Metastatic Neuroendocrine Tumor with Extensive Bone Marrow Involvement at Diagnosis: Evaluation of Response and Hematological Toxicity Profile of PRRT with (177)Lu-DOTATATE

The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium ((177)Lu)-DOTA-octreotate (DOTATATE) in metastatic neuroendocrine tumor (NET) with extensive bone marrow metastasis at the initial diagnosis. A retrospective evaluation was undertaken for this purpose: Patients with NET with extensive diffuse bone marrow involvement at diagnosis who had received at least three cycles of PRRT with (177)Lu-DOTATATE were considered for the analysis. The selected patients were analyzed for the following: (i) Patient and lesional characteristics, (ii) associated metastatic burden, (iii) hematological parameters at diagnosis and during the course of therapy, (iv) response to PRRT (using a 3-parameter assessment: Symptomatic including Karnofsky/Lansky performance score, biochemical finding, and scan finding), (v) dual tracer imaging features [with somatostatin receptor imaging (SRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT)]. Based on the visual grading, tracer uptake in somatostatin receptor (SSTR)-positive bone marrow lesions were graded by a 4-point scale into four categories (0-III) in comparison with the hepatic uptake on the scan: 0 - no uptake; I - clear focus but less than liver uptake; II - equal to liver uptake; and III - higher than liver uptake]. Hematological toxicity was evaluated using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 score. A total of five patients (age range: 26-62 years; three males and two females) with diffuse bone marrow involvement at the diagnosis was encountered following analysis of the entire patient population of 250 patients. Based on the site of the primary, three had thoracic NET (two patients bronchial carcinoid and one pulmonary NET) and two gastroenteropancreatic NET (one in the duodenum and one patient of unknown primary with liver metastasis). Associated sites of metastases included the liver (n = 5), breast (n = 1), and aortocaval nodes (n = 1). On baseline diagnostic study [(68) Ga-DOTANOC/TATE or the technetium ((99m)Tc)-hydrazinonicotinamide (HYNIC)-tektrotyd (TOC)], tracer uptake in the bone marrow in all patients was Grade III. At the time of analysis, the patients received three to four cycles of PRRT and a cumulative dose of 16.1-25.6 GBq with a follow-up duration ranging 10-27 months. The response as assessed by three parameters: (i) Symptomatic: All patients (except for one) reported excellent symptomatic palliation and better quality of life with improvement of Karnofsky/Lansky scores; the single case with nonresponse had shown symptomatic response in the initial 6 months following which he had a progressive disease and death at 18 months (ii) biochemical: Three patients had shown more than 50% reduction in the serum chromogranin level, one had shown increase but had demonstrated clinical evidence of response with radiologically stable disease while the other who had shown slight increase of chromogranin A (CgA) level had shown progressive disease thereafter (iii) radiological: Three patients demonstrated partial response (on FDG-PET/CT), one patient had stable disease and one patient had progressive disease following initial clinical response. As per the NCI-CTCAE score, only one patient had persistent Grade I anemia without any deterioration with the administered dose at the time of analysis. FDG uptake in the bone marrow metastatic lesions showed no obvious FDG avidity on visual assessment except for two patients (low-grade FDG uptake). Interestingly, the associated metastatic lesions [except for patient I with Mib1 labeling index (LI): 1-2%], demonstrated high FDG avidity. Thus, we observed that the majority (in our series four out of five patients, i.e. 80%) of the patients had excellent symptomatic response with at least stabilization of the disease at a follow-up period of 10-27 months. The single patient who had a progressive disease also had a good symptomatic response in the initial 6 months from the first dose of PRRT. Despite the extensive bone marrow involvement, no hematological toxicity was observed (only one patient showed Grade I anemia), suggesting that PRRT is well-tolerated by this particular subgroup.