Amir Sabet

The Significance of 99mTc-MAA SPECT/CT Liver Perfusion Imaging in Treatment Planning for 90Y-Microsphere Selective Internal Radiation Treatment

Selective internal radiation therapy (SIRT), a catheter-based liver-directed modality for treating primary and metastatic liver cancer, requires appropriate planning to maximize its therapeutic response and minimize its side effects. 99mTc-macroaggregated albumin (MAA) scanning should precede the therapy to detect any extrahepatic shunting to the lung or gastrointestinal tract. Our aim was to compare the ability of SPECT/CT with that of planar imaging and SPECT in the detection and localization of extrahepatic 99mTc-MAA accumulation and to evaluate the impact of SPECT/CT on SIRT treatment planning and its added value to angiography in this setting. Methods: Ninety diagnostic hepatic angiograms with 99mTc-MAA were obtained for 76 patients with different types of cancer. All images were reviewed retrospectively for extrahepatic MAA deposition in the following order: planar, non–attenuation-corrected SPECT, and SPECT/CT. Review of angiograms and follow-up of patients with abdominal shunting served as reference standards. Results: Extrahepatic accumulation was detected by planar imaging, SPECT, and SPECT/CT in 12%, 17%, and 42% of examinations, respectively. The sensitivity for detecting extrahepatic shunting with planar imaging, SPECT, and SPECT/CT was 32%, 41%, and 100%, respectively; specificity was 98%, 98%, and 93%, respectively. The respective positive predictive values were 92%, 93%, and 89%, and the respective negative predictive values were 71%, 73%, and 100%. The therapy plan was changed according to the results of planar imaging, SPECT, and SPECT/CT in 7.8%, 8.9%, and 29% of patients, respectively. Conclusion: In pre-SIRT planning, 99mTc-MAA SPECT/CT is valuable for identifying extrahepatic visceral sites at risk for postradioembolization complications.

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.

Significance of Oral Administration of Sodium Perchlorate in Planning Liver-Directed Radioembolization

99mTc-macroaggregated albumin (99mTc-MAA) scanning precedes radioembolization of the liver to detect extrahepatic shunting to the lung or gastrointestinal tract. Despite strict preventive measures in the production of 99mTc-MAA and in scanning protocols, the images frequently show a gastric concentration of free 99mTc-pertechnetate, hindering accurate evaluation of the gastroduodenal region. Our aim was to evaluate whether oral administration of sodium perchlorate (NaClO4) before 99mTc-MAA scanning will improve its accuracy by blocking free 99mTc-pertechnetate gastric uptake. Methods: In 144 patients, 171 diagnostic hepatic angiograms combined with a 99mTc-MAA scan were performed; 86 angiograms were performed after oral administration of NaClO4, and 85 were performed without this premedication. Clinical follow-up, esophagogastroduodenoscopy, and angiography served as reference standards. Results: 99mTc-MAA studies showed tracer uptake in the gastric region of 25 patients who did not receive NaClO4. The uptake was interpreted as a free 99mTc-pertechnetate concentration in 21 studies and as a 99mTc-MAA accumulation in 4 studies. In 5 patients with a free 99mTc-pertechnetate concentration, aberrant vessels were detected in angiographic reexamination, and 3 patients developed gastrointestinal ulcer. In 7 studies, gastric findings viewed pretherapeutically as free 99mTc-pertechnetate were retrospectively classified as equivocal. Of the patients receiving NaClO4, 2 showed gastric accumulation of 99mTc-MAA but no equivocal or free 99mTc-pertechnetate. Oral administration of NaClO4 increased the negative predictive value and accuracy of the test concerning the detection of gastric perfusion from 68% and 69%, respectively, to 93% and 94%, respectively. Conclusion: Oral administration of NaClO4 before the test angiogram with 99mTc-MAA resulted in effective avoidance of free 99mTc-pertechnetate concentration and, consequently, of equivocal findings in the gastroduodenal region. This technique increased test accuracy and reporter confidence, saved time in reviewing the angiograms, and can improve treatment planning and reduce therapeutic side effects.

