Veroorzaakt de RAI-behandeling bij de ziekte van Graves kanker?

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Veroorzaakt de RAI-behandeling bij de ziekte van Graves kanker?

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What's the Future Cancer Risk of RAI Treatment?
Re-examining the relationship between dose and response in radioactive iodine treatment
Lisa Jaffe | Endocrineweb

Association of Radioactive Iodine, Antithyroid Drug, and Surgical Treatments With Solid Cancer Mortality in Patients With Hyperthyroidism
Cari M. Kitahara, Dale L. Preston, Julie Ann Sosa, Amy Berrington de Gonzalez
JAMA Netw Open. 2020;3(7):e209660. doi:10.1001/jamanetworkopen.2020.9660

Does radioactive iodine therapy for Graves’ disease cause cancer?
Clinical Thyroidology for the Public

Key Points

Question Are radioactive iodine or antithyroid drug treatments for hyperthyroidism associated with greater risk of solid cancer mortality compared with surgical management?

Findings In this cohort study of 31 363 patients who were cancer free at baseline, no association was found between treatment group (radioactive iodine, medications, and/or surgery) and risk of solid cancer mortality. Among patients receiving radioactive iodine treatment, the association with solid cancer mortality increased with greater total administered activity.

Meaning The findings suggest that the association between radioactive iodine treatment and solid cancer mortality is dose dependent.

Abstract
Importance The long-term health effects of radioactive iodine (RAI) and antithyroid drug (ATD) treatments compared with surgery for hyperthyroidism remain uncertain.

Objective To compare solid cancer mortality rates associated with RAI and ATD treatments vs surgical management for hyperthyroidism.

Design, Setting, and Participants This multicenter cohort study assessed patients treated for hyperthyroidism from January 1, 1946, to December 31, 1964, with follow-up through December 31, 2014. Data analysis was performed from August 1, 2019, to April 23, 2020.

Exposures Management with RAI, ATDs, surgical intervention, or combinations of these treatments.

Main Outcomes and Measures Comparisons of solid cancer mortality rates in each treatment group with expected rates from the general population were assessed using standardized mortality ratios (SMRs), and internal comparisons were assessed using hazard ratios (HRs) adjusted for age, sex, and underlying diagnosis (Graves disease or toxic nodular goiter).

Results Of 31 363 patients (24 894 [79.4%] female; mean [SD] age, 46.9 [14.8] years) included in the study, 28 523 (90.9%) had Graves disease. The median follow-up time was 26.0 years (interquartile range, 12.3-41.9 years). Important differences in patient characteristics existed across treatment groups at study entry. Notably, the drug-only group (3.6% of the cohort) included a higher proportion of patients with prior cancers (7.3% vs 1.9%-4.0%), contributing to an elevated SMR for solid cancer mortality. After excluding prior cancers, solid cancer SMRs were not elevated in any of the treatment groups (SMR for surgery only, 0.82 [95% CI, 0.66-1.00]; SMR for drugs only, 0.90 [95% CI, 0.74-1.09]; SMR for drugs and surgery, 0.88 [95% CI, 0.84-0.94]; SMR for RAI only, 0.90 [95% CI, 0.84-0.96]; SMR for surgery and RAI, 0.66 [95% CI, 0.52-0.85]; SMR for drugs and RAI, 0.94 [95% CI, 0.89-1.00]; and SMR for drugs, surgery, and RAI, 0.85 [95% CI, 0.75-0.96]), and no significant HRs for solid cancer death were observed across treatment groups. Among RAI-treated patients, HRs for solid cancer mortality increased significantly across levels of total administered activity (1.08 per 370 MBq; 95% CI, 1.03-1.13 per 370 MBq); this association was stronger among patients treated with only RAI (HR, 1.19 per 370 MBq; 95% CI, 1.09-1.30 per 370 MBq).

Limitations
This study has limitations. Those not already mentioned include lack of information on some potential confounding factors, such as cigarette smoking, obesity, and reproductive factors21,26; however, we found no association between treatment type (or radiation-absorbed dose to the lung21) and lung cancer mortality, suggesting that a major smoking-related bias did not occur. We lacked laboratory measures of thyroid function to assess severity of the underlying disease. The reliance on cancer mortality, as opposed to incidence, follow-up was another limitation because we could not distinguish between factors associated with cancer development vs survival. In addition, mortality follow-up is not ideal for capturing cancers with high survival rates (eg, thyroid or breast) or for studying cancer subtypes. Findings related to RAI treatment may not be generalizable to patients with thyroid cancer, who typically receive higher administered activities (>3700 MBq) in the context of postsurgical remnant ablation or therapy for presumed or known advanced or metastatic disease, potentially yielding higher or lower doses to individual organs or tissues, depending on the size and location of the residual thyroid tissue.36

Conclusions
This study found positive associations between total administered activity of RAI and risks of death from total solid cancer, female breast cancer, and nonbreast solid cancers. These findings were consistent with earlier results from this cohort based on organ-absorbed doses.21 The low, narrow range of total administered activity and the potential for residual confounding by risk factors not captured in this study may have hindered our ability to detect differences in risk between RAI-treated and non–RAI-treated patients. No evidence supporting an association between ATD treatment and risk of solid cancer death was found in this cohort.
After controlling for known sources of confounding, the study found no significant differences in the risk of solid cancer mortality by treatment group. However, among RAI-treated patients, a modest positive association was observed between total administered activity and solid cancer mortality, providing further evidence in support of a dose-dependent association between RAI and solid cancer mortality.
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Commentaar op ‘Veroorzaakt de RAI-behandeling bij de ziekte van Graves kanker?’

