Problematic clinical trials in thyroid cancer: the issue ... - Future Medicine

PERSPECTIVE For reprint orders, please contact: [email protected]

Problematic clinical trials in thyroid cancer: the issue of papillary carcinoma and observational approaches M Sara Rosenthal*,1, Kenneth B Ain2, Peter Angelos3, Ryoko Hatanaka4,5 & Masaru Motojima6 We describe the clinical ethics problem of American thyroid cancer patients being offered ‘observation’ instead of the USA standard of care with questionable informed consent. This problem arose because some American practitioners misinterpreted 1990s Japanese studies. American proponents of these studies failed to recognize major differences in ethical oversight between Japanese and US clinical research, misrepresenting these studies as justifying clinical practices for higher risk patients that were not supported by data. The current professional environment in American thyroid cancer management is sufficiently problematic that consideration should be made, for patients who have inadvertently consented to nonevidence-based treatments, to be recontacted and provided an opportunity to revisit their care plans or seek second opinions regarding an observational approach. First draft submitted: 31 March 2017; Accepted for publication: 31 August 2017; Published online: 20 October 2017 Background Thyroid cancer occurs in both adults and children and is rising in incidence. It currently represents just under 4% of all newly diagnosed malignancies in the USA [1] . There are several types of thyroid cancer. Most respond well to therapy when diagnosed and treated optimally; known as well-differentiated thyroid cancer (WDTC; the term ‘differentiated’ indicating that the cancer cells have functional properties similar to normal thyroid cells, such as the ability to take up iodine, enabling radioactive iodine to be used for treatment and diagnostic scanning). Some types are far more aggressive with poor prognoses and without definitive curative treatments (known as poorly differentiated thyroid cancer). The most lethal type of thyroid cancer is known as anaplastic thyroid cancer (ATC), in which median survival is less than 6 months after diagnosis with rapid tumor growth and spread despite therapeutic efforts [2,3] . The thyroid cancers most responsive to treatment, about 85% of incident cases, are typical papillary thyroid carcinomas and follicular thyroid carcinomas, collectively termed ‘WDTC’. Such cancers may be diagnosed in various stages, University of Kentucky Program for Bioethics, Medical Science Building, MS-581, University of Kentucky, Lexington, KY 40536, USA Department of Internal Medicine & Thyroid Cancer Research Laboratory, University of Kentucky Thyroid Oncology Program, VA Medical Center, Lexington, KY 40536, USA 3 University of Chicago Department of Surgery & MacLean Center for Clinical Medical Ethics, 5841 S Maryland Ave, MC 4052, Chicago, IL 60637, USA 4 Institute of Gerontology, The University of Tokyo, Faculty of Engineering Bldg 8, #713 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8656, Japan 5 Sau Po Centre on Ageing, The University of Hong Kong 2/F, The Hong Kong Jockey Club Building for Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong 6 Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan *Author for correspondence: [email protected]

KEYWORDS

• clinical ethics • clinical trials • observational protocols • research ethics • thyroid cancer

1 2

10.2217/ije-2017-0008 © 2017 Future Medicine Ltd

Int. J. Endo. Oncol. (Epub ahead of print)

part of

ISSN 2045-0869

Perspective Rosenthal, Ain, Angelos, Hatanaka & Motojima accounting for size and growth features of the primary tumor and extent of spread of disease to neck regions or to distant sites (including: brain, lung, bone and other organs) [4,5] . The natural history of persistent or untreated WDTC is to become less differentiated over time, and less responsive to standard therapies (such as surgery and radioactive iodine) [6,7] . For example, most ATCs are believed to have started as WDTC that, over time, underwent further genetic changes to become ATC [8] ; however, many WDTC may remain stable without such changes. Unfortunately, it is not currently possible to predict which tumors will remain indolent – and for how long – and discriminate which tumors will become more aggressive and exhibit growth and metastatic dissemination [9] . Likewise, it is not possible to determine the timing of metastatic spread; whether this occurs early, when primary tumors are small, or later, when they are larger [10] . The usual management for thyroid cancer is surgery (ranging from partial to total thyroidectomy) and may include removal of lymph nodes [11,12] . There is a wide range of acceptable surgical approaches within the standard of care. In the case of small seemingly localized WDTC, removing only a lobe of the thyroid gland is acceptable as long as patients understand the potential that they might ultimately require a second operation to remove the remainder of the thyroid gland [13] . In most surgical practices, WDTC less than 1 cm, prompts consideration for less than a total thyroidectomy. When a total thyroidectomy is deemed appropriate and performed, it is then possible for radioactive iodine to be used for scanning for sites of residual or disseminated tumor and also, in larger doses, as treatment to eliminate those tumor sites. This is the only known effective systemic tumoricidal therapy for WDTC and is not able to be utilized without a preceding surgical thyroidectomy [14] . Utilization of radioactive iodine for diagnostic scanning permits identification of metastases throughout the body, including metastases that may be too small to be detected by other radiological methods [15] . In more aggressive presentations of thyroid cancer, the tumor may be poorly differentiated, losing the ability to take up and respond to radioactive iodine. In such situations, there are no known effective chemotherapy agents capable of killing thyroid cancer cells [16] . Instead, patients must rely upon appropriate combinations of

