Radiotheranostics is here to help

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INTRODUCTION

Recent studies and nuclear medicine advancements showed the leading role of radiotheranostics in oncology. Whatever the term of this promising area (radiotherapy, theranostics, radiotargeting, radioligand, peptide-receptor, or radionuclide therapy), this is a new area of nuclear medicine, particularly, in the diagnosis and treatment of malignant tumors using radioactive isotopes (Fig. 1).

Fig. Radioactive isotopes for the diagnosis and treatment of various diseases.

The situation with the coronavirus disease-2019 pandemic did not diminish the interest in radioteranostics. Contrarily, only the demand for visualization of pathological processes using ultrasound and tomographic studies, such as computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission CT (SPECT), and positron emission tomography (PET), as well as hybrid methods, has increased. The world saw the exponential growth of investments in new radiopharmaceuticals (RPHs) for radioteranostics over the past 15 months. This trend is due to both the availability of funds from promising investors and the realization of the enormous growth market potential of radioactive isotope-labeled molecules for therapy. The growing investments in radiotherapy are based on the advances achieved in this field over the past 10 years. The monetary capital growth estimation in this industry revealed that the nuclear medicine market in 2019 was $4.1 billion and this figure is expected to increase within 5 years to $5.2 billion at an average annual growth rate of 4.7% by 2024¹. Key players see growing revenues from therapeutics as clearly superior to those from diagnostics. The increased attention to radionuclide technologies in the last 20 years is comparable to the growing interest in cancer immunotherapy in 1980–2000. At that time, the pharmaceutical industry preferred to watch the evolution of technologies through start-ups and small companies, most of which went bankrupt, whereas the rest perfected the technologies and made multibillion-dollar profits.

Currently, the range of radiotherapeutic drugs exceeds 300 items and has long surpassed the list of diagnostic RPHs, which require much fewer financial investments. For the past 50 years, the global RPH industry had an insufficient budget to develop such drugs in government agencies. Only “traditional” pharmaceutical companies had sufficient capital and infrastructure to develop and market RPHs. In addition to huge financial resources, they have access to the target audience, i.e., doctors (oncologists, radiologists, endocrinologists, etc.). The pharmaceutical companies, Bayer (Germany) and Novartis (Switzerland), were the first to engage in this area and brought therapeutic RPHs (²²³Ra-Xofigo and ¹⁷⁷Lu-Lutathera, respectively) to the market, which were limited to generic patents, thus have not reached (at least so far) blockbuster levels (annual sales of over $1 billion). Nevertheless, the next generation of therapeutic RPHs, such as glutamate carboxypeptidase II or prostate-specific membrane antigen (PSMA), will be based on proprietary names. The first radioligand, ¹⁷⁷Lu-PSMA-617 for prostate cancer (Novartis), is expected to hit the global market next year. In addition to Novartis, which is actively investing in new radiotherapeutic drugs (for example, based on fibroblast activity protein inhibitor for radionuclide therapy of a large number of malignancies or CXCR4, a chemokine receptor-4, which is used in myeloma, lymphoma, aldosterone, esophageal cancer, and glioblastoma), a growing interest is noted in the industry worldwide from iTheranostics (Switzerland), Sofie Biosciences (USA), Aktis Oncology (USA), Astellas (Japan) and Actinium Pharma (USA) collaborations, Jubilant (India), Lantheus and Noria Therapeutics (USA), Bracco Blue Earth Diagnostics (Italy), Scintomics (Germany), Fusion Pharma (Canada), Ipsen (France), and, more recently, EZAG and Pentixapharm consortium (Germany). New names appear annually on the RPH market, such as Abscint (Belgium), Abdera Therapeutics (Canada), Precirix (Belgium), and RayzeBio (US).

All of these companies are very young and emerged at the nexus of nuclear medicine, radiopharmacy, and medical physics. Thus, Telix Pharmaceutical (Australia) develops cutting-edge radiotheranostical agents for prostate cancer (iPSMA, J591), glioblastoma, kidney, bladder, and ovarian cancers by combining ¹⁷⁷Lu-labeled peptide-based RPHs and monoclonal antibodies with ¹⁷⁷Lu and ¹³¹I in its product portfolio.

Current approaches to neuroendocrine tumors and prostate cancer treatment are represented by both radiotargeting therapy in a single-mode, i.e., one RPH during all courses, and the use of “tandem” RHPs by combining the same base molecules with different radiolabels. An example is the sequential use of ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617. One of the first companies to specialize in ligand radiolabeling with ²²⁵Ac alpha emitter was Fusion Pharmaceuticals (2014). The profile of Precision Molecular Inc. (the US, 2019) is radio targeting therapy for prostate cancer and other malignancies using ¹⁷⁷Lu and ²²⁵Ac. Since 2020, Point Biopharma (USA) and RayzeBio (with a focus on similar ²²⁵Ac-labeled ligands) have actively developed and used radiotheranostical drugs for neuroendocrine tumors and prostate cancer based on ¹⁷⁷Lu RPH.

Currently, over 60 radiotheranostical agents that target over 20 malignancies are in various stages of clinical trials; of these, 6 agents are in Phase III. Among the first 27 RPH names (9 for neuroendocrine tumors and 18 for prostate cancer), only a few (the most effective and safe ones) will enter the medical market.

Further development of radiotheranostics, especially in combination with existing anticancer therapy methods, will significantly expand the range of cancers with highly positive treatment responses. In oncology, radiotheranostics is an alternative to surgery (e.g., radioiodine therapy for thyrotoxicosis) or adjuvant treatment (as in thyroid cancer) in conjunction with surgery and hormonal therapy, or with distant radiotherapy, chemotherapy, and targeted drugs in other cases.

