Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-014-2710-1
ORIGINAL ARTICLE
177
Lu-DOTATATE therapy in patients with neuroendocrine tumours: 5 years’ experience from a tertiary cancer care centre in India
Madhav Danthala & K. G. Kallur & G. R. Prashant & K. Rajkumar & M. Raghavendra Rao
Received: 3 December 2013 / Accepted: 20 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The choice of an appropriate treatment option in patients with inoperable or metastatic neuroendocrine tumours (NETs) is limited, and approximately 50 % of patients have advanced NET at diagnosis, and 65 % die within 5 years. Treatment with 177Lu-DOTATATE (177Lu-[DOTA0,Tyr3] octreotate) is a promising new option in the treatment of metastatic NETs. Methods Patients with metastatic NET who underwent 177LuDOTATATE during the period 2009 to 2013 were included in this retrospective study. Follow-up imaging studies including a 68Ga-DOTANOC PET/CT scan and a posttherapy 177LuDOTATATE scan were compared with baseline imaging to determine response to treatment. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and Cox regression analysis was also done. Results Ten patients (25 %) had a minimal response, 13 (32.5 %) had a partial response and 9 (22.5 %) had stable disease. Progressive disease was seen in 8 patients (20 %), including 6 patients who died during or after the treatment period. The estimated mean PFS in those who received one or two cycles of 177Lu-DOTATATE was 8.3 months (95 % CI 6.2 to 10.3 months) compared to an estimated mean PFS of 45.6 months (95 % CI 40.9 to 50.2 months) in those who received more than two cycles of 177Lu-DOTATATE (logrank Mantel-Cox Χ 2 =8.01, p=0.005). Conclusion Our study showed that treatment with 177LuDOTATATE should be considered in the management of M. Danthala (*) : M. Raghavendra Rao HCG Oncology Hospitals, Number 8, P Kalinga Rao Road, Near-GEO Hotel, Sampangirama Nagar, Bangalore, Karnataka, India e-mail: [email protected] K. G. Kallur : G. R. Prashant : K. Rajkumar Department of Nuclear Medicine, HCG Oncology Hospitals, Bangalore, Karnataka, India
NETs, considering the limited success of alternative treatment modalities. Treatment response and PFS is determined primarily by the dose delivered and best results are obtained when more than two cycles of 177Lu-DOTATATE are given, with careful monitoring for possible side effects. Keywords NET – neuroendocrine tumours . PRRT – peptide receptor radionuclide therapy . 177Lu-DOTATATE – lutetium octreotate
Introduction Neuroendocrine tumours (NETs) are a complex and heterogeneous group of tumours arising from neuroendocrine cells dispersed in the body from different primary sites including the gastrointestinal tract, lung, pancreas and thymus. NETs produce peptides causing characteristic hormonal syndromes and can be clinically symptomatic (functioning) or silent (nonfunctioning). The choice of an appropriate treatment option in patients with inoperable or metastatic NETs is limited, and approximately 50 % of patients have advanced NET at diagnosis, and 65 % die within 5 years [1, 2]. Identification of the neoplastic overexpression of particular subclasses of somatostatin receptors (SSTRs) on NETs formed the basis for the use of peptide receptor radionuclide therapy (PRRT) as a promising new therapeutic tool in the management of NETs [3]. 177Lu is a medium-energy β-emitter with a maximum energy of 0.5 MeVand a maximal tissue penetration of 2 mm. Its half-life is 6.7 days. 177Lu also emits low-energy γ-rays at 208 and 113 keV with 10 % and 6 % abundance, respectively, which allows scintigraphy and subsequent dosimetry with the same therapeutic compound [4]. Tetraazacyclododecane tetra-acetic acid (DOTA) is now used as a chelator instead of diethylene triamine pentaacetic acid for the coupling of the radionuclide and the somatostatin
Eur J Nucl Med Mol Imaging
analogue in PRRT for improved stability. The modified somatostatin analogues [DOTA0,Tyr3] octreotate (DOTATATE), [DOTA0, Tyr3] octreotide (DOTATOC), and [DOTA0-1-Nal3] octreotide (DOTANOC) have been compared in several studies of 177Lu-based PRRT [5–8]. The advantages of DOTATA TE over DOTATOC are higher uptake of radioactivity (expressed as a percentage of the injected dose) that can be achieved in most tumours without increases in the doses to potentially dose-limiting organs such as the kidneys, spleen and liver [9, 10], and lower whole-body retention compared to DOTANOC [6]. Several similar treatment protocols with minor differences have been used, and guidelines on the use of PRRT in NETs have recently been published [11]. Side effects found in previous studies are acute side effects occurring within 24 h of administration of 177Lu including nausea, vomiting, abdominal discomfort or pain, subacute haematological toxicity occurring 4 – 8 weeks after administration, and delayed toxicities including renal insufficiency and myelodysplastic syndromes [8]. It is important to estimate the absorbed radiation doses to dose-limiting organs such as the kidneys and bone marrow to allow the dose delivered to the tumour to be maximized and individualized. The use of fixed-dose regimens while leading to fewer side effects may result in a proportion of patients being undertreated. PRRT using 177Lu as the therapeutic radionuclide has been successful with objective response rates ranging from 30 % to 50 % with significant increases in progression-free survival (PFS) [8, 12–15], and significant improvements in global health and quality of life and in several function and symptom scales [16]. We performed a retrospective analysis of patients with NET treated with 177Lu-DOTATATE during the period 2009 to 2013 at HCG Oncology Hospitals, Bangalore, Karnataka, India.
