Metastatic neuroendocrine tumor with extensive bone marrow involvement at diagnosis: Evaluation of response and hematological toxicity profile of PRRT with 177Lu-DOTATATE

Abstract

The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium (177Lu)-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 177Lu-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 (99mTc)-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 ...

Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups

“…In a meta-analysis comprising 16 studies, short-term myelotoxicity was observed in 10% (221/2104) with PRRT monotherapy. At the same time the grade 3/4 hematotoxicity was observed in 10.2% (7/68) of NET patients treated with 177 Lu (Sabet et al 2013b) having bone metastases and no hematotoxicity apart from grade 1 anemia in one out of six NET patients treated with 177 Lu (Basu et al 2016) having extensive bone marrow involvement shows that PRRT is well tolerated in this group of patients. Furthermore, MDS or AL were reported to range from 1.4% (3/208) with 177 Lu (Sabet et al 2013a); 2.0% (22/148) with 90 Y or 177 Lu (Baum et al 2018); 2.2% (13/582) with 177 Lu (Brabander et al 2017); and to 1.4% (32/2225) in the meta-analysis comprising 16 studies (Kesavan & Turner 2016).…”

Eruption of Metastatic Paraganglioma After Successful Therapy with 177Lu/90Y-DOTATOC and 177Lu-DOTATATE

“…In patient B, prior radiotherapy could also be one of the reasons of rapid progression which has been associated with myelotoxicity apart from age > 70 years, impaired renal function, baseline cytopenias, prior number of therapies, and prior chemotherapy (alkylating agents) [21]. In 2016, Basu et al performed a retrospective analysis on 5 neuroendocrine tumor patients with bone marrow involvement who underwent 177 Lu-DOTATATE therapy, which reported no hematological toxicity in any of their patients [33]. However, 18 F-FDG PET/ CT uptake in the bone marrow lesions was non-existent, barring just two patients who showed low-grade 18 F-FDG uptake [33].…”

“…In 2016, Basu et al performed a retrospective analysis on 5 neuroendocrine tumor patients with bone marrow involvement who underwent 177 Lu-DOTATATE therapy, which reported no hematological toxicity in any of their patients [33]. However, 18 F-FDG PET/ CT uptake in the bone marrow lesions was non-existent, barring just two patients who showed low-grade 18 F-FDG uptake [33]. In the two cases we present here, both patients had very high SUV max values of their bone marrow lesions prior to PRRT therapy.…”

Response to Single Low-dose 177Lu-DOTA-EB-TATE Treatment in Patients with Advanced Neuroendocrine Neoplasm: A Prospective Pilot Study

“…The standard guideline recommendation for PRRT includes well-differentiated Grade 1 and Grade 2 NETs that express SSTR positivity, as evaluated by SRI with 68 Ga-DOTA-TOC/TATE/NOC PET/CT or 99m Tc-HYNIC-TOC scintigraphy or 111 In-octreoscan. The recently published European Society for Medical Oncology Clinical Practice Guidelines (ESMO CPG) have recommended PRRT up to the upper limit of Ki-67 LI to 30% 28 . Haug et al 29 applied SUV T/S (SUV max of the tumor-to-spleen ratio) to evaluate the response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors and proved ΔSUV T/S was superior to baseline SUV max and ΔSUV max for the prediction of treatment outcome.…”