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Commentary/Perspective/Editorial –

There is No Association of Radioactive Iodine Treatment with Cancer Mortality in Patients with Hyperthyroidism
Bennett S. Greenspan, Jeffry A. Siegel, Aamna Hassan and Edward B. Silberstein
Journal of Nuclear Medicine, published on October 4, 2019 as doi:10.2967/jnumed.119.235929

The appropriate use of radioactive iodine therapy in hyperthyroidism has been undermined by the recent paper of Kitahara, et al. in JAMA Internal Medicine, published online on July 1, 2019 (1). The paper is flawed in many ways, and we are writing to refute the claims made by Kitahara et al. This paper uses the same hyperthyroid patient cohort of the original paper by Saenger et al. in 1968 (2), and the follow up paper by Ron et al. in 1998 (3). These two papers (2,3) reviewed the use of I‐131 therapy (RAI [radioactive iodine]) for treatment of hyperthyroidism and compared RAI to treatment with antithyroid drugs (ATDs) and thyroid surgery. The current paper by Kitahara et al. follows this patient cohort for another 24 years and investigates a dose‐risk relationship for these hyperthyroid patients; however, the authors did not compare risk of cancer mortality with RAI to risk of ATD therapy or thyroid surgery.

There was no appropriate control group, a basic methodological error. Also, there was no correction for other more significant risk factors for cancer, especially smoking, which are known to have significant causal relationships with cancer risk, as acknowledged by the authors.

Saenger et al. and Ron et al. (2, 3) both concluded that RAI was a safe treatment for hyperthyroidism and neither found any increase in cancer mortality compared to ATDs and thyroid surgery. In the paper by Ron et al. there was a significant increase in cancer mortality from ATDs compared to RAI (3).

One of the most important issues, the known increase in cancer incidence and cancer mortality in patients with hyperthyroidism (4,5), especially Graves’ Disease, was not considered in the Kitahara paper. Hyperthyroidism itself has a known positive association with an increased risk of thyroid and breast cancer (4), leukemia (2), and colon, lung, prostate, and breast malignancy (5). Saenger et al. reported that the risk of leukemia in hyperthyroid patients was 50% greater than in the US population (2), yet Kitahara et al. calculated no dose‐response relationship at all for leukemia in these patients. This is because they used assumptive model‐based calculations that are likely incorrect and additionally because the causative factor of hyperthyroidism overwhelms the assumed low‐dose contribution to the leukemia risk. Ryodi et al. (6) in a comparison of RAI therapy and thyroid surgery found that “the increased cancer risk in hyperthyroid patients is attributable to hyperthyroidism and shared risk factors, not the treatment modality.”

Much more importantly, a very recent publication (7) by two of the coauthors of Kitahara et al. is now contradicting their findings: “The overall perception of death from cancer risk associated with I‐131 is inflated and not supported by evidence. As co‐authors of this article, we offer previously unpublished data and analysis that 1) disputes clinical significance of the associated risk from I‐131 and 2) shows, again, that antithyroid drugs carry a statistically significant and a much more obvious cancer death risk.”

And “In conclusion, the Kitahara et al. publication provides a numerical estimate of excess cancer deaths after RAIT using assumptive model‐based calculations. No excess cancer deaths were actually observed after I‐131 treatment relative to that predicted in contemporaneous population (using SMR analyses). In contrast, ATD treatment is strongly associated with the excess cancer deaths in TTFUS [Cooperative Thyrotoxicosis Follow Up Study (Saenger (2)]. Due to the article's sole focus on the hypothetical and very doubtful I‐131‐associated cancer risks, it completely missed the highly statistically and clinically significant ATD‐associated cancer risks that begs for immediate attention.”

There is no effect at all below an exposure of 0.1 Gy (10 rad), as shown in their own graph (Figure B). Results above 0.1 Gy to 0.5 Gy (10‐50 rad) show no dose response. It is reported that an exposure to the stomach of 0.17 Gy (17 [+/‐ 18] rad) causes an increase in all solid cancer mortality, but that inexplicably exposure to the esophagus of 1.60 Gy (160 [+/‐ 150] rad), 10 times as much, does not cause an increase in solid cancer mortality. Interestingly, there is no statistically significant increase in leukemia. The incidence of cancer mortality noted in the patients treated with RAI, 15.3%, is actually substantially less than that in the general US population of 20‐25% (8). In light of the known increased cancer mortality due to hyperthyroidism, this result of only 15.3% is notable in being so small. As stated by Giovanella and Verburg, “In fact, as in spite of nearly 8 decades of radioiodine therapy, no study has yet been able to prove the latter hypothesis” [a relationship between radioiodine therapy for hyperthyroidism and cancer mortality] (9,10).

Dose modeling was used instead of actual dose assessment, and these dose estimates have very large error bars. Using these dose estimates to correlate with patient risk, estimated using an assumed, but not supported, linear model is problematic. The linear no‐threshold dose‐risk model is simply assumed; this is known to be inaccurate (11) and is not even supported by the reported data. As mentioned above, the data shown in Figure 1B in this paper do not indicate a linear dose‐response relationship for breast cancer, even though this relationship is reported to be statistically significant. Thus, the authors have attempted to find a dose‐risk relationship even though both the assumed doses and risks are likely highly inaccurate. Therefore, the authors’ assumption that association is related to causation and other conclusions have little basis in reality (12).

