Samer Ezziddin

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 (18)F-FDG PET in inoperable multifocal disease. Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing (18)F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent (18)F-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. 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. This study demonstrated the feasibility of prognostic 3-grade stratification of metastatic gastroenteropancreatic NENs by whole-body molecular imaging using (18)F-FDG PET.

Tc-MAA uptake in the portal vein tumor thrombus may be a predictor of a favorable response to radioembolization. We report here 2 patients with hepatocellular carcinoma and massive intrahepatic and extrahepatic tumor thrombus that showed Tc-MAA uptake in SPECT/CT, who underwent radioembolization with Y resin microspheres. The patients did not experience any adverse effects.

The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with ¹⁷⁷Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with ¹⁷⁷Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial ^99mTc-DTPA clearance measurements. The median follow-up period was 58 months (range 4 – 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 – 42) and 53 months (95 % CI 46 – 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤70 %, p = 0.007), a high hepatic tumour burden (≥25 % liver volume, p = 0.017), and an elevated plasma level of neuron-specific enolase (NSE >15 ng/ml, p = 0.035). The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient’s performance status, tumour burden and baseline plasma NSE level.

Aim: This retrospective study aims to evaluate the predictive value of FDG PET/CT in patients with unresectable hepatocellular carcinoma (HCC) undergoing radioembolization with yttrium-90 labeled microspheres (RE). Patients, methods: The study cohort comprised 33 patients who were treated with RE at our institution and underwent FDG PET/CT at baseline and four weeks after radioembolization. According to the baseline FDG metabolic status of the HCC lesions, patients were divided into two groups: FDG-negative (n = 12) and FDG-positive (n = 21) HCC. FDG-positive patients were further divided into early metabolic responders and non-re- sponders according to the relative change in SUV_max of the treated lesions. Survival analyses were performed with the Kaplan-Meier method (log-rank test, p < 0.05). Multivariate analysis was performed to assess the influence of prognostic factors on overall survival (OS). Results: FDG-negative patients had a significantly longer OS (13 months, 95%CI 7-19) than FDG-positive patients (9 months, 95%CI 7-11; p = 0.010). Among FDG- positive patients, metabolic responders survived significantly longer than metabolic non- responders (10 months, 95%CI 8-12 vs. 5 months, 95%CI 4-6; p = 0.003). From the other baseline factors (including performance status, hepatic tumour burden, presence of extra-hepatic disease, administered activity) only the BCLC stage had a significant impact on OS (p = 0.028). Conclusion: Pre- and post- therapeutic FDG PET independently predicts overall survival in patients with HCC undergoing radioembolization. Interestingly, early metabolic response seems to be assessable as early as four weeks post-treatment.

Aim: Highly advanced metastatic bone disease with extensive osseous infiltration of neuroendocrine tumours (NET) may preclude patients from treatment with peptide receptor radionuclide therapy (PRRT) in concern about haematotoxicity. This study aims to assess the safety and efficacy of PRRT with ¹⁷⁷Lu-octreotate in a patient cohort with this condition. Patients, methods: 41 PRRT courses were performed in 11 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) and florid bone metastases (severely advanced widespread metastatic bone disease). A mean activity of 6.95 GBq ¹⁷⁷Lu-octreotate was administered per treatment cycle, aimed at four courses with standard intervals of 3 months. Haematological parameters were determined prior to each treatment course, in 2-4 weeks intervals between the courses, 8-12 weeks after the last course of PRRT and in 3 monthly intervals thereafter. Toxicity was recorded using Common Terminology Criteria for Adverse Events v3.0. Restaging was performed 3 months after termination of PRRT with CT/MRI and functional imaging (modified MDA criteria). Results: Significant (grade III-IV), reversible haematotoxicity occurred in 4 (35%) patients and after 10 (24%) administrations. It either resolved spontaneously (1 patient) or was controlled by supportive measures (3 patients), such as blood transfusions (3 patients) or deferral of the subsequent therapy cycle (1 patient). Patients returned to baseline blood values within up to 23 months after termination of PRRT. The observed treatment response of bone metastases consisted of a partial response in 2, a minor response in 1, stable disease in 7, and progressive disease in 1 patient. Of the 4 patients with metastatic bone pain, 1 experienced complete and 3 partial resolution of symptoms within 3-10 weeks after commencement of PRRT. Conclusion: These preliminary data indicate that PRRT with ¹⁷⁷Lu-octreotate can be safely applied even in florid bone metastases with extensive, severely advanced osseous replacement. The higher myelosuppression rate was not associated with serious complications and should not preclude patients from being treated and potentially experiencing remarkable treatment efficacy despite the very advanced stage.

