLUSION This study documents the long-term outcome of [(90)Y-DOTA]-TOC treatment in a large cohort. Response to [(90)Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [(90)Y-DOTA]-TOC treatment and occurrence of renal toxicity.

68Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5

Existing somatostatin-based radiotracers (e.g. In-DOTA TOC) have sole affinity for somatostatin receptor subtype 2 (sst2). This represents a drawback, given that sst1–5 have been shown to be over-expressed in different tumours, alone or concomitantly [1]. Our goal, therefore, was to develop radiopeptides with broader receptor subtype profiles. Ga-DOTANOC is a first compound for PET imaging with high affinity for sst2 and sst5 [2]. Its affinity profile (IC50 nM) for human sst1–5 is, respectively, >10,000, 1.9± 0.4, 40±5.8, 260±74 and 7.2±1.6. For comparison, the values for the standard compound, In-DOTATOC, are >10,000, 4.6±0.2, 120±26, 230±82 and 130±17. Here we present the 60 min p.i. Ga-DOTANOC PET images and the 21 h p.i. In-DOTATOC planar images of a 52-year-old patient with an advanced neuroendocrine tumour. The two examinations were performed within 4 weeks. During this time interval the patient received bisphosphonates. Preparation and application of Ga-DOTANOC PET and Ga-DOTATOC PET are comparable [3]. In the reported case study, the Ga-DOTANOC PET scan shows high radioligand uptake in the liver and bone metastases. Although many bone metastases appeared visually similar in the two scans, the right sixth rib and left occipital bone metastases (arrows) are much more visible on the Ga-DOTANOC PET scan. This selective difference cannot be explained simply by the advantages of the PET technique. The possible predominance of sst5 in these two bone metastases and the high sst5 affinity of GaDOTANOC are in fact the probable reasons for the high Ga-DOTANOC and low In-DOTATOC uptake. The enlarged liver and somatostatin receptor-positive organs such as the spleen (high uptake) and pituitary gland and thyroid (moderate uptake) are also visible. These normal organs, known to express more sst than just sst2, are better visualised with Ga-DOTANOC (see in particular the spleen). We conclude that Ga-DOTANOC is an excellent candidate for primary diagnostic and follow-up investigations in patients with suspected or proven somatostatin receptorpositive tumours. Furthermore, in this case, predictive imaging indicates that Yor Lu-DOTANOC has greater potential for treatment of this patient than Yor LuDOTATOC.

The impact of 18F-FDG PET on the management of patients with suspected large vessel vasculitis

PurposeWe aimed to assess the impact of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis.MethodsAn international expert panel determined diagnoses and clinical management in patients with suspected large vessel vasculitis, with and without the results of 18F-FDG PET, respectively. The accuracy of the clinical diagnosis and the resulting clinical management with and without the 18F-FDG PET results were compared using logistic regression models.ResultsThe analysis included 30 patients referred to a tertiary care centre with large vessel vasculitis and 31 controls. 18F-FDG PET had an overall sensitivity of 73.3% [95% confidence interval (CI) 54.1–87.7%], a specificity of 83.9% (95% CI 66.3–94.5%), a positive predictive value of 81.5% (95% CI 61.9–93.7%) and a negative predictive value of 76.5% (95% CI 58.8–89.3%). The diagnostic accuracy of 18F-FDG PET was higher in patients not receiving immunosuppressive drugs (93.3 vs 64.5%, p = 0.006). Taken in context with other available diagnostic modalities, the addition of 18F-FDG PET increased the clinical diagnostic accuracy from 54.1 to 70.5% (p = 0.04). The addition of 18F-FDG PET increased the number of indicated biopsies from 22 of 61 patients (36.1%) to 25 of 61 patients (41.0%) and changed the treatment recommendation in 8 of 30 patients (26.7%) not receiving immunosuppressive medication and in 7 of 31 patients (22.6%) receiving immunosuppressive medication.Conclusion18F-FDG PET is a sensitive and specific imaging tool for large vessel vasculitis, especially when performed in patients not receiving immunosuppressive drugs. It increases the overall diagnostic accuracy and has an impact on the clinical management in a significant proportion of patients.

Cohort Study of Somatostatin-Based Radiopeptide Therapy With ( 90 Y-DOTA)-TOC Versus ( 90 Y-DOTA)-TOC Plus ( 177 Lu-DOTA)-TOC in Neuroendocrine Cancers

PURPOSE Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of radioisotopes. PATIENTS AND METHODS In a cohort study, patients with metastasized neuroendocrine cancer were treated with repeated cycles of (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) or with cycles alternating between [(90)Y-DOTA]-TOC and (177)lutetium-labeled DOTA-TOC ([(177)Lu-DOTA]-TOC) until tumor progression or permanent toxicity. Multivariable Cox regression and competing risk regression were used to study predictors of survival and renal toxicity in patients completing three or more treatment cycles. RESULTS A total of 486 patients completed three or more treatment cycles; 237 patients received [(90)Y-DOTA]-TOC and 249 patients received [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC. Patients receiving [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC had a significantly longer survival than patients receiving [(90)Y-DOTA]-TOC alone (5.51 v 3.96 years; hazard ratio, 0.64; 95% CI, 0.47 to 0.88; P = .006). The rates of severe hematologic toxicities (6.3% v 4.4%; P = .25) and severe renal toxicity (8.9% v 11.2%; P = .47) were comparable in both groups. CONCLUSION [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC was associated with improved overall survival compared with [(90)Y-DOTA]-TOC alone in patients completing three or more cycles of treatment. Contrary to the current practice in radiopeptide therapy, our results suggest an advantage of using a combination of radioisotopes.

Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials

Objective To determine the effect of adjunctive antithyroid drugs on the risk of treatment failure, hypothyroidism, and adverse events after radioiodine treatment. Design Meta-analysis. Data sources Electronic databases (Cochrane central register of controlled trials, Medline, Embase) searched to August 2006 and contact with experts. Review methods Three reviewers independently assessed trial eligibility and quality. Pooled relative risks for treatment failure and hypothyroidism after radioiodine treatment with and without adjunctive antithyroid drugs were calculated with a random effects model. Results We identified 14 relevant randomised controlled trials with a total of 1306 participants. Adjunctive antithyroid medication was associated with an increased risk of treatment failure (relative risk 1.28, 95% confidence interval 1.07 to 1.52; P=0.006) and a reduced risk for hypothyroidism (0.68, 0.53 to 0.87; P=0.006) after radioiodine treatment. We found no difference in summary estimates for the different antithyroid drugs or for whether antithyroid drugs were given before or after radioiodine treatment. Conclusions Antithyroid drugs potentially increase rates of failure and reduce rates of hypothyroidism if they are given in the week before or after radioiodine treatment, respectively.

Response to [90Yttrium-DOTA]-TOC Treatment is Associated with Long-term Survival Benefit in Metastasized Medullary Thyroid Cancer: A Phase II Clinical Trial

Purpose: We aimed to explore the efficacy of 90Yttrium–1,4,7,10-tetra-azacyclododecane N,N′,N″,N-‴-tetraacetic acid (90Y-DOTA)–Tyr3-octreotide (TOC) therapy in advanced medullary thyroid cancer. Experimental Design: In a phase II trial, we investigated the response, survival, and long-term safety profile of systemic [90Y-DOTA]-TOC treatment in metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Survival analyses were done using multiple regression models. Results: Thirty-one patients were enrolled. A median cumulative activity of 12.6 GBq (range, 1.7-29.6 GBq) of [90Y-DOTA]-TOC was administered. Response was found in nine patients (29.0%). Four patients (12.9%) developed hematologic toxicities and seven patients (22.6%) developed renal toxicities. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio, 0.20; 95% confidence interval, 0.05-0.81; P = 0.02) and from time of first [90Y-DOTA]-TOC therapy (hazard ratio, 0.16; 95% confidence interval, 0.04-0.63; P = 0.009). The visual grade of scintigraphic tumor uptake was not associated with treatment response or survival. Conclusions: Response to [90Y-DOTA]-TOC therapy in metastasized medullary thyroid cancer is associated with a long-term survival benefit. Treatment should be considered independently from the result of the pretherapeutic scintigraphy.

Chronic post-traumatic osteomyelitis of the lower extremity: comparison of magnetic resonance imaging and combined bone scintigraphy/immunoscintigraphy with radiolabelled monoclonal antigranulocyte antibodies

Abstract Objective. A retrospective study of the validity of combined bone scintigraphy (BS) and immunoscintigraphy (IS) using 99mTc-labelled murine antigranulocyte antibodies (MAB) and magnetic resonance imaging (MRI) in chronic post- traumatic osteomyelitis. Design and patients. The results of MRI and combined BS/IS of 19 lesions in 18 patients (13 men, 5 women; mean age 45 years, range 27–65 years) were independently evaluated by two radiologists and one nuclear medicine physician with regard to bone infection activity and extent. The patient group was a highly selective collection of clinical cases: the average number of operations conducted because of relapsing infection was eight (range 2–27), the average time interval between the last surgical intervention and the present study was 6.5 years (range 3 months to 39 years), and from the first operation was 14 years (range 1.5–42 years). Interobserver agreement on MRI was measured by kappa statistics. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for MRI and the nuclear medicine studies. Results. For MRI/nuclear medicine, a sensitivity of 100%/77%, a specificity of 60%/50%, an accuracy of 79%/61%, a PPV of 69%/58% and a NPV of 100%/71% were calculated. Four MR examinations were false positives because of postsurgical granulation tissue. A high degree of interobserver agreement was found on MRI (κ=0.88). A low-grade infection was missed on two scintigrams, while four were false positive because of ectopic haematopoietic bone marrow, and in one examination the anatomical distortion resulted in an inaccurate assignment of the uptake leading to false positive findings. Image analysis was frequently hindered by susceptibility artefacts due to residual abrasions of metallic implants after removal of orthopaedic devices (15/18 patients); this led to limited assessment in 17% (3/18 patients). Conclusion. Acute activity in a chronic osteomyelitis can be excluded with high probability if the MRI findings are negative. In the first postoperative year fibrovascular scar cannot be distinguished accurately from reactivated infection on MRI and scintigraphy may improve the accuracy of diagnosis. MRI is more sensitive in low-grade infection during the later course than combined BS/IS. Scintigraphic errors due to ectopic, peripheral, haematopoietic bone marrow can be corrected by MRI.

