The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable

Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology (Impact Factor: 3.01). 09/2011; 38(1):64-71. DOI: 10.1016/j.ejso.2011.08.129
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To assess the clinical utility of peptide receptor chemoradionuclide therapy (PRCRT) using (177)Lu-octreotate (LuTate) with concurrent 5FU chemotherapy in patients with inoperable primary pancreatic and duodenal neuroendocrine tumours (NETs).
Between December 2006 and October 2009, five patients with progressive inoperable pancreatic and duodenal NETs without distant metastatic disease or with a potentially resectable solitary distant metastasis were treated with PRCRT; in combination with external beam radiotherapy in one case. Patients were followed up three months post-treatment with somatostatin receptor scintigraphy, radiology, biochemical markers and clinical assessment. Radiological response classification was defined by Response Evaluation Criteria in Solid Tumours (RECIST) with the addition of a minor response (MR; 10-30% size reduction) classification. Long-term follow up was performed until July 2011.
At three months post-treatment, all five patients had a scintigraphic response, four had a radiological response and three of the four symptomatic patients responded clinically. All five patients had an ongoing treatment response beyond three months including one where further tumour shrinkage facilitated curative surgery. All five patients are alive with 12-42 months of follow-up post-treatment.
PRCRT can be effective in inoperable pancreatic and duodenal neuroendocrine tumours and may play a role as neoadjuvant therapy in this patient group.

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    • "One patient who responded significantly on both CT and functional imaging underwent complete resection of residual disease, which had initially been assessed to be inoperable, supporting the role of PRCRT. Thus, PRCRT may render a small proportion of inoperable NET resectable [16]. In addition, 16 % of patients also demonstrated further response beyond 12 months after completion of induction treatment, including one patient who achieved a complete response on molecular imaging and CT criteria at 3 years after the induction cycle without any additional therapy, suggesting an ongoing and potentially delayed therapeutic effect in some patients (Fig. 4). "
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    ABSTRACT: Purpose To review the response and outcomes of 177Lu-DOTA-octreotate chemoradionuclide therapy (LuTate PRCRT) in patients with neuroendocrine tumour (NET) expressing high levels of somatostatin receptors with uncontrolled symptoms or disease progression. Methods A total of 68 patients (39 men; 17 – 76 years of age) who had completed an induction course of at least three cycles of LuTate PRCRT between January 2006 and June 2010 were reviewed. Ten patients were treated for uncontrolled symptoms and 58 had disease progression despite conventional treatment. The majority had four induction LuTate cycles (median treatment duration 5 months and cumulative activity 31 GBq), and 63 patients had concomitant 5-FU radiosensitizing infusional chemotherapy. Factors predicting overall survival were assessed using the log-rank test and Cox proportional hazards regression. Results Of those treated for uncontrolled symptoms, 70 % received benefit maintained for at least 6 months after treatment. Among patients with progressive disease 68 % showed stabilization or regression on CT, 67 % on molecular imaging and 56 % biochemically up to 12 months after treatment; 32 patients died. Overall survival rates at 2 and 5 year were 72.1 % and 52.1 %, respectively. Median overall survival was not estimable at a median follow-up of 60 months (range 5 – 86 months). Nonpancreatic primary sites, dominant liver metastases, lesion size 5 cm) appeared to have lower objective response rates and may need a more aggressive treatment approach.
    European journal of nuclear medicine and molecular imaging 05/2014; 41(10). DOI:10.1007/s00259-014-2788-5 · 5.38 Impact Factor
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    • "The use of PRRT as a neoadjuvant treatment has also been advocated in animal studies by Breeman et al. [52] who reported an increased survival in rats treated for 8 days with 177Lu-DOTATATE after infusion of 0.25 × 106 viable CA20948 cells into the portal vein, which mimics liver micrometastases. In humans, the use of PRRT in previously judged inoperable NETs has been described by Kaemmerer et al. [53] in a case report with PRRT used in a neoadjuvant setting before surgery, by Kwekkeboom et al. [13] who reported that PRRT enabled surgery in four patients in a large cohort of more than 500 patients, by Sowa-Staszczak et al. [54] in two of six patients treated in a neoadjuvant setting, and by Barber et al. [55] who found the same in five. "
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    ABSTRACT: Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours.
    European Journal of Nuclear Medicine 03/2012; 39 Suppl 1(S1):S103-12. DOI:10.1007/s00259-011-2039-y · 5.38 Impact Factor
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    ABSTRACT: High-administered activity In-111 octreotide (HA-Oc) therapy has been used for patients with disseminated neuroendocrine tumors (NET) with high somatostatin receptor (SSR) expression. Combining HA-Oc with radiosensitizing 5-fluorouracil (5FU) chemotherapy could enhance efficacy. Our other aim was to assess whether concomitant 5FU would contribute to significant additional toxicity. Fifteen (15) consecutive patients who received 3 cycles of HA-Oc+5FU were evaluated. Symptomatic, octreoscan, computed tomography (CT), hormonal responses, and toxicity were reviewed at 3 months post-last treatment. Long-term follow-up was performed to death or April 2008 to assess late toxicity and time to progression requiring retreatment. At 3 months post-treatment, 67% of patients had symptomatic improvement, with 20% experiencing a complete resolution of symptoms. Overall, 90% achieved stabilization or a decrease in hormone levels. Octreoscan improvement/stabilization occurred in 95% and CT stabilization in 80% of patients with previously progressive disease, but no partial or complete regression by Response Evaluation Criteria in Solid Tumors criteria. Transient lymphopenia and nausea were the most common side-effects, and there was no significant renal or grade 4 hematologic toxicity. Subacute side-effects included a peripherally inserted central catheter line thrombosis (1 patient), discomfort/pain associated with lesion necrosis, and 1 lymph node swelling. Median time to retreatment was 23 months (range, 6-34) for 10 patients. Six (6) patients deceased (no deaths directly related to 5FU); 9 patients (60%) are alive at 36-139 months. HA-Oc+5FU achieve a high rate of symptomatic response associated with stabilization/improvement in hormonal and functional scan abnormalities. Combination treatment achieved disease stabilization in the majority of patients with previously progressive disease. There was no significant observed increase in toxicity with additional 5FU, making it a promising adjunct to radiopeptide receptor therapy for progressive NET.
    Cancer Biotherapy & Radiopharmaceuticals 10/2009; 24(5):527-33. DOI:10.1089/cbr.2009.0644 · 1.78 Impact Factor
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