10.2217/ije-2017-0008


further surgery and/or external beam radiotherapy in an attempt to eliminate disease sites. This may be insufficient or inapplicable, particularly when poorly differentiated thyroid cancers disseminate to distant sites, such as the lungs. In those cases, the only current therapeutic options utilize expensive medications to diminish tumor progression with limited clinical efficacy [17] . In the early 1990s, some Japanese clinicians decided to observe their patients, who had been diagnosed (by biopsy) with papillary thyroid cancers under 1 cm in diameter (papillary microcarcinomas), rather than treat them with surgery [18,19] . These reports [20–22] fostered the adaptation of these practices as a new ‘standard of care’ for Japanese thyroid surgeons [20–22] , but the potentially problematic methods and ethical justification for these studies were not explored. Subsequently, these reports were misunderstood or overinterpreted by some American physicians who treated this as an acceptable practice for patients with papillary carcinomas larger than 1 cm in the USA, and apparently presented it to their American patients as a standard of care [23] , when the practice of observation had not been adopted as the standard of care in the USA. In addition, some clinicians in the USA have proposed that observational approaches to papillary microcarcinomas should become the standard of care [24,25] in the absence of sufficient published evidence and consensus [26] misconstruing conclusions unsupported by the Japanese data. Even when cancers have spread to lymph nodes in the neck, patients have been managed by observation of their cancer, again based upon the ostensible Japanese approach [27] ; whereas Japanese practitioners excluded patients with metastatic lymph nodes from their observation protocol. While these practices warrant a careful review of the Japanese studies that inspired such departures from standard therapy in the USA, we conclude that the gravity of ethical transgressions lie more with certain American practices than in the referenced Japanese practice. This is due to a failure of certain American practitioners to properly interpret data at best; and, at worst, a failure to ethically justify changing the standard of care based on scientific criteria. Although, there has been interest in observational protocols raised in some countries because of an increasing abundance of incidental diagnoses of low risk thyroid cancer, due to imaging of other medical conditions or due to screening [28,29] , such protocols have not yet been shown to offer

future science group

Problematic clinical trials in thyroid cancer: the issue of papillary carcinoma & observational approaches greater benefits, which is why observation is not routinely done in Europe, for example. The practice was first introduced into the USA based on specific efforts from one prominent American medical institution. ●●The ethics of thyroid tumor size

The size of the primary thyroid carcinoma has long been correlated with the disease prognosis. Outside of Japan, there is an international consensus that thyroid nodules under 1 cm in diameter, usually discovered during ultrasound examinations, are not typically subjected to biopsy or surgical resection. The Japanese standard of care recommends biopsying all thyroid nodules regardless of size [21,22] , resulting in a high incidence of malignant tumors under 1 cm (called ‘microcarcinoma’). In general, regardless of what country you live in, when a biopsy reveals a microcarcinoma, it is not ethically defensible to withhold that information from the patient, or to withhold the traditional standard of care from the patient (surgery) because every thyroid cancer – no matter whether it is aggressive or indolent in its behavior – starts as a microcarcinoma. Autopsy studies have shown that from 10 to 20% of people dead of causes unrelated to thyroid disease harbored thyroid microcarcinomas in their thyroid that were not revealed during their life and did not alter their health [30–32] . Against this large background of indolent thyroid cancer, there is a much smaller number of cases of thyroid cancer that grow and disseminate, causing significant disease and potential mortality [1] . Although recent advances in cancer genetics have provided some suggestions of features that are associated with aggressive tumors, the current state of knowledge does not permit us sufficient assurance in discriminating between microcarcinomas that will remain indolent and those that are able to spread to local and distant sites, presenting risk of disability and death. In addition, new understandings of how the immune system protects us from cancers that have developed in our bodies, suggests that part of the reason why some microcarcinomas progress to cause clinical disease and others do not may reside in the idiosyncrasies of each person’s immune response to the tumor, rather than to measurable characteristics of the tumor itself [33] . For those microcarcinomas that metastasize to other sites in the body, this process may start at any time – when the tumor


