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177Lu-DOTA-octreotate Radionuclide Therapy of Neuroendocrine Tumours: Dosimetry-Based Therapy Planning and Outcome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peptide receptor radionuclide therapy for the internal radiation of neuroendocrine tumours expressing somatostatin receptors has made great advances and offers promising results. 177Lu-DOTA-octreotate is one of the most widely used radiopeptides, but kidneys and bone marrow are organs at risk. Methods of measuring radiation doses to at-risk organs and tumours (dosimetry) on an individual patient basis have been regarded as impracticable and a maximum of 4 treatment cycles has widely been accepted as the treatment standard instead.

The first aim of this thesis was to establish a clinically feasible protocol to calculate absorbed doses to bone marrow and the kidneys during therapy with 177Lu-DOTA-octreotate. A new dosimetry protocol for the bone marrow was described. Dosimetry for solid organs had previously been described based on 3-dimensional imaging by the research group. In the current thesis it was demonstrated that in most patients only minor changes of the effective half-life occurred in the kidneys. By performing complete dosimetry during the first cycle and comparing it with the uptake in later cycles, it was shown that the absorbed dose can be cal-culated based on the activity concentration at 24 hours after therapy. The study concluded that 50% of all patients could receive more than the standard 4 treatment cycles with 7.4 GBq 177Lu-DOTA-octreotate without passing the limit of 23 Gray to the kidneys or 2 Gray to the bone marrow, whereas 20% would tolerate fewer than 4 cycles. 

The second aim was to describe treatment outcomes of dosimetry-guided therapy with 177Lu-DOTA-octreotate. Patients with metastasized colorectal neuroendocrine tumours and bronchial carcinoids were shown to have longer survival with this method than previously reported. Morphological tumour response could be correlated to time to progression. Furthermore, in a case of low-differentiated neuroendocrine cancer it was shown that large tumours with high proliferation can also be treated with this method and that tumour-to-risk organ ratios can improve in later cycles, resulting in a more effective treatment.

Dosimetry-guided, fractionated radionuclide therapy with 177Lu-DOTA-octreotate is a valuable treatment option for patients with advanced neuroendocrine tumours expressing somatostatin receptors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 831
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-183417ISBN: 978-91-554-8513-9 (print)OAI: oai:DiVA.org:uu-183417DiVA: diva2:562732
Public defence
2012-12-08, Grönwallsalen, Akademiska Sjukhuset Ing. 70, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-16 Created: 2012-10-25 Last updated: 2013-01-23Bibliographically approved
List of papers
1. Minor changes in effective half-life during fractionated 177Lu-Octreotate therapy
Open this publication in new window or tab >>Minor changes in effective half-life during fractionated 177Lu-Octreotate therapy
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2011 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, 86-96 p.Article in journal (Refereed) Published
Abstract [en]

Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. Patients. Thirty patients, 13 women and 17 men, were included in the study. Methods. During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. Results. The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively. Discussion. The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). Conclusion. With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

Keyword
Absorbed dose, Neuroendocrine tumour, 177Lu-octreotate
National Category
Cancer and Oncology
Research subject
Physics; Oncology; Radiology
Identifiers
urn:nbn:se:uu:diva-158969 (URN)10.3109/0284186X.2011.618511 (DOI)000298002000012 ()21961497 (PubMedID)
Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
2. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment
Open this publication in new window or tab >>Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment
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2013 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 1, 33-41 p.Article in journal (Refereed) Published
Abstract [en]

The organs at risk in radionuclide therapy with 177Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys. Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of 177Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT. Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of 177Lu-octreotate could be administered before the upper dose limit for the individual patient was reached. Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of 177Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.

Keyword
177Lu-DOTA-octreotate, Bone marrow, Dosimetry, Individualized, Kidney
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183412 (URN)10.2967/jnumed.112.107524 (DOI)000313606800027 ()
Available from: 2012-10-25 Created: 2012-10-25 Last updated: 2017-12-07Bibliographically approved
3. Favorable outcome of dosimetry-guided therapy with 177Lu-DOTA-octreotate in patients with advanced stages of colorectal neuroendocrine tumors (NETs)
Open this publication in new window or tab >>Favorable outcome of dosimetry-guided therapy with 177Lu-DOTA-octreotate in patients with advanced stages of colorectal neuroendocrine tumors (NETs)
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183415 (URN)
Available from: 2012-10-25 Created: 2012-10-25 Last updated: 2012-11-22Bibliographically approved
4. Outcome of dosimetry-guided fraction-ated therapy with 177Lu-DOTA-octreotate in patients with ad-vanced stages of bronchial carcinoids
Open this publication in new window or tab >>Outcome of dosimetry-guided fraction-ated therapy with 177Lu-DOTA-octreotate in patients with ad-vanced stages of bronchial carcinoids
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183416 (URN)
Available from: 2012-10-25 Created: 2012-10-25 Last updated: 2012-11-22Bibliographically approved
5. Lessons on Tumour Response: Imaging during Therapy with Lu-177-DOTA-octreotate. A Case Report on a Patient with a Large Volume of Poorly Differentiated Neuroendocrine Carcinoma
Open this publication in new window or tab >>Lessons on Tumour Response: Imaging during Therapy with Lu-177-DOTA-octreotate. A Case Report on a Patient with a Large Volume of Poorly Differentiated Neuroendocrine Carcinoma
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2012 (English)In: Theranostics, ISSN 1838-7640, Vol. 2, no 5, 459-471 p.Article in journal (Refereed) Published
Abstract [en]

Favourable outcomes of peptide receptor radiotherapy (PRRT) of neuroendocrine tumours have been reported during the last years. Still, there are uncertainties on the radionuclides to be used, the treatment planning, and the indication in patients with a high proliferation rate. This case report describes a patient with a high tumour burden of poorly differentiated neuroendocrine carcinoma of unknown primary with a proliferation rate in liver metastases up to 50%, undergoing fractionated treatment with 7 cycles of Lu-177-DOTA-octreotate (7.4 GBq each) after disease progression on two different chemotherapy regiments. Based on initial staging scintigraphy, somatostatin receptor expression was very high. Longitudinal dosimetry studies during therapy indicated ongoing increases in tumour-to-organ ratios that coincided with an objective response. We conclude that fractionated therapy with Lu-177-DOTA-octreotate should be considered a treatment option also for those patients with large tumours, high proliferation, and high receptor expression.

Keyword
Neuroendocrine tumour, PRRT, 177Lu-DOTA-octreotate, radionuclide therapy, dosimetry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-176912 (URN)10.7150/thno.3594 (DOI)000304488100005 ()22768026 (PubMedID)
Available from: 2012-06-28 Created: 2012-06-27 Last updated: 2012-11-28Bibliographically approved

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