Impact of Nuclear Medicine and Radiopharmaceuticals on Health-care Delivery: Advances, Lessons, and Need for an Objective Value-matrix.

The nuclear medicine (NM) growth has gone through both evolutionary and revolutionary changes over decades, mostly attributable to the dynamic and responsive trends in the global development and deployment of radiopharmaceuticals (RPh), as well as the advent of superior technology imaging systems (single-photon emission computed tomography/computed tomography [CT], positron emission tomography [PET]/CT, PET/magnetic resonance) with quantification capability. There are naturally many crucial lessons learnt along the way of NM-RPh progress achieved. It is felt imperative for the NM-RPh community to have consensus-based list(s) of indications for NM, classified on the value-level basis, at NM gross-level and specific medical specialty-wise, and the corresponding RPh needed, to ensure harmonious communication with the referral medical fraternity and health-care policymakers. For this purpose, a "NM value-matrix" is proposed in terms of "NM utility grading" (unique value, significant value, useful value, and others) versus "patient volume" (i.e., large, medium, low, and rare cases), covering the established and emerging indications for NM procedure, and the corresponding RPh product(s) in use. A consensus-based NM Value-Matrix will portray in an unequivocal manner, the merits of NM-RPh options (also limitations, if any) for serving needy patients.

Introduction

The field of nuclear medicine (NM) is unique regarding its intricate cum essential dependence on the use of radiopharmaceuticals (RPh) for every procedure. RPh comprises a radioisotope (radioisotopes [RI), produced in a research reactor [RR] or particle accelerator like medical cyclotron [MC] delivering radiation used for detection-based imaging, or for targeted therapy, and a carrier-molecule to render bio-specificity for the organ or lesion or dysfunction being addressed.

The NM growth has gone through both evolutionary and revolutionary changes over decades, mostly attributable to the dynamic and responsive trends in the global development and deployment of RPhs, as well as the advent of superior technology imaging systems (single-photon emission computed tomography [SPECT]/computed tomography [CT], positron-emission tomography [PET]/CT, PET/magnetic resonance) with quantification capability. Beginning with the excitement of visualization in vivo of the organ functioning, efforts to address clinically useful issues registered considerable progress, leading to a large number of RPh products and NM procedures, and in turn, making a positive impact on patient management. Currently, the volume of global diagnostic NM studies is reported to be over 40 million per annum, and that of NM therapies 10%–15% of the above. The annual conferences of SNM India and several other similar events attempt to showcase the important trends of the NM-RPh roles and various accomplishments in serving patients.

Advances and Milestones in Growth of Nuclear Medicine - Radiopharmaceuticals

Beginning with the use of the ubiquitous 131I for both diagnosis and therapy, a great surge was first provided by 99mTc based imaging agents in NM during 1980s and 1990s (planar initially and SPECT later on), and subsequently, by PET tracers, 18F in particular (since 2000). The RPh evolution has gone through an increasingly sound pathway of developments, starting from chemistry-based developments to multi-disciplinary efforts, and strengthened further by adopting superior targeting strategies by carefully identifying appropriate moieties of biochemical origin, associated with a specific lesion or dysfunction of clinical concern. The R and D focus placed on addressing clinical needs led to the development and launch of several RPh, especially in three major areas: (i) for skeletal system-bone being the frequent site of cancer metastasis; (ii) for myocardial imaging-management aid for the large-volume cardiac patients-utility proven first with 201TlCl and later more widely done with 99mTc based RPh (sestamibi, tetrofosmin); and (iii) for tumor targeting in cancer patients, for both imaging and therapy. One can cite the following major milestones of high clinical significance:

The advent of 99mTc generator and its RPh, along with “kits” for ease of compounding at user end

Use of 201TlCl for myocardial perfusion imaging (MPI), and later launch of 99mTc products (sestamibi, tetrofosmin) for similar use

High-value utility in oncology proven in terms of: (a) bone scanning (with 99mTc-phosphonate and SPECT, 18F-fluoride and PET), (b) metastatic bone pain palliation therapy (using 89SrCl2 and 153Sm-ethylene diamine tetra methylene phosphonate (EDTMP); later on 177Lu-EDTMP, 223RaCl2), and (c) use of 18F-fluorodeoxyglucose (FDG) (also other tracers of higher specificity) availed from MC and automated radiochemical synthesis module

Advances in strategic targeting of tumors, for both imaging and therapy (I and T, theranostics) and success stories of applying small molecule vectors along with the RI pair, 68Ga and 177Lu, for PET imaging and therapy, respectively-for neuroendocrine tumor (NET) metastasis using peptide-ligand-conjugates for binding somatostatin receptors, and for prostate cancer using enzyme-inhibitor-ligand-conjugates for binding prostate-specific membrane antigen.

