Samer Ezziddin

Radioembolization of Liver Tumors With Yttrium-90 Microspheres

Radioembolization (RE), also termed selective internal radiation therapy (SIRT), has been gradually introduced to the clinical arsenal of cytoreductive modalities in recent years. There is growing evidence for efficiency in liver tumors of various entities, with the most prominent ones being hepatocellular carcinoma, colorectal cancer, and neuroendocrine tumors. Hepatic metastases of numerous other tumor entities including breast cancer, cholangiocarcinoma, and pancreatic cancer are treatment-sensitive, even when being refractory to other treatment modalities such as bland-embolization, regional, or systemic chemotherapy. The antitumor effect of SIRT is related to radiation rather than embolization, with extraordinary high local radiation doses obtained selectively at the site of viable tumor and little affection of the surrounding normal liver tissue. Morphologic changes after RE may pose difficulties for interpretation in conventional restaging with regard to tumor viability and true response to treatment. Therefore, functional imaging, that is, metabolic imaging with (18)F fluorodeoxyglucose positron emission tomography (computed tomography) in the majority of treated tumors, is regarded the gold standard in this respect and should be included for pre- and post-SIRT assessment. To prevent serious toxicity to be associated with the potent antitumor efficacy, meticulous pretreatment evaluation is of particular importance. Improvements in predicting dosimetry will help optimize treatment and patient selection. Nuclear medicine procedures are essential for planning, performing, and monitoring of RE. However, the interdisciplinary aspect of patient management has to be emphasized for this particular treatment form. As SIRT is moving forward from the salvage setting indication to the use in earlier stages of hepatic tumor disease and with the advent of new treatment protocols and targeted therapies, embedding SIRT into a multidisciplinary approach will become even more important. This article focuses on procedural and technical aspects for selection, preparation, and performance of treatment as well as post-therapeutic monitoring and response assessment.

Imaging of prostate cancer metastases with 18F-fluoroacetate using PET/CT.

Fluorine-18 fluoroacetate [1] appears to be an interesting alternative to 11C-acetate [2, 3] for imaging prostate cancer with PET. We acquired the first 18F-fluoroacetate PET images in a patient with prostate cancer, rising PSA (101 ng/ml) and progressive bone metastases. Scanning started 70 min after i.v. injection of 280 MBq 18F-fluoroacetate using a combined PET/CT system (Siemens Biograph). The images demonstrate moderate to intense uptake in several (thick arrows) but not all (thin arrows) metastatic bone lesions, with SUVmean of 2.82–4.10 and SUVmax of 3.36–5.11. This compared favourably to accumulation in the liver, with SUVmean of 2.35–2.71 and SUVmax of 3.0–3.58. The mode of excretion was predominantly via the bowel (arrowheads), with low activity in the urine. Compared with 11C-acetate PET, 18F-fluoroacetate offers the possibility of delayed imaging with the potential to further increase the tumour-to-background ratios. Upper row: CT image slices; middle row: combined 18F-fluoroacetate PET/CT; lower row: 18F-fluoroacetate PET References

131I-Metaiodobenzylguanidine Therapy of Neuroblastoma and Other Neuroendocrine Tumors

Treatment with (131)I-metaiodobenzylguanidine (MIBG) has been introduced to the management of neuroendocrine tumors (NET) nearly 30 years ago. It provides efficient internal radiotherapy of chromaffin tumors (neuroblastoma, pheochromocytoma, and paraganglioma), but also of carcinoid and other less frequent tumors. Although for various NET types the role of this treatment form decreased by the emergence of peptide receptor radionuclide therapy, (131)I-MIBG still remains the primary radiopharmaceutical for targeting chromaffin tumors with outstanding efficiency. Results in neuroblastoma with overall response rates around 30% in refractory or recurrent diseases have been improved by combinations with chemotherapy, radiosensitizers, and autologous stem cell support. For adult chromaffin tumors, that is, pheochromocytoma and/or paraganglioma, (131)I-MIBG therapy is currently the most efficient nonsurgical therapeutic modality and applies for inoperable, disseminated disease. The antisecretory effect with powerful palliation of symptomatic disease (response rate: 75%-90%) should also be considered when judging treatment benefit. The results in carcinoid tumors are less pronounced, primarily achieving arrest of tumor growth, and most importantly effective functional control. With the presence of peptide receptor radionuclide therapy, (131)I-MIBG remains the alternative radionuclide in this tumor entity, for example, for patients with renal impairment. Another worthwhile mentioning indication-although less prevalent-are metastatic medullary thyroid carcinomas, especially if functioning. These patients are good candidates for this treatment form in the absence of reasonable surgical options and presence of diagnostic MIBG uptake. This article outlines the current status, results, and methodological improvements of (131)I-MIBG therapy.

