How smart is peptide receptor radionuclide therapy of neuroendocrine tumors especially in the salvage setting? The clinician’s perspective

Abstract

In the recent past there has been a substantial growth in the understanding of cancer biology with a consequent opening of a Pandora’s box of scientific knowledge and advance in the biological perception of the disease. Paradoxically, this indepth, sun-burst-like knowledge has fogged the several established management protocols rather than clearing the doubts. The ‘knowledge’ that the hitherto established and proven therapeutics do not only target cancer cells but also ‘normal’ cells has shifted the attention more onto toxicity. To overcome the toxicity related to the ‘generalized’ treatment approach medical scientists across the world have gleefully (and possibly gullibly) accepted targeted therapy and the ‘theranostic concept’. This evolved approach should eventually, supposedly, tackle the intelligent cancer cells which have successfully challenged ‘Darwin’s Theory of Evolution’ by replacing the normal ‘chosen’ cells of the best creation and evolved creature of nature. Paradoxically survival of the fittest in this instance leads to extinction of the organism! This has generated a new intellectual theocracy whereby new knowledge has been embraced with almost religious zeal and rigorous assessment diminished in the face of fervor as we seek to reverse a biological Darwinian conundrum. As a consequence a note of caution needs to be placed here because the knowledge of the scientific medical community about neoplasia is juvenile, whereas the cancer cells, by the time they are diagnosed, are evolved and are up to 40 years old [1]. In effect they are the adults in the evolutionary cascade, and thereby not only challenging but also winning the natural selection process which decrees that “growth and spread is to the strongest”. In consideration of such (very old) philosophy, direct implementation of the promising but not matured theranostic concept in a patient with aggressive cancer, with a relatively shorter life expectancy, might not have a significant adverse influence on an already poor quality of life. The problem however achieves a different degree of proportionality when the concept is translated to the treatment of an indolent tumor associated with a relatively good overall survival following the initial diagnosis. Neuroendocrine tumors (NETs) are a group of such tumors, whose incidence and prevalence appear to be increasing at an alarming rate, partially due to highly advanced diagnostic methods and raised awareness [2]. Nuclear medicine is the first exponent of the theranostic concept dating back to early 1950s. The classical example is the use of radioiodine for diagnosis and therapy of various benign and malignant thyroid diseases targeting the thyroid cell sodium iodine transporters. A similar analogy is the identification of the overexpression of somatostatin receptors on NETs. This has enabled nuclear medicine physicians to deal with the complex and heterogeneous tumor by addressing the neoplastic overexpression of particular subclasses of somatostatin receptor. Thus somatostatin receptor-based molecular imaging has become established as an essential tool in the management of NET. Alternatively however, peptide receptor radionuclide therapy (PRRT), using peptides such as DOTATATE or DOTATOC, despite the fact that numerous retrospective (often single-center) studies during the last 10 years have provided evidence of success, has led to controversial discussions amongst oncologists, surgeons and gastroenterologists. The critical points of discussion include toxicity (hematotoxicity and nephrotoxicity) rather than the efficacy of the therapy. Objective response rates range from 4% to 30 %with significant increases in progression-free survival (PFS) compared to established approved therapy regimens [3]. V. Prasad (*) :W. Brenner Department of Nuclear Medicine, Campus Virchow-Klinikum, Charite University Hospital, Berlin, Germany e-mail: vikas.prasad@charite.de