Nomogram including pretherapeutic parameters for prediction of survival after SIRT of hepatic metastases from colorectal cancer.

OBJECTIVES: Pre-therapeutic prediction of outcome is important for clinicians and patients in determining whether selective internal radiation therapy (SIRT) is indicated for hepatic metastases of colorectal cancer (CRC). METHODS: Pre-therapeutic characteristics of 100 patients with colorectal liver metastases (CRLM) treated by radioembolization were analyzed to develop a nomogram for predicting survival. Prognostic factors were selected by univariate Cox regression analysis and subsequent tested by multivariate analysis for predicting patient survival. The nomogram was validated with reference to an external patient cohort (n = 25) from the Bonn University Department of Nuclear Medicine. RESULTS: Of the 13 parameters tested, four were independently associated with reduced patient survival in multivariate analysis. These parameters included no liver surgery before SIRT (HR:1.81, p = 0.014), CEA serum level ≥ 150 ng/ml (HR:2.08, p = 0.001), transaminase toxicity level ≥2.5× upper limit of normal (HR:2.82, p = 0.001), and summed computed tomography (CT) size of the largest two liver lesions ≥10 cm (HR:2.31, p < 0.001). The area under the receiver-operating characteristic curve for our prediction model was 0.83 for the external patient cohort, indicating superior performance of our multivariate model compared to a model ignoring covariates. CONCLUSIONS: The nomogram developed in our study entailing four pre-therapeutic parameters gives good prediction of patient survival post SIRT. KEY POINTS: • Four individual parameters predicted reduced survival following SIRT in CRC. • These parameters were combined into a nomogram of pre-therapeutic risk stratification. • The model provided good prediction of survival in two independent patient cohorts.

Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours.

PURPOSE: 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 (177)Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). METHODS: We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with (177)Lu-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 (99m)Tc-DTPA clearance measurements. RESULTS: 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). CONCLUSION: 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.

May bone-targeted radionuclide therapy overcome PRRT-refractory osseous disease in NET? A pilot report on (188)Re-HEDP treatment in progressive bone metastases after (177)Lu-octreotate.

Bone metastases (BM) of gastroenteropancreatic neuroendocrine tumours (GEP-NET) can be effectively controlled by peptide receptor radionuclide therapy (PRRT). Eventually, however, BM may become refractory and determine survival. We aimed to assess the clinical benefit of bone-targeted radionuclide therapy (BTRT) in this subgroup of patients failing PRRT. A small cohort of n=6 patients with progressive BM failing PRRT with (177)Lu-octreotate (mean cumulative activity, 46.7 GBq) were treated with a total of 11 cycles BTRT using 2.6-3.3 GBq (188)Re-HEDP per cycle and a median cumulative activity of 5.9 GBq. Pain palliation was quantified applying the visual analogue scale (VAS). The mean VAS decreased from 6.6 (range 5-8) to 3.7 (range 2-7). Five patients experienced partial resolution of bone pain (≥ 2 steps reduction on the VAS for at least 2 weeks) and one patient had no significant improvement. Flare phenomena occurred in 2 patients and lasted for 2-3 days. Tumor response consisted of stable disease in 2 and progressive disease in 4 patients. No regression of bone metastases has been observed. The median overall survival was 5 months (range 2-9). Relevant myelosuppression (grade 3-4; self-limited with no interventions or hospitalization), occurred 4-6 weeks post-treatment, and after 2 (18.1%) administrations or in 1 (16.7%) patient. No other relevant toxicities or treatment-related death was observed. (188)Re-HEDP may be safely applied in patients with bone metastatic GEP-NET previously treated with (177)Lu-octreotate. While acceptable pain relief may be expected, no tumor-regression or long-term disease stabilization with apparent survival benefit has been observed. This disputes the use of BTRT as salvage anti-tumor therapy in PRRT-refractory neuroendocrine bone metastases.

Bone metastases in GEP-NET: response and long-term outcome after PRRT from a follow-up analysis.

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 <0.05, and Cox proportional hazards model for uni- and multivariate analyses. Median follow-up was 48 months. The observed response of BMs consisted of complete remission in 2 (2.9%), partial remission in 23 (33.8%), minor response in 8 (11.8%), stable disease in 26 (38.2%), and progressive disease in 8 (13.2%) patients. Median time-to-progression (TTP) of BMs and overall survival (OS) were 35 mo (95% CI: 25-45) and 51 mo (95% CI: 38-64), respectively. Patients with responding BMs survived significantly longer than other patients (median 56 mo vs. 39 mo, p=0.034). NSE >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.