Most of the doses reported in this paper are very low and have not been previously shown to cause an increase in cancer mortality. The breast exposure of 15 rad would not be expected to cause an increase in cancer incidence or mortality.

The conclusion of the Kitahara paper, “In RAI‐treated patients with hyperthyroidism, greater absorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer” is not justified by the data, as indicated by Tulchinsky (7). This lack of justification is further supported by the findings of a previous article by the Kitahara group analyzing a different cohort of individuals (13) as noted by Giovanella and Verburg (10), that indicate increased breast cancer mortality in women with hyperthyroidism over 60 years of age, but no effect of RAI on this association.

In summary, major flaws of this paper include:
1) poorly characterized dose estimates that were not directly measured and therefore have enormous and unknown uncertainties;
2) an analysis that does not even support the paper’s conclusion that there is an association between RAI therapy and increased cancer mortality ‐ there is no effect below 0.1 Gy (10 rad), and no dose response up to 0.5 Gy (50 rad);
3) the estimated doses are too low to expect increased cancer incidence or mortality;
4) since the relative risks are likely inaccurate, comparing them to the assumed and not directly measured doses is meaningless, especially since there are other known causative factors that are much more important contributors to cancer risk;
5) the known increase in cancer mortality associated with hyperthyroidism was not considered,
6) the greater cancer mortality of ATD therapy compared to I‐131 therapy was ignored, and
7) the assumption that a mild association indicates causation is unsupported.

The real harm of this paper is that clinicians may decline to use I‐131 therapy for the treatment of hyperthyroidism, in the belief that they are protecting their patients from cancer. In reality, aside from the fact that no evidence is presented of cancer risk at low doses, the use of ATDs will actually increase cancer incidence and mortality, in addition to the other problems with ATDs, including hepatic toxicity and agranulocytosis.

Based on the major flaws discussed above, and the major harm to clinical practice we anticipate, we suggest the readers submit a rebuttal paper to JAMA Internal Medicine.

References
1. Kitahara CM, Berrington de Gonzalez A, Bouville A, et al, Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism. JAMA Internal Medicine. published online July 1, 2019. doi: 10/1001/jamainternmed.2019.0981.
2. Saenger EL, Thoma GE, Tompkins EA. Incidence of leukemia following treatment of hyperthyroidism. Preliminary report of the Cooperative Thyrotoxicosis Therapy Follow‐Up Study. JAMA. 1968 Sept 16; 205(12):855‐862.
3. Ron E, Doody MM, Becker AB, et al, Cancer Mortality Following Treatment for Adult Hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow‐up Study Group. JAMA. 1998 Jul 22‐29; 280(4):347‐355.
4. Chen Y‐K, Lin CL, Chang YJ, et al, Cancer Risk in Patients with Graves’ Disease: A Nationwide Cohort Study. Thyroid. 2013 Jul; 23(7):879‐884. doi: 10.1089/thy.2012.0568.
5. Moeller LC and Fuhrer D. Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer. 2013;20(2):R19‐29.
6. Ryodi E, Metso S, Jaatinen P, et al. Cancer Incidence and Mortality in Patients Treated With RAI or Thyroidectomy for Hyperthyroidism. J Clin Endocrinol Metab. 2015 Oct;100(10):3710‐3717. doi: 10.1210/jc.2015‐1874. Epub 2015 Aug 11.
7. Tulchinsky M, Brill AB. Spotlight on the Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism Is Keeping the Highest Risk from Antithyroid Drugs in the Blind Spot. Clin Nucl Med 2019 Aug 22. doi: 10.1097/RLU.0000000000002792. [Epub ahead
of print]
8. National Research Council of the National Academies. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII. Washington DC: The National Academies Press; 2006.
9. Verburg FA, Luster M, Lassman M, and Reiners C. (131)I therapy in patients with benign thyroid disease does not conclusively lead to a higher risk of subsequent malignancies. Nuklearmedizin. 2011;50(3):93‐99. doi: 10.3413/Nukmed‐0341‐10‐08. Epub 2010 Dec 17.
10. Giovanella L, Verburg FA. Use of anti‐thyroid drugs in patients with hyperthyroidism: a case for shared decision‐making. Eur J Nucl Med Mol Imaging. 2019 Aug 9. doi: 10:1007/s00259‐019‐04476‐4. [Epub ahead of print]
11. Siegel JA, Brooks AL, Fisher DR, et al, A Critical Assessment of the Linear No‐Threshold Hypothesis: Its Validity and Applicability for Use in Risk Assessment and Radiation Protection. Clin Nucl Med 2019 Jul;44(7):521‐525. doi: 10.1097/RLU.0000000000002613.
12. Grady E, Zukotynski K, and Greenspan BS. Response to Kitahara. JAMA Int Med. in press.
13. Journy NMY, Bernier MO, Doody MM, Alexander BH, Linet MS, Kitahara CM. Hyperthyroidism, Hypothyroidism, and Cause‐Specific Mortality in a Large Cohort of Women. Thyroid. 2017 Aug:27(8):1001‐1010. doi: 10.1089/thy.2017.0063. Epub 2017 Jul 6.

Bennett S. Greenspan, MD, MS
150 River Club Lane
North Augusta, SC 29841
bengreenspan0708@gmail.com

Jeffry A. Siegel, MS, MS, PhD
President & CEO
Nuclear Physics Enterprises
2701 Wild Tamarind Blvd.
Orlando, FL 32828
nukephysics@comcast.net

Aamna Hassan, MD
Consultant nuclear physician
Shaukat Khanum memorial cancer Hospital and research center,
Lahore, 54000 Pakistan
Email: aamna1@hotmail.com

Edward B. Silberstein, MA, MD
Eugene L. and Sue R. Saenger Professor
of Radiological Health and Medicine, Emeritus
G026 Mont Reid Pavilion
University of Cincinnati Medical Center
234 Goodman St.
Cincinnati, OH 45219
silbereb@uc.edu
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Vertaling commentaar op ‘Veroorzaakt de RAI-behandeling bij de ziekte van Graves kanker?’