Does the pretherapeutic tumor SUV in 68Ga DOTATOC PET predict the absorbed dose of 177Lu octreotate

PURPOSE Selection of candidates for peptide receptor radionuclide therapy (PRRT) is increasingly based on receptor positron emission tomography (PET) imaging, including the common tracer 68Ga DOTATOC. However, no studies have yet compared standardized uptake values (SUVs) and absorbed doses in this field. MATERIALS AND METHODS We retrospectively analyzed a consecutive cohort of 21 patients with 61 evaluable tumor lesions undergoing both pretherapeutic 68Ga DOTATOC-PET/CT (Biograph Duo [Siemens Medical Solutions, Erlangen, Germany]; PET acquisition, 75.3 ± 15.4 minutes postinjection; 117.3 ± 33.9 MBq 68Ga DOTATOC) and PRRT with Lu octreotate (7.47 ± 1.39 GBq; intratherapeutic tumor dosimetry with serial whole-body scans; 1, 2, and 4 days postinjection) at our institution. SUVs were compared with the tumor-absorbed doses per injected activity (D/A0) of the subsequent first treatment cycle. RESULTS The correlation of SUV and D/A0 was r = 0.72 (SUVmean) and r = 0.71 (SUVmax), both P < 0.001. Pancreatic origin and hepatic localization were associated with higher D/A0, and chromogranin A level and Ki-67 index had no influence on SUV or D/A0. High-SUV lesions (SUVmean >15; SUVmax >25) resulted in high D/A0 (>10 Gy/GBq) in 66.7% to 70.8% and low D/A0 (<5 Gy/GBq) in only 8.3% to 12.5% on subsequent PRRT. The mentioned low D/A0 range, on the other hand, was achieved by all lesions with SUVmean <7 or SUVmax <9. CONCLUSIONS Somatostatin receptor PET imaging may predict tumor-absorbed doses. The ability to indicate insufficient target irradiation by a low SUV could aid in selection of appropriate candidates for PRRT. However, larger series are needed to confirm and validate these initial findings.

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.

Advances in Peptide Receptor Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) is a very effective treatment modality for advanced neuroendocrine tumors (NETs), representing a teaching model for truly targeted antitumor therapy. With the growing cumulative evidence of PRRT in various treatment settings, we are witnessing increased perception of this modality as a potent treatment option in advanced disease. Although most data derives from retrospective analyses, results from prospective comparative evaluations, such as the NETTER-1 trial, are eagerly awaited and should help to raise PRRT to a higher level of evidence. At the same time, as increased levels of evidence are anticipated by prospective evaluations, further methodological improvements are going on in different ways and aspects of radionuclide therapy, mainly regarding the radiopharmaceuticals, the combination with other radionuclides or cytotoxic drugs, and the route of administration. Although diversity of PRRT increases-not supporting cumulative evidence as opposed to uniform treatment-it is very likely to achieve significant increase of efficacy by these efforts in the near future. As the intraarterial administration of PRRT agents in liver-dominant metastatic disease has the potential to improve outcome, it would have to be shown as to which patients would benefit from this approach, to what extent the benefit would be, and to when it would justify the increased efforts for patients and treating institutes. The approach of combining cytotoxic or radiosensitizing drugs with the PRRT agents seems to trigger a major boost of efficacy in pancreatic NET. The midterm future would show the extent of benefit in terms of long-term outcome and would probably lead to inclusion into clinical routine for this particular NET entity. The translation of somatostatin-receptor antagonists into human application represents another major source of significant improvement in terms of PRRTs benefit-toxicity ratio. Eventually, it may not be completely unlikely to see another radiopharmaceutical being regarded as the PRRT agent of choice in the midterm future.

Iodine-131-lipiodol therapy in hepatic tumours.

The incidence of hepatocellular carcinoma (HCC) is worldwide sharply on the rise and patients with advanced disease carry a poor prognosis. HCC is the sixth most common cancer and the third leading cause of cancer associated deaths in the world. Intra-arterially administered (131)I-Lipiodol is selectively retained by hepatocellular carcinomas, and has been used as a vehicle for delivery of therapeutic agents to these tumours. In this review we focus on the therapeutic indications, usefulness and methods of treatment with 131-Iodine Lipiodol. The effectiveness of (131)I-Lipiodol treatment is proven both in the treatment of HCC with portal thrombosis and also as an adjuvant to surgery after the resection of HCCs. It is at least as effective as chemoembolization and is tolerated much better. Severe liver dysfunction represents theoretic contraindication for radioembolization as well as for TACE. In such cases (131)I-Lipiodol is an alternative therapy option especially in tumours smaller than 6cm.