Background: Peptide 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. Methods: Five 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 SUV_max of the target lesions to liver (SUV_T/L) and spleen (SUV_T/S) were calculated; paired Student's t test was performed with p < 0.05 for pre-/intra-PRRT comparisons. Results: The mean intra-therapeutic tumor SUV_max showed no significant change (per-lesion paired t test) compared to pretreatment values (-9.1%, p = 0.226). In contrast, the SUV_max of the normal liver parenchyma and spleen were significantly lower directly after infusion of 7.4 GBq ¹⁷⁷Lu-octreotate. Consequently, SUV_T/L and SUV_T/S increased significantly from pretreatment to intra-therapeutic examination: SUV_T/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 SUV_T/S (p < 0.001) from 1.2 ± 0.7 (0.4 to 3.0) to 3.5 ± 1.5 (1.6 to 7.9). Conclusions: This 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.

Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine—allowing only approximate estimates of GFR—the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using ^99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with ¹⁷⁷Lu-octreotate. The mean follow-up period was 21 months (range 12–50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by ^99mTc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean −2.1 ± 13.1 ml/min/m² per year, relative yearly reduction −1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2–10 ml/min/m² per year) and 16 patients (22 %) a significant (>10 ml/min/m² per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m² per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function. Serious nephrotoxicity after PRRT with ¹⁷⁷Lu-octreotate is rare (1.3 %). However, slight renal impairment (GFR loss >2 ml/min/m² per year) can frequently (43 %) be detected by ^99mTc-DTPA clearance assessments. Cumulative administered activity of ¹⁷⁷Lu-octreotate is not a major determinant of renal impairment in our study.

Bone metastases of gastroenteropancreatic neuroendocrine tumors (GEP NET) can be associated with pain and a poor prognosis. Peptide receptor radionuclide therapy (PRRT) has been shown to be effective against this tumor manifestation. This study represents an update of the therapeutic assessment of PRRT with (177)Lu-octreotate in GEP NET patients with bone metastases focusing on potential predictors for impaired outcome and overall survival.We retrospectively analyzed a consecutive subgroup of n=68 patients with bone metastases (BM) of GEP NET treated with (177)Lu-octreotate (4 intended cycles at 3 monthly intervals; mean activity per cycle, 8.1 GBq). Baseline characteristics, including age, performance status, tumor origin, tumor load, plasma chromogranin A (CgA), and neuron-specific enolase (NSE) were analyzed regarding the impact on tumor regression (modified M.D. Anderson criteria) and survival of the patients. Survival analyses were performed using Kaplan-Meier curves, log-rank test at a significance level of p 15 ng/ml (p=0.002) and Ki67 index >10% (p=0.008) were associated with shorter overall survival. BM of GEP NET are effectively controlled by PRRT with a long median progression-free survival of approx. 3 years. Non-regression of BM, high proliferation rate and increased plasma NSE at baseline are predictive of shorter survival. However, this study confirms that poor patient condition (Karnofsky-Index ≤70%) and multifocality of BM (>10 lesions) do not affect outcome efficacy, further encouraging the use of PRRT in advanced bone metastatic disease.