Peptides and Receptors in Image-Guided Therapy: Theranostics for Neuroendocrine Neoplasms

https://doi.org/10.1053/j.semnuclmed.2012.01.002Get rights and content

Theranostics of neuroendocrine neoplasms (NENs) based on molecular imaging using receptor positron emission tomography/computed tomography (PET/CT) with 68Ga-labeled somatostatin (SMS) analogs and molecular radiotherapy applying peptide receptor radionuclide therapy (PRRNT) with 90Y- and/or 177Lu-labeled peptides has paved the way to personalized medicine. SMS receptor PET/CT enables very accurate detection of NENs and their metastases with high diagnostic sensitivity and specificity and provides quantitative, reproducible data that can be used for selecting patients for PRRNT and evaluation of therapy response. Among other advantages are the fast imaging protocol (total study time, 60-90 minutes), low radiation burden (10-12 mSv), flexibility in daily use, and lower cost than octreotide scintigraphy. As we move toward personalized medicine, the diagnostic information obtained from PET/CT must be improved, that is, by fast routine quantification of lesions. PRRNT is highly effective for the treatment of NENs, even in very advanced cases, and lends a benefit in overall survival of several years. In addition, significant improvement in clinical symptoms and excellent palliation can be achieved. In patients with progressive NENs, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period (Bad Berka Concept) results in good therapeutic responses. By this concept, severe hematologic and/or renal toxicity can be reduced or completely avoided, and the quality of life can be improved. Sequential (DUO-PRRNT) and concurrent (TANDEM-PRRNT) administrations of radiopeptides are more effective in progressive NEN than using either radionuclide alone. PRRNT should only be performed at specialized centers, as NEN patients need highly individualized interdisciplinary treatment and long-term care.

Section snippets

Peptides and SSTRs in NEN

A new avenue in the field of molecular imaging was opened in the late 1980s with the use of radiolabeled SMS analogs for the localization of NENs.5 There are 5 different types of SSTR proteins that have been cloned (SSTR 1-5); SSTR 2 consists of 2 subtypes, SSTR 2A and SSTR 2B. The basis of peptide receptor imaging using radiolabeled SMS analogs is the overexpression of some of these receptors in NENs, especially SSTR 2.6 The advantages of small peptides as compared with antibodies are better

SSTR PET/CT Using 68Ga

The single most imperative aspect of PET/CT is its ability to quantify the disease at a molecular level. For a quantitative approach, 68Ga and PET/CT is clearly superior to gamma-emitting radionuclides and single-photon emission CT (SPECT)/CT. The development of 68Ga-labeled SMS analogs has been a major breakthrough. 68Ga-DOTATOC was the first peptide that has been studied in a larger number of patients. 68Ga is a diagnostic trivalent radiometal with convenient labeling characteristics, and is

Diagnosis, Staging, and Restaging

In a recent study in normal human tissues, maximum standardized uptake value (SUVmax) of 68Ga-DOTATOC imaging has been related to the expression of SSTR 2 at the level of mRNA.31 This highly interesting observation shows the real power of molecular imaging. The novel normative database may improve diagnostics, monitoring, and therapy of SSTR-expressing tumors or inflammation on a molecular basis. Another recent study from our group by Kaemmerer et al provided for the first time the proof of

Peptide Receptor Radionuclide Therapy

Following the scintigraphic localization of NENs with radiolabeled SMS analogs, therapeutic approaches with radiolabeled peptides were developed. The biological basis of PRRNT is the receptor-mediated internalization and intracellular retention of the radiopeptide. PRRNT can deliver radiation doses to tumors, which are adequate to achieve volume reduction or even cure. Upregulation of SSTR 2 in the peritumoral vessels, but not in the distant vessels, may constitute another target for

Clinical Results of PRRNT

In a study including 265 patients with neuroendocrine gastroenteropancreatic or bronchial tumors, treatment with 177Lu-DOTATATE resulted not only in reduction of tumors and prolongation of overall survival but also improved the patients' self-assessed quality of life.67 In a milestone study including 310 patients with GEP NEN (published by the group from Erasmus Medical Center, Rotterdam), PRRNT with 177Lu-DOTATATE showed complete and partial tumor responses in 30% of the patients (with very

Theranostics of NENs With Other Peptides

The success of the theranostic approach in the management of NENs with SSTR targeting also prompted a case for exploring the possibility of targeting other peptide receptors like vasoactive intestinal peptide, cholecystokinin, and bombesin receptors.89, 90, 91 The expression of the following bombesin receptor subtypes has been demonstrated in NENs: gastrin-releasing peptide (GRP) receptors in gastrinomas, neuromedin-B in gut carcinoids, and BB3 in lung carcinoids. Of particular interest was the

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