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Raadpleeg de in het artikel genoemde bronnen met: http://jnm.snmjournals.org/content/60/1 ... fc7d3f0444

Het juiste gebruik van radioactieve jodiumtherapie bij hyperthyreoïdie is ondermijnd door het recente artikel van Kitahara, et al. in JAMA Internal Medicine, online gepubliceerd op 1 juli 2019 (1). Het papier is op veel manieren gebrekkig, en we schrijven om de beweringen van Kitahara et al te weerleggen. Dit artikel maakt gebruik van hetzelfde hyperthyroïde patiëntencohort als het originele artikel van Saenger et al. in 1968 (2), en het vervolgdocument van Ron et al. in 1998 (3). Deze twee artikelen (2,3) bespraken het gebruik van I-131-therapie (RAI [radioactief jodium]) voor de behandeling van hyperthyreoïdie en vergeleken RAI met behandeling met antithyroid-medicatie (ATD's) en schildklieroperaties. Het huidige artikel van Kitahara et al. volgt dit patiëntencohort nog eens 24 jaar en onderzoekt een dosis-risicoverhouding voor deze hyperthyreoïde patiënten; de auteurs hebben het risico op kankersterfte met RAI echter niet vergeleken met het risico op ATD-therapie of schildklieroperaties.

Er was geen geschikte controlegroep, een fundamentele methodologische fout. Ook was er geen correctie voor andere, meer significante risicofactoren voor kanker, met name roken, waarvan bekend is dat ze een significant oorzakelijk verband hebben met het risico op kanker, zoals erkend door de auteurs.

Saenger et al. en Ron et al. (2, 3) concludeerden beiden dat RAI een veilige behandeling was voor hyperthyreoïdie en geen van beide vonden een toename in kankersterfte in vergelijking met ATD's en schildklieroperaties. In het artikel van Ron et al. er was een significante toename in kankersterfte door ATD's in vergelijking met RAI (3).

Een van de belangrijkste problemen, de bekende toename van de incidentie van kanker en kankersterfte bij patiënten met hyperthyreoïdie (4,5), met name de ziekte van Graves, werd niet in het document van Kitahara besproken. Hyperthyreoïdie zelf heeft een bekende positieve associatie met een verhoogd risico op schildklier- en borstkanker (4), leukemie (2), en colon-, long-, prostaat- en borstkanker (5). Saenger et al. meldde dat het risico op leukemie bij hyperthyreoïdie-patiënten 50% groter was dan bij de Amerikaanse bevolking (2), maar Kitahara et al. berekende helemaal geen dosis-responsrelatie voor leukemie bij deze patiënten. Dit komt omdat ze veronderstelde, op modellen gebaseerde berekeningen hebben gebruikt die waarschijnlijk onjuist zijn en bovendien omdat de oorzakelijke factor van hyperthyreoïdie de veronderstelde lage dosisbijdrage aan het leukemierisico te boven gaat. Ryodi et al. (6) in een vergelijking van RAI-therapie en schildklierchirurgie bleek dat "het verhoogde kankerrisico bij hyperthyreoïdiepatiënten toe te schrijven is aan hyperthyreoïdie en gedeelde risicofactoren, niet aan de behandelingsmodaliteit."

Veel belangrijker is dat een zeer recente publicatie (7) van twee van de co-auteurs van Kitahara et al. is nu in tegenspraak met hun bevindingen: “De algemene perceptie van overlijden door kankerrisico in verband met I-131 is opgeblazen en wordt niet ondersteund door bewijs. Als co-auteurs van dit artikel bieden we eerder niet-gepubliceerde gegevens en analyses die 1) de klinische significantie van het bijbehorende risico van I-131 betwisten en 2) nogmaals aantonen dat antithyroid-geneesmiddelen een statistisch significant en veel duidelijker kankersterfte met zich meebrengen risico."

En “Tot slot, de Kitahara et al. publicatie geeft een numerieke schatting van het aantal sterfgevallen door kanker na RAIT met behulp van veronderstelde, modelgebaseerde berekeningen. Er werden geen extra sterfgevallen door kanker waargenomen na I-131-behandeling in vergelijking met wat voorspeld werd in de huidige populatie (met behulp van SMR-analyses). Daarentegen is ATD-behandeling sterk geassocieerd met de extra sterfgevallen door kanker in TTFUS [Cooperative Thyrotoxicosis Follow Up Study (Saenger (2)]). Omdat het artikel zich uitsluitend richt op de hypothetische en zeer twijfelachtige I-131-geassocieerde kankerrisico's, miste de zeer statistisch en klinisch significante ATD-geassocieerde kankerrisico's die om onmiddellijke aandacht vragen. "