Perspective

is a microcarcinoma or when it is larger [34] . For those reasons, it is not possible to presume that people with microcarcinomas are free of disseminated disease. The traditional standard of care for the treatment of biopsy-confirmed papillary microcarcinomas is to offer the patient surgical removal of the entire or the affected half of the thyroid gland. Informed consent is the process by which patients accept or refuse surgical treatment for such microcarcinomas [11,14,35] . In patients with malignant tumors over 1 cm, the traditional standard of care is thyroid surgery, and additional therapies that are dependent on the surgical findings [36] . Some thyroid cancers exceeding 1 cm in diameter are also characterized as ‘low risk’ but there is clinical equipoise regarding what truly constitutes ‘lowrisk’ thyroid cancer, and thus, which treatments are appropriate. Ethicists have published elsewhere about what disclosures would constitute informed consent in this clinical context [35,37] . Generally, the surgical risks of recurrent laryngeal nerve damage and hypoparathyroidism must be weighed against the risk of disease progression. Many practitioners believe that reducing surgical risk – by not doing surgery – justifies observational practices despite any evidence that it is more beneficial. Thus, through informed consent, the patient’s preferences must guide treatment decisions. ●●Japanese observational studies:

methodological concerns

In order to understand and appreciate how Americans have misconstrued the Japanese studies, we present here a review of those studies. In 1993, patients with biopsy-proven papillary microcarcinomas at the Kuma Hospital in Kobe City, Japan, were offered the choice of immediate thyroid surgery or observation of their thyroid cancer without surgery [18] . The patients who were observed were assessed only with neck ultrasounds every 6–12 months. Between 1993 and 2001, no other diagnostic modalities were employed to determine the extent or progression of disease, essentially eliminating any opportunity to discern spread of disease into any part of the body outside of the neck. In those patients who chose immediate surgery or whose ultrasounds indicated local disease progression resulting in later surgery, neck ultrasounds “with or without chest (x-ray studies)” [18] were the only diagnostic studies monitored. Despite

www.futuremedicine.com

10.2217/ije-2017-0008

Perspective Rosenthal, Ain, Angelos, Hatanaka & Motojima the absence of any systematic disease assessment beyond the neck, these authors stated, “No distant metastases to the lung or bone have been detected by (x-ray studies) in any patients.” A later report [38] on these and additional patients (a total of 340 patients), extended to 2004 and added assessment of serum thyroglobulin (Tg) levels (a tumor marker), although this was only for the years 2001–2004 and 39% of the patients had autoantibodies that invalidated Tg assessment. This later study utilized chest x-ray studies or chest CT scans only for those patients who underwent thyroid surgery. As would be expected, this study was not capable of accurately assessing disease outside of the neck and, ultimately, 32% of ‘observation patients’ underwent later surgery [38] . Nonetheless, this paper is frequently cited as verifying that papillary microcarcinomas may be safely handled by observation alone when there is insufficient evidence that this is the case [12] . Another trial of observation for thyroid microcarcinoma was undertaken at The Cancer Institute Hospital in Tokyo, Japan, from 1995 to 2008 [19] . In this study, neck ultrasound examinations, chest x-ray studies (or CT scans) and serum Tg measurements were performed on participating patients every 6–12 months, avoiding methodological problems of the solely neck-focused approach in the Kuma Hospital studies. The 230 patients with papillary microcarcinoma who chose observation rather than immediate surgery were monitored for a mean of 5 years with only 7% later undergoing thyroid surgery [19] . These studies, in combination with the Kuma Hospital studies, seem insufficient to define a national standard of care as suggested by the Japanese Society of Thyroid Surgeons and the Japanese Association of Endocrine Surgeons [22] . Notwithstanding, these Japanese studies of observation of papillary microcarcinoma patients certainly lack the traditionally accepted evidentiary power necessary to be adopted for clinical practice in the USA. ●●Japanese observational studies: ethical

concerns

When the Kuma Hospital patients were enrolled in thyroid studies in the 1990s, it was a timeframe in which there were no research ethics guidelines in Japan, and absolutely no regulation regarding clinical research (with the exception of drug trials) [39] . In this time period, trial design, recruitment and what counted as valid ‘informed