Technology (Mumbai, India), Bhabha Atomic Research Centre (Mumbai, India) and IDB Holland (Baarle-Nassau, The Netherlands). 177Lu was used at a dose of 200 mCi as part of a fixed dosing scheme per cycle and the interval between each cycle was 6 to 9 weeks. Ondansetron 4 mg was injected intravenously prior to therapy. Gelofusine infusion (540 cm3) was given half an hour prior to and half an hour after 177Lu-DOTATATE administration. A coinfusion of a mixture of arginine and lysine was given for 2 h before 177 Lu-DOTATATE administration and was continued for 4 h after completion of gelofusine infusion to reduce exposure of the kidneys to radiation (tubular reabsorption of the radiopeptide by the kidney) [17, 18]. Hydration with 4 l of normal saline was given for 24 h after 177Lu-DOTATATE administration. Patients were isolated for 48 h after 177LuDOTATATE administration for radiation safety purposes. 131 I-Lipiodol was administered intraarterially via a hepatic arterial catheter in selected patients with extensive hepatic metastases. 131I-Lipiodol was used at a dose of 40 – 50 mCi as part of a fixed dosing scheme per cycle. Adriamycin (20 mg) was infused intraarterially as a radiation sensitizer prior to Lipiodol administration [19]. Patients were isolated for 1 week post 131I-Lipiodol administration for radiation safety purposes. Response evaluation
Methodology
Routine haematology, liver and renal function tests, and serum electrolytes were measured prior to each treatment cycle, and at follow-up visits. Morphological response to therapy was evaluated by a 68Ga-DOTANOC PET/CT scan after completion of two cycles of 177Lu-DOTATATE and after the entire treatment. Follow-up CT studies were compared with the baseline imaging studies to determine the objective tumour response based on the World Health Organization criteria: a complete response (CR) was defined as the complete disappearance of all recognizable tumour in the liver, a partial response (PR) was defined as a reduction of ≥50 % in tumour size, a minimal response (MR) was defined as a reduction of
ORIGINAL ARTICLE
177
Lu-DOTATATE therapy in patients with neuroendocrine tumours: 5 years’ experience from a tertiary cancer care centre in India
Madhav Danthala & K. G. Kallur & G. R. Prashant & K. Rajkumar & M. Raghavendra Rao
Received: 3 December 2013 / Accepted: 20 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The choice of an appropriate treatment option in patients with inoperable or metastatic neuroendocrine tumours (NETs) is limited, and approximately 50 % of patients have advanced NET at diagnosis, and 65 % die within 5 years. Treatment with 177Lu-DOTATATE (177Lu-[DOTA0,Tyr3] octreotate) is a promising new option in the treatment of metastatic NETs. Methods Patients with metastatic NET who underwent 177LuDOTATATE during the period 2009 to 2013 were included in this retrospective study. Follow-up imaging studies including a 68Ga-DOTANOC PET/CT scan and a posttherapy 177LuDOTATATE scan were compared with baseline imaging to determine response to treatment. Progression-free survival (PFS) was calculated using the Kaplan-Meier method and Cox regression analysis was also done. Results Ten patients (25 %) had a minimal response, 13 (32.5 %) had a partial response and 9 (22.5 %) had stable disease. Progressive disease was seen in 8 patients (20 %), including 6 patients who died during or after the treatment period. The estimated mean PFS in those who received one or two cycles of 177Lu-DOTATATE was 8.3 months (95 % CI 6.2 to 10.3 months) compared to an estimated mean PFS of 45.6 months (95 % CI 40.9 to 50.2 months) in those who received more than two cycles of 177Lu-DOTATATE (logrank Mantel-Cox Χ 2 =8.01, p=0.005). Conclusion Our study showed that treatment with 177LuDOTATATE should be considered in the management of M. Danthala (*) : M. Raghavendra Rao HCG Oncology Hospitals, Number 8, P Kalinga Rao Road, Near-GEO Hotel, Sampangirama Nagar, Bangalore, Karnataka, India e-mail: [email protected] K. G. Kallur : G. R. Prashant : K. Rajkumar Department of Nuclear Medicine, HCG Oncology Hospitals, Bangalore, Karnataka, India
NETs, considering the limited success of alternative treatment modalities. Treatment response and PFS is determined primarily by the dose delivered and best results are obtained when more than two cycles of 177Lu-DOTATATE are given, with careful monitoring for possible side effects. Keywords NET – neuroendocrine tumours . PRRT – peptide receptor radionuclide therapy . 177Lu-DOTATATE – lutetium octreotate