Long-Term Hematotoxicity After Peptide Receptor Radionuclide Therapy with 177Lu-Octreotate

Myelosuppression may be the dose-limiting toxicity in peptide receptor radionuclide therapy (PRRT). The aim of this study was to investigate the incidence, severity, and reversibility of long-term hematotoxicity in a large cohort of patient undergoing PRRT with 177Lu-octreotate for metastatic neuroendocrine tumors. The impact of potential risk factors, including initial cytopenia, advanced bone metastatic disease, previous chemotherapy, and cumulative administered activity, and the protective effects of splenectomy were of particular interest. Methods: A total of 632 PRRT courses were performed in 203 patients with metastatic neuroendocrine tumors. A mean activity of 7.9 GBq of 177Lu-octreotate was administered per treatment cycle, with a goal of 4 courses at standard intervals of 3 mo. Hematologic parameters were determined before each treatment course, at 2- to 4-wk intervals between the courses, 8–12 wk after the last course of PRRT, and at 3-month intervals for further follow-up. Toxicity was recorded with Common Terminology Criteria for Adverse Events (version 3.0). Results: Myelodysplastic syndrome as a delayed adverse event was documented in 3 patients (1.4%). Relevant but reversible hematotoxicity (grade 3 or 4) occurred in 23 patients (11.3%) and 29 administrations (4.6%), with leukopenia in 2.7% and thrombocytopenia in 1.7%. The mean time to blood count recovery was 12 mo after the termination of PRRT (range, 3–22 mo). The only preexisting factor that contributed to hematotoxicity was initial cytopenia (P < 0.001). A high level of cumulative administered activity (>29.6 GBq) was associated with relevant leukopenia (P < 0.001). None of the patients with a history of splenectomy developed grade 3 or 4 hematotoxicity, and splenectomy was inversely associated with the incidence and degree of leukopenia (P = 0.02) and thrombocytopenia (P = 0.03) Conclusion: PRRT-induced myelosuppression is almost invariably reversible and rarely requires clinical measures. Administered activity and initial cytopenia are the only factors contributing to myelosuppression, whereas splenectomy may exert a protective effect.

Predictors of Long-Term Outcome in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy with 177Lu-Octreotate

Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival. Methods: We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with 177Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan–Meier curve method (log-rank test) and multivariate analysis (P < 0.05). Results: The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3–33.7) and 55 mo (95% confidence interval, 48.8–61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1–3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively. Conclusion: The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient’s performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2—in particular, between G1 (Ki-67 index of 1%–2%) and low-range G2 (Ki-67 index of 3%–10%)—provides prognostic stratification.

Prognostic Stratification of Metastatic Gastroenteropancreatic Neuroendocrine Neoplasms by 18F-FDG PET: Feasibility of a Metabolic Grading System