Accumulating an evidence-based clinical base will refine the indications for radioactive isotopes in the third, second, and first line of anticancer therapy. The concept of radiotheranostics generates much interest in personalized medicine, in which the patient is treated not according to a general, but to an individual plan, where specific targets and treatment mechanisms are determined using specific radiotheranostical agents (see Table 1). However, this is still a goal, for which a lot of logistical and regulatory issues will have to be resolved, allowing financial investments of pharmaceutical companies and private investors in the promising area of personalized medicine. Moreover, further informational and methodological work should be done with doctors, “non-nuclear” physicists, chemists, and public opinion.

RAPIDLY INCREASING DEVELOPMENT OF RADIOTHERANOSTICS WORLDWIDE

The international non-profit Oncidium² Foundation (headquartered in Belgium) was established in 2011 and operates globally to inform the public and professionals about radiotheranostics. The foundation aimed to promote and accelerate the development of radiotheranostics in oncology, making it more accessible to patients with cancer worldwide by updating information about the centers’ work. Hopefully, the number of such centers in the Russian Federation will increase.

The corresponding section of the website is continuously updated with information about new RPHs, evidence-based preclinical and clinical trials and practical application, mechanisms of action, efficiency and safety, and combinations with other technologies for cancer diagnosis and treatment. For example, the NOBLE Registry (a project of international collaboration) offers patients with prostate cancer access to SPECT or preferably to SPECT combined with CT (SPECT/CT) and PSMA, regardless of their place of residence and financial situation, particularly, if PET combined with PSMA is unavailable. The simplicity and convenience of SPECT/CT with PSMA (a technetium generator is always at hand) is much higher than PET combined with CT (PET/CT), and the cost is significantly lower, whereas virtual digital registration is possible if SPECT is not performed in hybrid mode using CT. The NOBLE Registry compares SPECT/CT and PET/CT results with PSMA, clarifying accuracy parameters, benefits, limitations, and indications. However, the foundation cannot solve all problems alone, thus 18 nuclear medicine and radiotherapy experts from 11 countries came for assistance, including the Russian Federation representatives, i.e., P.O. Rumyantsev and Ye.V. Kargapoltseva. The Scientific Board of Oncidium Foundation and the NOBLE Registry Steering Committee, consisting of respected leaders of nuclear medicine and I, are honored to be a member. The Scientific Board ensures international communication and radiotheranostic improvements, considering the development of new RPHs and Next-Generation Imaging.

In 2021, the Theranostics Development Association was registered in the Russian Federation³.

Table 1. The concept of radiotheranostics for prostate cancer

Note. * More preferable (theranostic pair with ¹⁷⁷Lu-PSMA); ** whole body posttreatment scintigraphy (SPECT for all, SPECT/CT if indicated). SPECT: single-photon emission computed tomography; CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography; TRUS: transrectal ultrasound; MSCT: multispiral computed tomography; OS: osteoscintigraphy; PSA: prostate-specific antigen.

Radiotheranostics provide an opportunity to update approaches to personalized diagnosis, treatment, and rehabilitation of patients with cancer. Therefore, many organizational, methodological, economic, and regulatory issues arise. According to foreign colleagues, the cost of a new-generation radionuclide therapy session per patient ranges between $15,000 and $50,000, excluding the cost for diagnostic examination using SPECT and/or PET, which are necessary for dosimetry-based treatment planning and monitoring.

The toxicity and frequency of radionuclide therapy are much lower than that of chemotherapy or radiation therapy; however, this information is often unknown to doctors who are unfamiliar and inexperienced with this area of medicine. Clinical practice shows that the patient has maximum compliance with a high benefit/convenience ratio of the treatment option.

CONCLUSIONS

Therefore, “nuclear” oncologists greatly enhance the potential of multidisciplinary teams in advanced clinics worldwide. Physicians improve both the treatment outcomes by increasing the radiation dose and the quality of life by minimizing the dose to surrounding tissues in patients with early tumor stages. This is commonly done through regression (not cure), tumor stabilization, or palliative care in advanced stages by a dose reduction for non-tumor tissues. The use and improvement of personalized dosimetry for radionuclide therapy planning are prioritized to ensure the delivery of the optimal dose in tumor tissues and minimize the effects of ionizing radiation on normal tissues for an effective and safe treatment for each patient.

ADDITIONAL INFORMATION

Funding source. The authors declare that there is no external funding for the exploration and analysis work.

Competing interests. The authors declare no obvious and potential conflicts of interest related to the publication of this article.

Author’s contribution. The author made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work.

¹ Nuclear Medicine/Radiopharmaceuticals Market by Type (Diagnostic [SPECT―Technetium, PET―F-18], Therapeutic [Beta Emitters―I-131, Alpha Emitters, Brachytherapy―Y-90]), Application (oncology and cardiology), Procedures―Global Forecast to 2026. Available at https://www.marketsandmarkets.com/Market-Reports/radiopharmaceuticals-market-417.html. Accessed on 07/10/2021.

² Oncidium. Official website: https://www.oncidiumfoundation.org.

³ Theranostics Development Association. Official website: http://theranostics.pro.

About the authors

Rumyantsev O. Rumyantsev

Author for correspondence.
Email: pavelrum@gmail.com
ORCID iD: 0000-0002-7721-634X
SPIN-code: 7085-7976
ResearcherId: C-6647-2012

MD, Dr. Sci. (Med.), ​​De​puty Head Physician, Chief oncologist-radiologist 

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