Nuclear medicine is currently taking great steps towards gaining a much more prominent role in the care of patients with prostate cancer. Prostate-specific membrane antigen (PSMA) has been a theranostic target of interest in prostate cancer for over two decades and 111In/177Lu antibody-based imaging and therapy have been studied extensively but without gaining widespread clinical acceptance [1–3]. However, since the introduction of novel functional ligands for PSMA such as Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA) [4, 5], PSMA-DKFZ-617 [6–8] or EuK-Subkff-68Ga-DOTAGA [9], the number of publications on specifically PSMA-targeted imaging has increased exponentially. This shows the extraordinary potential of this approach as a blockbuster modality for nuclear medicine.
68Ga-PSMA PET/CT is a fine example of theranostic nuclear medicine. The tracer 68Ga-PSMA is eminently suitable for selection of patients who can be treated with the novel 177Lu-labelled therapeutic tracer PSMA-DKFZ-617 [6]. Dramatic success has already been observed even in the small initial number of patients with extensively metastasized therapy-refractory prostate cancer metastases treated with this tracer once strong tracer uptake had been established in prior diagnostic 68Ga-PSMA PET/CT [6, 10]. Therapeutic nuclear medicine therefore now has a truly large new potential patient collective in whom molecular targeted endogenous radiotherapy may play a pivotal role. Furthermore, PSMA is not only expressed strongly by prostate cancer cells, but also in a variety of other normal tissues and solid tumours – mainly in the tumour vasculature [11–18]. This might open the door to nuclear medicine making the long-sought-after inroad into non-thyroid, non-neuroendocrine cancer therapy even though a sustainable multicentre effort has to be initiated to realize this potential.
In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Giesel et al. report a study comparing the performance of 68Ga-PSMA PET and conventional morphological imaging with CT in 21 patients scanned prior to radiation therapy [19]. Their findings (again) show the strong potential of 68Ga-PSMA PET/CT. With conventional morphological criteria based on the size of lymph nodes only 22 % of PET-positive lesions were identified as suspicious for malignancy, and only 7 of 14 patients (50 %) identified as having lymph node metastases on PET were also identified as such using CT-based lymph node diameter measurements. Previous studies have shown the high signal-to-background ratio typical of 68Ga-PSMA PET/CT [18, 20, 21], Giesel et al. now provide further detail on the diagnostic power of this novel imaging modality: the smallest PET-positive lesions had a short-axis diameter of only 2.4 mm. This is hardly greater than the annihilation distance in water for 68Ga-emitted positrons of 1.7 mm, and thus approaches the lower limit of the physically possible resolution in human PET imaging.
It is exactly the setting of patients referred for salvage radiation therapy in which 68Ga-PSMA PET/CT may prove to be of great value. Currently standard treatment for postoperative elevation of prostate-specific antigen (PSA) levels is radiation therapy of the former prostate region. It is recommended that this therapy is best initiated at PSA levels ≤0.5 ng/ml [22]. It has already been shown that even at such low levels 68Ga-PSMA PET/CT is able to show pathological accumulation outside the prostate bed, mostly in pelvic lymph node metastases, in approximately half of patients with a positive PET/CT scan, thus affecting treatment in approximately a quarter of all patients referred for 68Ga-PSMA PET/CT with such low PSA levels [4, 23]. Here 68Ga-PSMA PET/CT will markedly influence treatment because it allows either avoidance of a non-effective radiation treatment with considerable potential side effects or modification of treatment by inclusion of the affected lymph nodes in the radiation field.
While CT imaging has its place in staging of prostate cancer, MRI, especially using multiparametric imaging including diffusion-weighed sequences, is the more sensitive morphological imaging method. Although choline, the de-facto standard nuclear medicine tracer for prostate cancer, labelled with either 18F or 11C, has been proven to be marginally better than diffusion-weighed MRI [24, 25], neither modality has so far achieved optimal sensitivity and specificity for clinical use. Direct comparison of 68Ga-PSMA PET imaging and multiparametric MRI would be of great interest for nuclear medicine, even though, as already indicated in initial studies, the best option for the future will probably consist of hybrid PET/MRI imaging rather than either modality alone [27, 27].
Still, with all these promising new developments and the great diagnostic and therapeutic potential currently being unlocked by what seems almost an avalanche of studies into 68Ga-PSMA PET/CT, we all need to treat the current situation with a high degree of alertness. Recent history of nuclear medicine is awash with examples of what can happen if nuclear medicine as a discipline remains fractured and will not close ranks for a unified effort to gain acceptance in mainstream medicine.
Currently a number of different competing and only marginally differing radiolabelled functional PSMA ligands are being investigated, and the preferences in the use of these experimental tracers among the nuclear medicine communities in those countries where the use of such tracers is relatively less restrictive appear to be becoming increasingly divergent. Furthermore, all research effort has so far been spearheaded by academic institutions which do not have either the financial and organizational power or the commercial incentive that a strong commercial partner might have to undertake the entire study process necessary for regulatory approval. Without such approval, many countries will not even allow the use of 68Ga-PSMA PET/CT, regardless of how good the tracer may appear in the initial studies being published now. A dire example of where this may lead is the situation with somatostatin receptor-targeted imaging and therapy. 68Ga-labelled somatostatin analogues have been reported for well over a decade now [28–32]. However, the multitude of available analogues and lack of a commercially interested industrial party has led to the situation where 111In-pentetreotide [33], which is clearly inferior in terms of both diagnostic performance and patients’ radiation exposure [34], remains the only registered radiopharmaceutical. This in turn means that in many countries the latter compound remains the only compound allowed for the practice or reimbursement of somatostatin-receptor targeted imaging.
We therefore call upon the nuclear medicine community not to waste this unique opportunity to greatly enlarge the role of nuclear medicine by the practice of the same petty rivalry that in the past could be seen so often. Instead we should confer and put in a strong united effort to quickly gain mainstream acceptance of targeted imaging and therapy with a functional PSMA ligand by performing proper prospective multicentre studies. We strongly believe that with such a concerted action in the end none will come to harm and all will benefit. We have a magic bullet in our hands and should be careful not to lose it.
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F.M.M. and F.F.B. have received grant support and speakers’ fees from Bayer Healthcare. F.A.V. is a consultant to Bayer Healthcare.
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This Editorial Commentary refers to the article http://dx.doi.org/10.1007/s00259-015-3106-6.
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Mottaghy, F.M., Behrendt, F.F. & Verburg, F.A. 68Ga-PSMA-HBED-CC PET/CT: where molecular imaging has an edge over morphological imaging. Eur J Nucl Med Mol Imaging 43, 394–396 (2016). https://doi.org/10.1007/s00259-015-3212-5
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DOI: https://doi.org/10.1007/s00259-015-3212-5