The tumor proliferation marker, Ki-67 index, is a well-established prognostic marker in gastroenteropancreatic neuroendocrine neoplasms (NENs). Noninvasive molecular imaging allows whole-body metabolic characterization of metastatic disease. We investigated the prognostic impact of 18F-FDG PET in inoperable multifocal disease. Methods: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing 18F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent 18F-FDG uptake (reference tumor lesion): mG1, tumor-to-liver ratio of maximum standardized uptake value ≤ 1.0; mG2, 1.0–2.3; mG3, >2.3. Other potential variables influencing overall survival, including age, tumor origin, performance status, tumor burden, plasma chromogranin A (≥600 μg/L), neuron-specific enolase (≥25 μg/L), and classic grading (Ki-67–based) underwent univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), with a P value of less than 0.05 considered significant. Results: The median follow-up period was 38 mo (95% confidence interval [CI], 27–49 mo); median overall survival of the 89 patients left for multivariate analysis was 29 mo (95% CI, 21–37 mo). According to metabolic grading, 9 patients (10.2%) had mG1 tumors, 22 (25.0%) mG2, and 57 (64.8%) mG3. On multivariate analysis, markedly elevated plasma neuron-specific enolase (P = 0.016; hazard ratio, 2.9; 95% CI, 1.2–7.0) and high metabolic grade (P = 0.015; hazard ratio, 4.7; 95% CI, 1.2–7.0) were independent predictors of survival. Conclusion: This study demonstrated the feasibility of prognostic 3-grade stratification of metastatic gastroenteropancreatic NENs by whole-body molecular imaging using 18F-FDG PET.

90Y Radioembolization After Radiation Exposure from Peptide Receptor Radionuclide Therapy

Previous radiation therapy of the liver is a contraindication for performing 90Y microsphere radioembolization, and its safety after internal radiation exposure through peptide receptor radionuclide therapy (PRRT) has not yet been investigated. Methods: We retrospectively assessed a consecutive cohort of 23 neuroendocrine tumor (NET) patients with liver-dominant metastatic disease undergoing radioembolization with 90Y microspheres as a salvage therapy after failed PRRT. Toxicity was recorded throughout follow-up and reported according to Common Terminology Criteria for Adverse Events (version 3). Radiologic (response evaluation criteria in solid tumors), biochemical, and symptomatic responses were investigated at 3 mo after treatment, and survival analyses were performed with the Kaplan–Meier method (log-rank test, P < 0.05). Results: The median follow-up period after radioembolization was 38 mo (95% confidence interval, 18–58 mo). The mean previous cumulative activity of 177Lu-DOTA-octreotate was 31.8 GBq. The mean cumulative treatment activity of 90Y microspheres was 3.4 ± 2.1 GBq, administered to the whole liver in a single session (n = 8 patients), in a sequential lobar fashion (n = 10 patients), or to only 1 liver lobe (n = 5 patients). Only transient, mostly minor liver toxicity (no grade 4) was recorded. One patient (4.3%) developed a gastroduodenal ulcer (grade 2). The overall response rates for radiologic, biochemical, and symptomatic responses were 30.4%, 53.8%, and 80%, respectively. The median overall survival was 29 mo (95% confidence interval, 4–54 mo) from the first radioembolization session and 54 mo (95% confidence interval, 47–61 mo) from the first PRRT cycle. A tumor proliferation index Ki-67 greater than 5% predicted shorter survival (P = 0.007). Conclusion: Radioembolization is a safe and effective salvage treatment option in advanced NET patients with liver-dominant tumor burden who failed or reprogressed after PRRT. The lack of relevant liver toxicity despite high applied 90Y activities and considerable previous cumulative activities of 177Lu-octreotate is noteworthy and disputes internal radiation exposure by PRRT as a toxicity risk factor in subsequent radioembolization.

Does PRRT with standard activities of 177Lu-octreotate really achieve relevant somatostatin receptor saturation in target tumor lesions?: insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors

BackgroundPeptide receptor radionuclide therapy (PRRT) with 177Lu-[DOTA0,Tyr3]octreotate (177Lu-octreotate) is generally performed using a fixed activity of 7.4 GBq (200 mCi) per course bound to 180 to 300 μg of the peptide. While this single activity may lead to suboptimal radiation doses in neuroendocrine tumors (NET) with advanced or bulky disease, dose escalation has been withheld due to concerns on potential tumor somatostatin receptor saturation with reduced efficacy of the added activity. In vivo saturation effects during standard-dose PRRT based on quantification of pre- and intra-therapeutic 68Ga-DOTATOC positron emission tomography (PET) imaging might guide potential dose escalation.MethodsFive patients with metastatic NET of the pancreas underwent 68Ga-DOTATOC PET/CT before and directly after standard-dose PRRT with 177Lu-octreotate. In each patient, four target tumor lesions, normal liver parenchyma, and the spleen were evaluated and the ratios of SUVmax of the target lesions to liver (SUVT/L) and spleen (SUVT/S) were calculated; paired Students t test was performed with p < 0.05 for pre-/intra-PRRT comparisons.ResultsThe mean intra-therapeutic tumor SUVmax showed no significant change (per-lesion paired t test) compared to pretreatment values (-9.1%, p = 0.226). In contrast, the SUVmax of the normal liver parenchyma and spleen were significantly lower directly after infusion of 7.4 GBq 177Lu-octreotate. Consequently, SUVT/L and SUVT/S increased significantly from pretreatment to intra-therapeutic examination: SUVT/L (p < 0.001) from 2.8 ± 1.3 (1.3 to 5.8) to 4.7 ± 3.0 (2.1 to 12.7) and SUVT/S (p < 0.001) from 1.2 ± 0.7 (0.4 to 3.0) to 3.5 ± 1.5 (1.6 to 7.9).ConclusionsThis small retrospective study provides preliminary evidence for the absence of relevant in vivo saturation of somatostatin receptor subtype 2 (sst2) in tumor lesions during PRRT with standard activities of 177Lu-octreotate in contrast to normal tissue (liver, spleen) showing limited receptor capacity. After being confirmed by larger series, this observation will have significant implications for PRRT: (1) Higher activities of 177Lu-octreotate might be considered feasible in patients with high tumor disease burden or clinical need for remission, and (2) striving to reduce the amount of peptide used in standard preparations of 177Lu-octreotate appears futile.

Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patients quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition.

Long-Term Outcome and Toxicity After Dose-Intensified Treatment with 131I-MIBG for Advanced Metastatic Carcinoid Tumors

Reported experience with systemic 131I-metaiodobenzylguanidine (131I-MIBG) therapy of neuroendocrine tumors comprises different dosing schemes. The aim of this study was to assess the long-term outcome and toxicity of treatment with 11.1 GBq (300 mCi) of 131I-MIBG per cycle. Methods: We performed a retrospective review of 31 patients with advanced metastatic neuroendocrine tumors (20 with carcinoid tumors and 11 with other tumors) treated with 131I-MIBG. Treatment outcome was analyzed for patients with carcinoid tumors (the most common tumors in this study), and toxicity was analyzed for the entire patient cohort (n = 31). Treatment comprised 11.1 GBq (300 mCi) per course and minimum intervals of 3 mo. The radiographic response was classified according to modified Response Evaluation Criteria in Solid Tumors. Toxicity was determined according to Common Terminology Criteria for Adverse Events (version 3.0) for all laboratory data at regular follow-up visits and during outpatient care, including complete blood counts and hepatic and renal function tests. Survival analysis was performed with the Kaplan–Meier curve method (log rank test; P < 0.05). Results: The radiographic responses in patients with carcinoid tumors comprised a minor response in 2 patients (10%), stable disease in 16 patients (80%; median time to progression, 34 mo), and progressive disease in 2 patients (10%). The symptomatic responses in patients with functioning carcinoid tumors comprised complete resolution in 3 of the 11 evaluable symptomatic patients (27%), partial resolution in 6 patients (55%), and no significant change in 11 patients. The median overall survival in patients with carcinoid tumors was 47 mo (95% confidence interval, 32–62), and the median progression-free survival was 34 mo (95% confidence interval, 13–55). Relevant treatment toxicities were confined to transient myelosuppression of grade 3 or 4 in 15.3% (leukopenia) and 7.6% (thrombocytopenia) of applied cycles and a suspected late adverse event (3% of patients), myelodysplastic syndrome, after a cumulative administered activity of 66.6 GBq. The most frequent nonhematologic side effect was mild nausea (grade 1 or 2), which was observed in 28% of administered cycles. No hepatic or renal toxicities were noted. Conclusion: Dose-intensified treatment with 131I-MIBG at a fixed dose of 11.1 GBq (300 mCi) per cycle is safe and offers effective palliation of symptoms and disease stabilization in patients with advanced carcinoid tumors. The favorable survival and limited toxicity suggest that high cycle activities are suitable and that this modality may be used for targeted carcinoid treatment—either as an alternative or as an adjunct to other existing therapeutic options.