A major turning point in NM took place, when PET/CT arrived in 2001, through the use of the combination of high-specificity biological tracers of 18F, 11C, and other positron emitters 68Ga, 64Cu, etc., and high-resolution PET/CT imaging, especially for applications in oncology and neurology. A paradigm shift occurred in this period with the acceptance of PET and PET/CT technology as a regular clinical tool. MC-produced 18F (110 min) and 18F-fluorodeoxyglucose (FDG) have become new common terms in NM since then (just as 131I and 99mTc were earlier). It is estimated that TBq (kCi) quantity of 18F, and almost 1000 lots of 18F-FDG, are being produced daily across the world, making use of the nearly 900 MC in operation! From the first MC, PET setup by DAE in Parel-Mumbai in Oct. 2002 (although belatedly, but fortunately coinciding with the launch of PET/CT), the Indian scene has registered an impressive growth to 18 MC facilities and over 150 PET/CT units in service today.

Another important progress has been in RPh-based radionuclide therapy (RNT). The growth in the use of 177Lu (6.7 d) as an attractive therapeutic RI for targeted tumor therapy has gained much momentum in the last decade and with Indian contributions well-acknowledged worldwide. Two alpha emitters, 223Ra for bone pain palliation, and 225Ac for use in place of 177Lu for more efficacious tumor therapy, are undergoing evaluation. With the advances in targeting tumors for imaging- and therapy-based on sound molecular basis of vectors identified for specific tumors such as peptide conjugates to bind receptors over-expressed on tumors (for NET metastasis), or other inhibitor-ligand-conjugates to bind enzyme moiety associated with tumors (for prostate cancer), the emergence of RNT for metastasis of NET and of prostate Ca has been the game changer in the field. The theranostic approach, namely, the same vector molecule used with diagnostic RI (e.g., 18F, 68Ga) for imaging, and with therapeutic RI (e.g., 177Lu, 90Y) for therapy, is gaining increasing attention. The good-old 131I use as a theranostic agent has been thus rediscovered to advantage, with scope to make use of several effective radioisotope pairs available, for example, 68Ga and 177Lu; 68Ga and 90Y; and 124I and 131I, 64Cu and 67Cu.

64Cu (12.7 h, produced by 64Ni (p, n) or by 64Zn (n, p) reaction) may well become in future the 131I analog for a single RI-based theranostic role, as 64Cu has all the radiation emissions required for both imaging (positron emission [about 17%]-PET/CT) and therapy (beta emission and conversion electrons). Further, copper is an essential element in human biochemistry involved in DNA replication, and in turn, having inherent ability to be marker of certain bio-physiological process, like tumor growth. Thus, 64Cu, in its simple inorganic form of copper chloride itself, seems well set for potential use in NM.

Lessons and Challenges

There are naturally many crucial lessons learnt along the way of NM-RPh progress achieved, and in the many developments underway:

Challenges in designing and developing more specific, efficacious RPh to offer effective patient management options, in cardiology, oncology, neurology, and among others

Small molecules are the most favorable moiety for targeting lesions (cf. macromolecules like antibodies) and developing RPh for I and T (theranostics)

Dosimetry issues in transforming the same vector-based RPh product for imaging applications to therapeutic use, especially to address radiation dose to excretory organs and unintended (nontarget) sites accumulating the RPh product

Addressing regulatory process issues for launch of new RPh (more in the case of RPh for lesion imaging and for therapy-where “normal-volunteer” study is not feasible) for clinical trials and subsequently for regular use

Fostering security of supplies of RR-based RI and RPh, recalling the severe jolt felt during 2008-10 99Mo supply crisis, when aged RR serving RI community had a series of problems

Addressing the associated techno-economics and viability aspects of RI production industry and supply chain logistics

Strengthening cooperation and networking among all the stakeholders in RI-RPh industry and close engagement with NM fraternity

Role of professional bodies such as NM societies and international institutions such as IAEA, NEA-OECD, WHO, in the above context

Nurturing industrial/corporate support for vital “hardware and software,” like robust MC, high-current target system, user-friendly and versatile RPh synthesis modules, superior imaging systems, enriched targets, etc.