Er is helemaal geen effect onder een blootstelling van 0,1 Gy (10 rad), zoals te zien is in hun eigen grafiek (figuur B). Resultaten boven 0,1 Gy tot 0,5 Gy (10-50 rad) laten geen dosisrespons zien. Er wordt gemeld dat een blootstelling aan de maag van 0,17 Gy (17 [+/- 18] rad) een toename van alle sterfte aan vaste kanker veroorzaakt, maar dat de blootstelling aan de slokdarm op onverklaarbare wijze 1,60 Gy (160 [+/- 150] rad) ), 10 keer zoveel, veroorzaakt geen toename van de sterfte aan vaste kanker. Interessant genoeg is er geen statistisch significante toename van leukemie. De incidentie van sterfte aan kanker bij de patiënten die met RAI werden behandeld, 15,3%, is feitelijk aanzienlijk lager dan bij de algemene Amerikaanse bevolking van 20-25% (8). In het licht van de bekende verhoogde sterfte aan kanker als gevolg van hyperthyreoïdie, valt dit resultaat van slechts 15,3% op omdat het zo klein is. Zoals Giovanella en Verburg stellen: "In feite, zoals ondanks bijna 8 decennia van radioactief jodiumtherapie, heeft nog geen enkele studie de laatste hypothese kunnen bewijzen" [een verband tussen radioactief jodiumtherapie voor hyperthyreoïdie en kankersterfte] (9,10 ).

Dosismodellering werd gebruikt in plaats van de werkelijke dosisbeoordeling, en deze dosisschattingen hebben zeer grote foutbalken. Het gebruik van deze dosisschattingen om te correleren met het risico voor de patiënt, geschat met behulp van een verondersteld, maar niet ondersteund, lineair model is problematisch. Er wordt eenvoudigweg uitgegaan van het lineaire dosisrisicomodel zonder drempelwaarde; dit is bekend onnauwkeurig te zijn (11) en wordt zelfs niet ondersteund door de gerapporteerde gegevens. Zoals hierboven vermeld, duiden de gegevens in figuur 1B in dit artikel niet op een lineaire dosis-responsrelatie voor borstkanker, ook al wordt gerapporteerd dat deze relatie statistisch significant is. De auteurs hebben dus geprobeerd een dosis-risico-relatie te vinden, ook al zijn zowel de aangenomen doses als de risico's waarschijnlijk zeer onnauwkeurig. Daarom hebben de veronderstellingen van de auteurs dat associatie verband houdt met oorzakelijk verband en andere conclusies in werkelijkheid weinig basis (12).

De meeste doses die in dit artikel worden vermeld, zijn erg laag en er is niet eerder aangetoond dat ze een toename van de sterfte aan kanker veroorzaken. De blootstelling aan de borsten van 15 rad zou naar verwachting geen toename van de incidentie of mortaliteit van kanker veroorzaken.

De conclusie van het Kitahara-document: "Bij RAI-behandelde patiënten met hyperthyreoïdie leken grotere geabsorbeerde doses een bescheiden positief verband te houden met het risico op overlijden door vaste kanker, waaronder borstkanker", wordt niet gerechtvaardigd door de gegevens, zoals aangegeven door Tulchinsky (7 ). Dit gebrek aan rechtvaardiging wordt verder ondersteund door de bevindingen van een eerder artikel van de Kitahara-groep die een ander cohort van individuen analyseert (13), zoals opgemerkt door Giovanella en Verburg (10), die wijzen op een verhoogde sterfte aan borstkanker bij vrouwen met hyperthyreoïdie gedurende 60 jaar. leeftijd, maar geen effect van RAI op deze associatie.

Samengevat zijn de belangrijkste tekortkomingen van dit artikel:
1) slecht gekarakteriseerde dosisschattingen die niet direct werden gemeten en daarom enorme en onbekende onzekerheden hebben;
2) een analyse die niet eens de conclusie van de paper ondersteunt dat er een verband bestaat tussen RAI-therapie en verhoogde kankersterfte - er is geen effect onder 0,1 Gy (10 rad) en geen dosisrespons tot 0,5 Gy (50 rad);
3) de geschatte doses zijn te laag om een verhoogde incidentie of mortaliteit van kanker te verwachten;
4) aangezien de relatieve risico's waarschijnlijk onnauwkeurig zijn, is het zinloos om ze te vergelijken met de veronderstelde en niet direct gemeten doses, vooral omdat er andere bekende oorzakelijke factoren zijn die veel belangrijker bijdragen aan het kankerrisico;
5) er werd geen rekening gehouden met de bekende toename van sterfte aan kanker geassocieerd met hyperthyreoïdie,
6) de grotere kankersterfte van ATD-therapie in vergelijking met I-131-therapie werd genegeerd, en
7) de aanname dat een milde associatie wijst op een causaal verband wordt niet ondersteund.

Het echte nadeel van dit artikel is dat clinici mogelijk weigeren I-131-therapie te gebruiken voor de behandeling van hyperthyreoïdie, in de overtuiging dat ze hun patiënten tegen kanker beschermen. In werkelijkheid, afgezien van het feit dat er geen bewijs wordt geleverd voor het risico op kanker bij lage doses, zal het gebruik van ATD's de incidentie en mortaliteit van kanker zelfs verhogen, naast de andere problemen met ATD's, waaronder hepatische toxiciteit en agranulocytose.

Op basis van de belangrijkste tekortkomingen die hierboven zijn besproken en de grote schade aan de klinische praktijk die we verwachten, raden we de lezers aan een weerleggingsdocument in te dienen bij JAMA Internal Medicine.
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Geen extra kans op kanker na behandeling met radioactief jodium

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No Excess Cancer Risk from Radioactive Iodine Treatment in Hyperthyroidism
Katherine Wandersee | Endocrineweb

Artikel Cari Kitahara: https://schildkliertje.blogspot.com/202 ... ij-de.html
Arikel Naomi Gronich: https://schildkliertje.blogspot.com/202 ... nlijk.html

Despite conflicting findings, new data refuting any discernible link between increased risk of all cancers gains the endorsement of endocrine community. Concerns about whether radioiodine (radioactive iodine, RAI) treatment for hyperthyroidism confers an increased risk of cancer persist given results of recent large-scale studies that have yielded conflicting results.