Introduction Neuroendocrine tumours (NETs) are a complex and heterogeneous group of tumours arising from neuroendocrine cells dispersed in the body from different primary sites including the gastrointestinal tract, lung, pancreas and thymus. NETs produce peptides causing characteristic hormonal syndromes and can be clinically symptomatic (functioning) or silent (nonfunctioning). The choice of an appropriate treatment option in patients with inoperable or metastatic NETs is limited, and approximately 50 % of patients have advanced NET at diagnosis, and 65 % die within 5 years [1, 2]. Identification of the neoplastic overexpression of particular subclasses of somatostatin receptors (SSTRs) on NETs formed the basis for the use of peptide receptor radionuclide therapy (PRRT) as a promising new therapeutic tool in the management of NETs [3]. 177Lu is a medium-energy β-emitter with a maximum energy of 0.5 MeVand a maximal tissue penetration of 2 mm. Its half-life is 6.7 days. 177Lu also emits low-energy γ-rays at 208 and 113 keV with 10 % and 6 % abundance, respectively, which allows scintigraphy and subsequent dosimetry with the same therapeutic compound [4]. Tetraazacyclododecane tetra-acetic acid (DOTA) is now used as a chelator instead of diethylene triamine pentaacetic acid for the coupling of the radionuclide and the somatostatin
Eur J Nucl Med Mol Imaging
analogue in PRRT for improved stability. The modified somatostatin analogues [DOTA0,Tyr3] octreotate (DOTATATE), [DOTA0, Tyr3] octreotide (DOTATOC), and [DOTA0-1-Nal3] octreotide (DOTANOC) have been compared in several studies of 177Lu-based PRRT [5–8]. The advantages of DOTATA TE over DOTATOC are higher uptake of radioactivity (expressed as a percentage of the injected dose) that can be achieved in most tumours without increases in the doses to potentially dose-limiting organs such as the kidneys, spleen and liver [9, 10], and lower whole-body retention compared to DOTANOC [6]. Several similar treatment protocols with minor differences have been used, and guidelines on the use of PRRT in NETs have recently been published [11]. Side effects found in previous studies are acute side effects occurring within 24 h of administration of 177Lu including nausea, vomiting, abdominal discomfort or pain, subacute haematological toxicity occurring 4 – 8 weeks after administration, and delayed toxicities including renal insufficiency and myelodysplastic syndromes [8]. It is important to estimate the absorbed radiation doses to dose-limiting organs such as the kidneys and bone marrow to allow the dose delivered to the tumour to be maximized and individualized. The use of fixed-dose regimens while leading to fewer side effects may result in a proportion of patients being undertreated. PRRT using 177Lu as the therapeutic radionuclide has been successful with objective response rates ranging from 30 % to 50 % with significant increases in progression-free survival (PFS) [8, 12–15], and significant improvements in global health and quality of life and in several function and symptom scales [16]. We performed a retrospective analysis of patients with NET treated with 177Lu-DOTATATE during the period 2009 to 2013 at HCG Oncology Hospitals, Bangalore, Karnataka, India.
Technology (Mumbai, India), Bhabha Atomic Research Centre (Mumbai, India) and IDB Holland (Baarle-Nassau, The Netherlands). 177Lu was used at a dose of 200 mCi as part of a fixed dosing scheme per cycle and the interval between each cycle was 6 to 9 weeks. Ondansetron 4 mg was injected intravenously prior to therapy. Gelofusine infusion (540 cm3) was given half an hour prior to and half an hour after 177Lu-DOTATATE administration. A coinfusion of a mixture of arginine and lysine was given for 2 h before 177 Lu-DOTATATE administration and was continued for 4 h after completion of gelofusine infusion to reduce exposure of the kidneys to radiation (tubular reabsorption of the radiopeptide by the kidney) [17, 18]. Hydration with 4 l of normal saline was given for 24 h after 177Lu-DOTATATE administration. Patients were isolated for 48 h after 177LuDOTATATE administration for radiation safety purposes. 131 I-Lipiodol was administered intraarterially via a hepatic arterial catheter in selected patients with extensive hepatic metastases. 131I-Lipiodol was used at a dose of 40 – 50 mCi as part of a fixed dosing scheme per cycle. Adriamycin (20 mg) was infused intraarterially as a radiation sensitizer prior to Lipiodol administration [19]. Patients were isolated for 1 week post 131I-Lipiodol administration for radiation safety purposes. Response evaluation
Methodology
Routine haematology, liver and renal function tests, and serum electrolytes were measured prior to each treatment cycle, and at follow-up visits. Morphological response to therapy was evaluated by a 68Ga-DOTANOC PET/CT scan after completion of two cycles of 177Lu-DOTATATE and after the entire treatment. Follow-up CT studies were compared with the baseline imaging studies to determine the objective tumour response based on the World Health Organization criteria: a complete response (CR) was defined as the complete disappearance of all recognizable tumour in the liver, a partial response (PR) was defined as a reduction of ≥50 % in tumour size, a minimal response (MR) was defined as a reduction of