NM requires reliable access to RPh, and in turn RI supplies, regularly and frequently, from local or regional or global suppliers (corporates, national centers, others). The associated supply-chain aspects need to be duly addressed for the sustenance of NM services to patients. Given the above, and taking into account the short half-life of the commonly used RI in RPh, it is imperative to build and nurture local and regional capability to produce RI-RPh products. In this context, the scope for entrepreneurship in setting up and operating central radiopharmacies and MC facilities is considered significant. Assessment of techno-economics and viability analysis, and with the involvement of relevant stakeholders, would be important.

Almost all NM-RPh procedures invariably provide functional, physiological, and molecular insights into the diagnosis, staging, restaging, and planning treatment options and assessment of treatment efficacy in patients. It is yet imperative for the NM-RPh community to have consensus-based list(s) of indications for NM, classified on value-level basis, at NM gross-level and specific medical specialty-wise (e.g., cardiology, oncology, neurology, etc.), and the corresponding RPh needed, to ensure harmonious, unequivocal communication with the referral medical fraternity and health-care policymakers. In turn, it will help expanding the use of NM services in already established areas, as well as facilitate seeking/availing adequate resources and support for reliable, safe operations of NM-RPh practices and sustainable practice and delivery of NM services to patients in need.

Need for Objective Classification of Nuclear Medicine - Radiopharmaceuticals Roles and Option of “Value Matrix” Projection

NM-RPh offers “unique value (indispensable role)” in certain specific cases, e.g., radioiodine treatment of metastatic (well-differentiated) thyroid cancer; high-resolution PET/CT imaging to precisely locate cancer metastasis (and plan apt treatment option), e.g., metastasis of NET and of prostate cancer, (using 18F-FDG, 68Ga-ligand-vector conjugates). NM-RPh provides “significant value addition” in many other cases, e.g., myocardial imaging (perfusion using 99mTc products, 82Rb, 13NH3, and viability using 18F-FDG), infection imaging (using 99mTc-leucocytes, 99mTc-UBI, 18F-FDG, 68Ga-UBI), palliative treatment of metastatic bone pain in cancer patients (using 89SrCl2, 153Sm/177Lu-EDTMP). The fast-growing developments of NM-RPh for neurology will soon add entries to the “significant value addition” list, if not to the “unique value list,” Further, NM-RPh plays a “useful value addition” role in other cases like renal studies, HB imaging, etc. The final category comprises all other uses not covered above.

Judicious use of NM-RPh combination will continue to make a crucial difference in patient management through its proven valuable roles in numerous areas, as well as emerging scope to be further harnessed. One can draw a “NM value-matrix” of “utility grading” (namely, unique value, significant value addition, useful role, others) versus “patient volume” (i.e., large, medium, low, and rare cases), covering all the “established and emerging indications” for NM procedure, and the corresponding RPh product(s) in use [Table 1]. This can be updated at periodic intervals, say on biennial frequency. In this context, the professional societies such as Society of Nuclear Medicine, India, the Indian College of Nuclear Medicine (ICNM), Association of NM Physicians of India, NCSI, as the source of authentic information on NM-related matters, and having a mandate to play advisory roles and responsibilities, would be the best placed to provide a platform for informed discussions among relevant stakeholders, especially with the other medical specialty experts.

Table 1

Proposed model for nuclear medicine - radiopharmaceuticals value matrix (to be evolved at two levels, one at gross nuclear medicine level and the second at specialty-wise level, viz. nuclear cardiology, nuclear oncology, etc.,)

A consensus-based NM Value-Matrix thus evolved will portray to every stakeholder and medical policy-maker, unequivocally, the merits of NM-RPh options (also limitations, if any) for serving needy patients. The Indian journal of NM (IJNM) publication can capture this NM Value Matrix as an Annex, say in the issue in even years like 2018, say the issue carrying annual SNMICON abstracts, and after that contain updated versions released every 2nd year. In future, the need is to naturally endeavor for populating more and more of the columns of “unique-value” and “significant value addition” of the NM Value-Matrix, and with widely accessible and sustainable RPh products. The challenge lies in convincing the referral medical fraternity to consider NM-RPh as the first line of procedure in as many areas as applicable (“unique value” list indications), and as a definitive procedure to be included, for all the indications wherein NM brings “significant value addition.” The NM Value-Matrix cited above, to be developed as a consensus-based product under the auspices of the IJNM-ICNM, can be the ideal step forward and is strongly recommended for consideration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.