Silent ischemia after percutaneous transluminal coronary angioplasty: Incidence and prognostic significance

OBJECTIVES The objective of this observational study was to assess the incidence and prognostic significance of silent ischemia after percutaneous transluminal coronary angioplasty. BACKGROUND Apart from coronary angioplasty, prognosis of patients with silent ischemia is similar to that of patients with angina pectoris. However, similar data concerning silent ischemia associated with restenosis after coronary angioplasty are missing. METHODS A consecutive series of 490 patients was investigated for asymptomatic ischemia on thallium-201 scintigraphy 6 months after successful coronary angioplasty. Repeat angiography was performed in a subgroup of patients with ischemia and repeat angioplasty was performed when clinically indicated. Patients were followed up for 2.2 +/- 0.8 years for cardiac events. RESULTS Six months after coronary angioplasty, ischemia was present in 112 (28%) of 405 patients, and 60% of these 112 were asymptomatic. Ischemia was associated with significant stenosis in 97%; in contrast, results of exercise electrocardiography were negative in 74% of patients with scintigraphic ischemia and angiographic restenosis. The degree of restenosis was similar in patients with symptomatic or silent ischemia (80 +/- 16% vs. 81 +/- 21%). The long-term prognosis of patients with silent ischemia was remarkably similar to that of symptomatic patients. A worse outcome of symptomatic patients was found only if repeat coronary angioplasty for restenosis was considered a separate event (p < 0.01). Silent and symptomatic ischemia predicted an increased risk for recurrent ischemic events but not for death. CONCLUSIONS Thus, absence of symptoms and negative findings on an exercise electrocardiogram may not reflect a good angioplasty result. In addition, silent ischemia due to restenosis after coronary angioplasty has a significant prognostic importance for recurrent symptomatic ischemic events that may be reduced by repeat angioplasty.

Radionuclide-labeled somatostatin analogues for diagnostic and therapeutic purposes in nonmedullary thyroid cancer.

Despite the fact that several recent studies report an expression of somatostatin receptors in nonmedullary thyroid cancer (non-MTC), there is still no consensus concerning the diagnostic and therapeutic usefulness of radionuclide-labeled somatostatin analogues in non-MTC. We present the results of 50 scintigraphic studies with (111)In-Pentetreotide ((111)In-P) in 48 patients with metastasizing non-MTC (n = 9 papillary, n = 9 follicular, n = 29 Hurthle cell, n = 1 insular carcinoma). The findings were compared with histology and with other imaging modalities. (111)In-P provided unequivocally positive results in 37 of 50 (74%) of the patients (27% in the 11 patients with current thyroglobulin levels <10 ng/mL and 85% in the patients with thyroglobulin >10 ng/mL). Histopathology demonstrated that maximal uptake was observed in Hurthle cell carcinoma (95% positive examinations if thyroglobulin exceeds 10 ng/mL). We also describe for the first time dosimetric and clinical data from the courses of 90Y-DOTATOC therapy in three patients with progressive, somatostatin-receptor-positive non-MTC (up to 9.3 GBq per 4 cycles). Tumor progression could not be stopped in any of the patients treated with 90Y-DOTATOC. We conclude that (111)In-P is a promising tool for whole-body diagnosis in nonradioiodine-accumulating non-MTC, especially in Hürthle cell cancer, and if 2-[18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) is not available. Although the number of patients treated with 90Y-DOTATOC is still limited, our applied treatment protocol appears to be ineffective in metastasizing non-MTC.

The Dental Safety Profile of High-Dose Radioiodine Therapy for Thyroid Cancer: Long-Term Results of a Longitudinal Cohort Study

The long-term dental safety profile of high-dose radioiodine therapy remained elusive despite more than 6 decades of clinical use. Methods: In a cohort study, we investigated the incidence of sialadenitis, xerostomia, caries, and tooth extractions after high-dose radioiodine therapy for differentiated thyroid cancer and explored risk factors by multiple regression models. Results: One hundred seventy-six participants were recruited (median follow-up, 6.6 y; range, 1.1–32.6 y; patient-years: 8,472 before and 1,421 after radioiodine therapy). Scintigraphic salivary gland uptake during radioiodine treatment predicted development of sialadenitis (odds ratio: 1.31 [1.05–1.63], P = 0.015) and xerostomia (odds ratio: 1.58 [1.16–2.16], P = 0.004). The caries risk increased by postradioiodine xerostomia (% increase: 98.8 [26.5–212], P = 0.003). The long-term risk for postradioiodine tooth extractions increased with increasing cumulative radioiodine activities (% increase [per gigabequerel]: 8.14 [1.07, 15.7], P = 0.02). Conclusion: High-dose radioiodine treatment can impair the long-term dental health, depending on the cumulative radioiodine activity and individual salivary gland radioiodine uptake.