Findings from a large-scale cohort study on this topic by a team of Israeli researchers (Naomi Gronich et al), and published in the journal Thyroid, may offer a clearer answer for your patients. The authors found no significant associations between radioiodine treatment and increased risk of overall cancer.

Latest study refutes worries of increase cancer risk with RAI treatment for hyperthyroidism.

No Link Evident from Radioactive Iodine for Hyperthyroidism and Future Risk of Cancer

After evaluating data gathered from more than 16,000 patients in the Clalit healthcare database encompassing 123,166 person‐years of follow‐up, Gronich et al reported no increased risk among individuals with thyroid disease who received RAI as compared with those who received other forms of treatment for overactive thyroid disease. This is a substantial population-based study as the database represents more than half of the Israeli population.

All adults identified with a new diagnosis of hyperthyroidism between 2002 and 2015 who were treated with RAI or thionamides (propylthiouracil, thiamazole) were included in the analysis whereas patients with prior history of cancer were excluded, according to lead author Naomi Gronich, MD, assistant professor of clinical pharmacology and internal medicine at Lady Davis Carmel Medical Center in Haifa, Israel.

Among the participants, about one in five (21%) presented with obesity and 13% had a diagnosis of type 2 diabetes (13%) but those factors were not evaluated as risk factors for cancer in this study, Dr. Gronich told EndocrineWeb.

Solid Study Refutes Increased Cancer Risk with RAI Therapy

The results stand in stark contrast to those of another cohort study (Cari Kitahara), published in JAMA Internal Medicine, in which the authors reported: "greater organ-absorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer."

This second study was a multicenter, 24-year extension of the data from the Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFS), involving 18,805 patients (mean age at study 49 years; 78% women; 93.7% had Graves’ disease; 34.1% had multiple RAI treatments.

The authors concluded that, for every 1,000 patients treated with RAI at the age of 50, an estimated lifetime excess of 18 to 31 solid cancer deaths would occur (including 4 to 6 breast cancers), most occurring more than 20 years after treatment with radioactive iodine.

"Greater organ-absorbed doses appear to be modestly positively associated with risk of death from solid cancer," according to Cari M. Kitahara, PhD, MHS, and colleagues.

For patients with hyperthyroidism who opt for radioiodine treatment, the risk of developing cancer is ''very low," according to the study findings.

Endocrine Society Calls Cancer Scare "Unjustified"

Findings from the CTTFS sparked renewed concerns in the endocrinologist community and among patients, promoting an editorial, "Association of Radioactive Iodine Treatment of Hyperthyroidism with Cancer Mortality: An Unjustified Warning?"

This commentary was published in the Endocrine Society's Journal of Endocrinology and Metabolism, to call attention to significant design flaws in the Kitahara-led study:

- The analysis assessed whether greater absorbed RAI doses to specific organs were associated with increased mortality risk from specific cancers, with the dose to the stomach used arbitrarily as the reference.
- CTTFS included patients treated between 1946 and 1964 with follow-up after 1968, and many patients were lost to follow-up.
- The study was initially designed to compare cancer risk between RAI-treated patients and those treated differently. An original report of the CTTFS data (mean 21-year follow-up) concluded that RAI was not linked to cancer deaths (except thyroid cancer, with the underlying thyroid disease appearing to play a role). In this early analysis, increased risk of breast and lung cancer were found in patients treated with surgery but not in those treated with RAI.

Comparing the CTTFS study design with that of study conducted by the Israeli team, the senior author of the editorial, endocrinologist Anca M. Avram, MD, professor of radiology, and director of the Nuclear Medicine Therapy Clinic at the University of Michigan in Ann Arbor, told EndocrineWeb:

"The CTTFS study used data collected in the 1960s, when even smoking was not a known confounder of cancer risk. While Gronich reported on actual observed cancer rates, Kitahara's findings were based on a hypothetical model and derived cancer mortality," she said.

"Conversely, the Gronich paper is performed with adjustment for multiple variables and confounders, using modern data collection, and thus is a much better basis for discussions of cancer risks following radioiodine therapy."

In addition, Dr. Avram called attention to three previous studies, all concluding that RAI does not contribute to increased cancer risk.

Is the Univariate Analysis Finding of Lymphoma Risk Important?

In the Israeli-based study, the univariate analysis identified a small association between radioactive iodine and non-Hodgkin lymphoma (NHL) but this was not seen in the multivariable analysis.

"The univariate analysis is always flawed in a retrospective clinical observational study, because there is never just one variable and always confounders. On that basis, the lymphoma finding is not significant," Dr. Avram told EndocrineWeb since a statistical (Bonferroni) adjustment is needed to analyze the findings of a univariate analysis among 20 cancer types (requiring a P value of < 0.0025 to gain statistical significance).

"There is no significant risk after Bonferroni adjustment even for the univariant P value. Endocrinologists should not make any clinical decisions based on this insignificant mention," said Dr. Avram. In fact, in the Israeli population prior use of thionamides was associated with higher mortality rates than RAI treatment using both the univariate and multivariable Cox proportional hazards models.1

Clinical Implications, Management of Hyperthyroidism

Dr. Avram added that the article by Kitahara et al "has the potential to influence clinical choices and cause unwarranted distress," in patients receiving RAI for hyperthyroidism.

