Long-Term Clinical Studies in the Outpatient Sector—Medullary Carcinoma of the Thyroid as an Example

An editorial to accompany the article: “The Long-Term Cure of Patients With Hereditary Medullary Thyroid Carcinoma: 40 Years of Follow-Up in a Single Center” by Prof. Dr. med. Friedhelm Raue et al. in this issue of Deutsches Ärzteblatt International

In this issue of Deutsches Ärzteblatt, Prof. Friedhelm Raue and Prof. Karin Frank-Raue, together with biometrician Dr. Thomas Bruckner, report in a remarkable long-term study on cure rates of medullary thyroid carcinoma in patients who carry the gene associated with multiple endocrine neoplasia type 2 (MEN2) (1). MEN2 is the association of medullary thyroid carcinoma (MTC) and pheochromocytoma, which was identified in 1961 by John H. Sipple and is linked to other diseases such as primary hyperparathyroidism (2).

40-Year follow-up

Since 1978 (3), the authors have been committed to in scientific research into MEN2, initially at Heidelberg University Hospital, Germany, and later in their own practice (1). During this time, the RET (rearranged during transfection) gene was identified in vitro as a proto-oncogene (4). Starting in 1993, medical research discovered that germline mutations in the RET gene are responsible for the hereditary forms of MTC and that somatic RET mutations cause the majority of sporadic cases of MTC (5, 6, 7).

With the help of these two German scientists, the clinical management of MEN2 has been standardized over the years based on genotype–phenotype correlations, for example in the guideline of the American Thyroid Association (8). The introduction of initially non-selective inhibitors of the tyrosine kinase receptor encoded by RET (9) and the recent availability of selective RET inhibitors have made the concept of personalized treatment for this disease a reality (10).

In their retrospective analysis, Raue et al. classified 277 MEN2 patients according to treatment outcome. To this end, they used a serum calcitonin level of < 10 pg/mL as an indicator of biochemical cure. The identification of affected individuals via family screening and (as a consequence thereof) a low tumor stage at the time of surgery were associated with a significantly higher chance of cure. Thus, the identification of gene mutation carriers and thyroidectomy, which may be performed in infancy depending on the risk of the respective RET genotype, offer the potential for a long-term cure. Calcitonin level at 2–6 months following surgery is highly predictive of long-term cure. The authors also conclude that “that patients with undetectably low serum Ctn levels at 15 years are not expected to experience a recurrence.” Nevertheless, those affected require lifelong follow-up, not least to ensure early diagnosis of the pheochromocytoma development associated with MEN2.

The study presented in this issue of Deutsches Ärzteblatt differs from other publications in two respects: Firstly, there are very few studies—not only on this disease in particular but also in general—with a similarly long period of recruitment of over 40 years and a median follow-up of 15 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) years. Secondly, the study predominantly reports cases that were observed in the outpatient setting of a medical practice and not somewhere like a university center.

The great potential of outpatient research

Thus, this study encourages reflection on the potential of long-term clinical research in the outpatient sector in Germany. Outpatient diagnosis and treatment in Germany largely takes place in medical practices or medical care centers. It is safe to say that this potential has not yet been fully exploited and may not even have been fully recognized.

In contrast to the research conducted by Raue et al., the funding and project times for university medical research rarely exceed a timescale of 3–4 years. Although collaborative research centers allow for the long-term elaboration of research topics, they are generally reserved for basic scientific research. Long-term research projects are also hampered by the university medical center’s own high turnover of scientists, with the resulting interruptions in research topics as well as patient care. Naturally, long-term studies in the outpatient sector are also subject to methodological limitations insofar as patients are lost to follow-up or suitable comparison groups are lacking.

With the now well-advanced digitalization of outpatient care, the time is ripe to conduct retrospective as well as, in particular, prospective clinical registry studies. As the study by Raue et al. shows (1), these are not restricted to healthcare research in terms of topic. Multicenter studies are desirable not only to obtain reliable data on disease prevalence as well as diagnostic and treatment standards and their outcomes but also to identify new scientific problem areas.

In its 2021 “Recommendations on the future role of university hospitals at the interface between the scientific and the healthcare systems,” the German Science and Humanities Council concluded that: “University medical centers are nodes in a trans-regional and national network of health research close to where the care is provided.” It also recommends that “In the coming years, the federal and state governments […] give strategic priority to the networking of medical research through cooperation and coordination in their research and funding policy in the coming years.”

Suitable targeted funding programs for networked research in the outpatient sector, “access to research and information technology infrastructures,” as the German Science and Humanities Council refers to it, uniform standards for the sharing of patient data beyond the future electronic patient file, as well as uniform contractual arrangements for data processing in, for example, disease-specific registries are needed in order to make research in the outpatient sector in Germany a standard.

A successful combination

Creative approaches are needed in order that, ultimately, even biobanks can be incorporated in research projects of this kind, which naturally further increases the organizational and financial requirements. Nevertheless, it seems to me that making it easier to conduct decentralized drug trials—which will at least get started with the German Medical Research Act (Medizinforschungsgesetz, MFG) currently going through the parliamentary process—and outpatient observational studies outside (or not exclusively in) university institutions is an essential factor in promoting Germany as a research location and, in particular, promoting the health of the population. The study by Raue et al. is an excellent example of how the two can be successfully combined.

Conflict of interest statement
MK has received speaker’s fees from Sanofi and Lilly. He received travel grants or congress fee reimbursement from Endoscience GmbH and Lilly. He served as an Advisory Board member at Bayer and Lilly. He is spokesperson of the Advisory Board of the Adrenal Gland, Steroids and Hypertension Department of the German Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie), co-opted board member of the German Working Group of Internal Oncology (Arbeitsgemeinschaft Internistische Onkologie, AIO) of the German Cancer Society (Deutsche Krebsgesellschaft), and co-spokesperson of the AIO’s Endocrine Tumors Working Group.

Manuscript received on 8 September 2024, revised version accepted on 9 September 2024.

Translated from the original German by Christine Rye.

Corresponding author
Prof. Dr. Dr. med. Matthias Kroiß
Medizinische Klinik und Poliklinik IV
Ziemssenstraße 5, 80336 München, Germany

Cite this as:
Kroiss M: Long-term clinical studies in the outpatient sector—medullary carcinoma of the thyroid as an example. Dtsch Arztebl Int 2024; 121: 655–6. DOI: 10.3238/arztebl.m2024.0185

References

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