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Theranostics: patient-centered care at its best

By: Jana Brajdih Čendak

Theranostics (the concept of combining diagnostics and therapy) represent a holistic transition from the standard “trial and error” medical practice to a safer, efficient, predictive personalized medicine. The concept was first introduced in nuclear medicine. It has roots back in 1940, when radioiodine was first utilized to diagnose and manage thyroid cancers.  This fundamental principle has evolved significantly in the last decade, owing its progress to pharmacogenetics, proteomics and biomarker profiling.

Why do therapies fail? The most common cause has been identified to be adverse drug reactions, which are common and often severe in nonspecific, “one size fits all” therapies. Age, gender, diet, lifestyle and the patient’s intestinal microflora also play a significant role (1).  And this is exactly where theranostics demonstrate its highest value. The concept uses the so called “P4” principle: predictive, preventive, personalized and participatory. In a broader sense, theranostics represent a diagnostic methodology for personalizing the treatment intervention.

Theranostics are, therefore, diagnostic procedures, used to select appropriate patients for the appropriate therapy, maximizing the success rate and minimizing the adverse reactions. A brilliant example of such principle is the use of 68Ga-labelled PSMA-11 to select patients with advanced, metastatic prostate cancer that will benefit most from receiving the radioligand therapy with 177Lu-labelled PSMA-617. Patients who are expected to have a good therapy response, will have high PSMA expression and a high uptake (measured by standard uptake value; SUVmax) of 68Ga-labelled PSMA-11 in the tumorous lesions.

An international clinical trial that was conducted on 1179 patients with metastatic prostate cancer in 84 centres worldwide (2) evaluated the efficacy and safety of 177Lu-labelled PSMA-617 treatment, as well as the efficacy of 68Ga-labelled PSMA-11 to adequately select patients for this treatment. A total of 1003 patients underwent 68Ga PSMA-11 PET/CT scan and the PET images were red by a reader, blinded to clinical information. In a sub-study, the inter-reader interpretation agreement and intra-reader reproducibility was determined to be 0.60 (95% CI: 0.50, 0.70; Fleiss k) and 0.78 (95% CI: 0.49, 0.99), 0.76 (95% CI: 0.46, 0.99) and 0.89 (95% CI: 0.67, 0.99; Cohen k) for three re-readers, respectively. This result enabled the approval of the indication (Selection of patients for Lutetium therapy) for Locametz® (68Ga PSMA-11; Novartis) in the US.

Similar concepts are already being used for other oncologic diseases, such as neuroendocrine tumors, which express somatostatin receptors and are targeted by somatostatin analogues. With a similar principle, 68Ga or 64Cu-labelled somatostatin analogues (such as DOATATE or DOTATOC) can help select the eligible patients for radioligand therapy with 177Lu.

In paediatric oncology, a theranostic principle is also used to diagnose and treat neuroblastoma that express norepinephrine transporter (NET).  mIBG is a structural analog of the neurotransmitter norepinephrine and is actively transported into the tumor by NET. 123I-mIBG SPECT imaging is currently the standard of care to diagnose primary tumors and distant metastases in neuroblastoma and for staging and disease response evaluation after treatment, while 131I-mIBG is used for radioligand therapy (3).

Several other tracers are being currently tested. Just as an example, three potentially interesting agents are presented, although many more are being investigated. C-X-C chemokine receptor 4 (CXCR4) is expressed in breast, prostate, lung, colorectal and brain cancer cells, as well as in rare malignancies, such as rhabdomyosarcomas. For theranostic development, the PET tracer and cyclic-pentapeptide 68Ga -pentixafor is currently being investigated together with the proposed 177Lu-pentixather as the therapeutic radioligand (4,5). Fibroblast activation protein α (FAP) is also a promising agent for theranostics, again labelled with 68Ga for diagnostic and with 177Lu for therapeutic purposes (6).

The regulatory approval of radiopharmaceuticals is complex and requires a fundamentally different approach compared to classic medicines. Especially for diagnostic agents, the demonstration of “efficacy” refers to the product’s diagnostic performance, which is an overall evaluation of measured variables (such as sensitivity and specificity) and the impact of the results on the management of patients. The quality aspects are also challenging due to the radioactivity of the agent.  Therefore, it is crucially important to understand not only the pharmacological, but also the legislative landscape governing radiopharmaceuticals in order to be successful in bringing them to the market.

  • Nimita L. Pharmacogenomics, theranostics and personalized medicine-The complexities of clinical trials: challenges in the developing world. Appl Transl Genomics. 2013;2:17–21.
  • Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
  • Hoefnagel CA, De Kraker J, Valdes Olmos RA, Voûte PA. 131I-MIBG as a first-line treatment in high-risk neuroblastoma patients. Nucl Med Commun(1994) 9:712–7. 
  • Peled A, Klein S, Beider K, Burger JA, Abraham M. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine(2018) 109:11–6.
  • search term: Pentixafor, CXCR4(2020). Available at: https://www.clinicaltrials.gov/ct2/results?cond=&term=pentixafor&cntry=&state=&city=&dist=  (Accessed May 30, 2022).
  • Busek P, Mateu R, Zubal M, Kotackova L, Sedo A. Targeting Fibroblast Activation Protein in Cancer – Prospects and Caveats. Front Biosci (Landmark Ed)(2018) 23:1933–68.