For worried patients, here's a consumer-focused article on RAI.

A concern that patients may reject the use of RAI therapy as the preferred treatment to manage hyperthyroidism, prompted a statement from the British Thyroid Association, in which the authors concluded: "...it would be unfortunate if patients were deprived of the option of rapid, effective control of their hyperthyroidism with radioiodine due to concerns of cancer risk." This is in line with guidelines for treating hyperthyroidism issued by the American Thyroid Association

"Current evidence shows no excess cancer risk, [so] it would be reasonable to continue with current approaches to the management of hyperthyroidism," Both the British statement and the Endocrine Society's statement encourage further study on this subject to help settle the debate of radioactive iodine and cancer risk.

For patients with hyperthyroidism getting the radioiodine treatment, the study suggests that the cancer risk is ''very low."

These results [of the Gronich-led study are reassuring, said Bryan Haugen, MD, FACP, professor of medicine and pathology and head of the division of endocrinology, University of Colorado School of Medicine in Aurora, who reviewed the study for EndocrineWeb but was not involved in the research.

None of the cited authors had any financial conflicts with regard to this work.
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Re: Veroorzaakt de RAI-behandeling bij de ziekte van Graves kanker?

Bericht door laura »

Joint statement from the Society for Endocrinology and the British Thyroid Association regarding ‘Association of Radioactive Iodine Treatment with cancer mortality in patients with hyperthyroidism’
Peter N. Taylor Onyebuchi E. Okosieme Krishna Chatterjee Kristien Boelaert
On behalf of the Executive Committees of the Society for Endocrinology and the British Thyroid Association
First published: 01 December 2019 https://doi.org/10.1111/cen.14136 Citations: 5

We are aware of the substantial interest shown in the recent publication in JAMA internal medicine by Kitahara et al1 This retrospective analysis of data from the large multicentre co‐operative thyrotoxicosis therapy follow‐up study (CTTFUS) suggests a modest increase in potential risk of death from cancer in people who receive radioiodine therapy for hyperthyroidism. These findings have obviously raised considerable concern as radioiodine is one of the key treatment options in hyperthyroidism, particularly in those who relapse or have disease that is difficult to control. Experience with radioiodine is longstanding, and it is a widely used treatment modality for hyperthyroidism. The conclusion in this paper that ‘in RAI‐treated patients with hyperthyroidism, greater organ‐absorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer’ has naturally caused anxiety for both patients and clinicians. Whilst the work in the study is innovative and detailed, the Society for Endocrinology (SFE) and the British Thyroid Association (BTA) are concerned that the conclusion will need to be interpreted cautiously for the following reasons.

There was no control cohort with hyperthyroidism in this study. This is a substantial limitation of the study. It is not clear why patients with hyperthyroidism who did not receive radioiodine were not used as controls since these data are available in the CTTFUS cohort. The lack of a hyperthyroidism control group makes it difficult to ascertain whether the increase in cancer risk is a consequence of hyperthyroidism and poor disease control or of radioiodine per se. This is important, as several previous analyses of large data sets which used a control group did not find increased risk of secondary cancers from radioiodine.2 Furthermore, a further analysis of the CTTFUS data set by two of the study co‐authors has shown no excess cancer mortality attributable to radioiodine whereas an increased risk of solid cancer deaths was observed in hyperthyroid patients who were not treated with radioiodine or surgery.3 This discrepancy with findings of the original study is a cause for concern and calls for a more detailed evaluation of cancer risks in the entire CTTFUS cohort.

The model used to calculate the absorbed radioiodine dose is novel but not validated. A complex mathematical model has been used to estimate the absorbed radioiodine dose, based on a series of assumptions on thyroid gland weight and radioiodine uptake in a small preliminary sample of patients. The biokinetic model was calibrated from 197 patients with hyperthyroidism who underwent serial iodine‐131 measurements in the thyroid, blood and urine.4 The model was applied to each patient in the cohort using their Iodine‐131 thyroid uptake, thyroid gland weight and administered radioiodine dose in multivariable regression equations to calculate the number of Iodine‐131 disintegrations in source organs. Following this, reference standards were then used to estimate the mean absorbed organ dose from the Iodine‐131 disintegrations.4 However, the validity of the model has been questioned due to the wide error margins incurred in the estimates and the assumptions required of the thyroid gland weight and uptake measures.3, 5 These assumptions leave significant uncertainties in organ dose exposure, and whilst impressive, the model will need to be replicated and further validated.

In the analysis, important confounders such as smoking and obesity have not been considered. The analysis did not correct for a number of important confounders for cancer risk including smoking, obesity, alcohol intake and biochemical disease severity. Smoking is an important cause of cancer mortality, and amongst patients with Graves' disease, smokers have a higher risk of drug treatment relapse6, 7 and are more likely to receive radioiodine. Hyperthyroidism in itself is associated with an increased risk of death8 and an increased risk of breast cancer occurrence and mortality.9-11 Without correcting for these factors, it becomes problematic to attribute mortality to the effects of radioiodine. The failure to account for these confounders is likely due to the nature of the data set used, but it remains an important limitation which should warrant further caution in the interpretation of data and conclusions.

Excess solid cancer risk is not seen following administration of substantially higher doses of radioiodine to patients with thyroid cancer. Studies in radioiodine‐treated thyroid cancer patients show development of secondary cancers when the administered cumulative iodine‐131 activity is in ranges of 7400‐1400 MBq.12 A recent updated metanalysis showed no increased risk of second malignancies at the usual doses administered to thyroid cancer patients (mean iodine‐131 activity varied from 3700 to 5500 MBq).13 A small risk of leukaemia was observed at these doses but there was no significant increase in the occurrence of breast cancer or other solid malignancies.13 A causative role for radioiodine in the study by Kitahara et al thus seems unlikely given that excess risk was only observed for solid malignancies in their study, and the mean administered radioiodine activity (375 MBq for Graves' disease and 488 MBq for toxic nodules) was only about 10% of those administered to thyroid cancer patients. This argues against a dose‐response association and makes a causal role for radioiodine less plausible according to criteria for causation set by Bradford Hill.14
Whilst statistically significant, the magnitude of observed effects in this study is modest. The risks observed were marginal, with an estimated relative risk of 1.06, 95% confidence interval, 1.02‐1.10, for total solid cancer mortality. Thus, given the uncertainties in the radioiodine dose estimates, the potential for unexplored confounding by indication, and the lack of patient control groups, these marginal risks will need to be interpreted with caution.

Recent observations have shown the importance of achieving good control of hyperthyroidism in a timely fashion to improve long‐term cardiovascular and mortality outcomes.15, 16 In this context, it would be unfortunate if patients were deprived of the option of rapid, effective control of their hyperthyroidism with radioiodine, due to concerns of cancer risk. Overall, on the basis that current evidence shows no excess cancer risk, it would be reasonable to continue with current approaches to the management of hyperthyroidism, whilst further, appropriately controlled studies are undertaken. We believe that long‐term monitoring of outcomes, including cancer mortality risk, is essential for patients who have undergone radioiodine therapy. We endorse and would actively support efforts to construct large national databases of radioiodine‐treated hyperthyroid patients to assess such outcomes.
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Re: Veroorzaakt de RAI-behandeling bij de ziekte van Graves kanker?

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Should radioiodine now be first line treatment for Graves’ disease?
Onyebuchi E. Okosieme, Peter N. Taylor & Colin M. Dayan
Thyroid Research volume 13, Article number: 3 (2020) Cite this article

Abstract

Background

Radioiodine represents a cost-effective treatment option for Graves’ disease. In the UK, it is traditionally reserved for patients who relapse after initial thionamide therapy. In a change from current practice, the new guidelines of the National Institute for Health and Care Excellence (NICE) recommends that radioiodine should now be first line therapy for Graves’ disease. However, the safety of radioiodine with respect to long-term mortality risk has been the subject of recent debate. This analysis examines evidence from treatment related mortality studies in hyperthyroidism and discusses their implications for future Graves’ disease treatment strategies.

Main body

Some studies have suggested an excess mortality in radioiodine treated cohorts compared to the background population. In particular, a recent observational study reported a modest increase in cancer-related mortality in hyperthyroid patients exposed to radioiodine. The interpretation of these studies is however constrained by study designs that lacked thionamide control groups or information on thyroid status and so could not distinguish the effect of treatment from disease. Two studies have shown survival advantages of radioiodine over thionamide therapy, but these benefits were only seen when radioiodine was successful in controlling hyperthyroidism. Notably, increased mortality was associated with uncontrolled hyperthyroidism irrespective of therapy modality.

Conclusions

Early radioiodine treatment will potentially reduce mortality and should be offered to patients with severe disease. However, thionamides are still suitable for patients with milder disease, contraindications to radioiodine, or individuals who choose to avoid permanent hypothyroidism. Ultimately, a patient individualised approach that prioritises early and sustained control of hyperthyroidism will improve long-term outcomes regardless of the therapy modality used.

Background

The choice of primary therapy in Graves’ disease is one of the more contentious issues in clinical thyroidology. Three well established therapies, namely antithyroid drugs, radioiodine, and thyroidectomy have been available for decades, and their efficacy and limitations are well recognised (Table 1) [1, 2]. Thionamide drugs offer the prospect of remission without the need for lifelong thyroid hormone replacement but only about 45% of patients achieve long-term remission [3]. Ablative treatment with radioiodine or thyroidectomy result in better cure rates and overcome the risk of non-compliance with thionamides, but both treatments incur the need for permanent levothyroxine therapy [1, 2]. Thyroidectomy also carries risks of permanent hypoparathyroidism and laryngeal nerve damage while radioiodine may aggravate orbitopathy and entails exposure to radioisotopes which is unsuitable for young children, pregnant women, or patients planning pregnancy [1, 2]. In practical terms radioiodine has the added advantage that it is administered in a single outpatient visit without the risks and overheads of surgery.

Conclusions

The controversy surrounding Graves’ disease management is likely to continue, but the emphasis must now move away from binary positions on treatment modality and seek pragmatic strategies to optimise the safety, efficiency, and outcomes of existing therapies. Regardless of therapy modality, a treatment approach that prioritises early control of hyperthyroidism will ultimately improve long-term outcomes. The challenge for clinicians will be to identify which patients will respond to thionamides and can be spared ablation and lifelong levothyroxine. A number of useful clinical scores for predicting thionamide response are in use [33, 34], but these scores will require further refinement and validation. Although randomised controlled trials with long-term mortality endpoints are now increasingly unlikely, further observational studies are needed to clarify the safety of radioiodine. Such studies will require thoughtful designs to avoid the usual traps of non-randomised data such as confounding by indication, lack of appropriate comparative groups, and bias from uneven treatment time exposures. Lastly, long-term quality of life studies will be essential to understand the impact of therapy on lifelong well-being.
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