10.2217/ije-2017-0008


consent’ was assessed voluntarily by ethics committees established in large hospitals, such as university hospitals and national hospitals, but submission of a research protocol was up to the individual practitioner, who had no obligation to seek outside peer review or approval for clinical research [39] . Thus, it is fair to say that no one knows whether the patients in these 1990s clinical research studies had written informed consent, and if so, to what degree potential risks and benefits were disclosed, or whether it was explained to patients that observation departed from usual practice. It was also customary in Japan at this time for patients to be offered treatments based on the ‘moral discretion’ of the researchers or their institutions [39] even if treatment recommendations deviated from the standard of care at times. Japanese physicians certainly had no obligation to offer the same standard of care as the USA. A deeper exploration into the culture of Kuma Hospital, where these nascent studies took place, reveals a small, private hospital that catered to thyroid diseases. Since, it was only in 1992 when all university hospitals in Japan had established ethics committees, mainly for dealing with controversial issues such as in vitro fertilization and transplantation [39] , it would have been unlikely for such a hospital to have had a functional ‘Ethics Committee’ to review clinical research at the beginning of the ‘observation study’. As of 2015, Japanese ethical guidelines required hospitals to provide Ethics Committee registration and disclosures to a database of the Ministry of Health, Labour and Welfare (MHLW) of Japan, but Kuma Hospital has not disclosed this information (based on a review of the MHLW database as of this writing), so it is not possible to ascertain the quality of its ethics review practices. However, based on published accounts by the investigators involved [18,40] , what counted as an ethics committee in Kuma Hospital at this time would not have been considered acceptable ethics review in the USA in that same time period. In short, there are both methodological concerns and ethical questions with respect to these studies. Ito’s conclusions from his early studies (1993–1995) were accepted uncritically in Japan, and followed by other Japanese observational studies in different time frames in the research ethics history of Japan [21] . Ethical guidelines for clinical studies were issued (but not codified) in 2003 by the Japanese MHLW [39] with


Problematic clinical trials in thyroid cancer: the issue of papillary carcinoma & observational approaches new provisions in 2009 mandating more effective Institutional [Ethics] Review Board (IRB) review. However, IRBs remain problematic because of variability with committee quality, member training and review rigor [39,41] . Even today, there are questions about whether Japanese practitioners respect government mandated guidelines since such guidelines have no legal power, although the Japanese government does have the power to stop funding grants that are not following these guidelines. For example, according to a September 2013 investigation of large hospitals conducted by the Japanese MHLW [42] , out of 24,414 clinical research studies performed in the past 5 years, 109 of them were not registered as clinical trials, while 103 were not IRB-reviewed, even though their protocols involved invasive interventions. In Japan, there are different clinical research guidelines for different types of research, which lies in contrast to the USA, which has unified guidelines for all clinical trials. In Japan, the differing guidelines involve complicated administrative and organizational hierarchies that result in what Japanese health law experts describe as an ‘incomprehensible system’. Additionally, Japan does not have an efficient management or evaluation system for its IRBs at either a national or regional level. Management of its IRBs is left up to each institution so there is variable quality control, without a unified system. This situation has led to quality disparities. For example, some IRBs involve a rigorous review while others may approve all protocols ‘blindly’. Regardless of differences in the ethical review process between Japan and the USA, it is reasonable to expect that any conclusions from Japanese studies need to be validated in the USA in accordance with its federally mandated research ethics guidelines. Unfortunately, that has not happened. ●●American observational trials:

methodological & ethical concerns

In the USA, Memorial Sloan Kettering Cancer Center (MSKCC), which has a prominent thyroid cancer practice, began to use published Japanese data to attempt to justify a new ‘institutional’ standard of care without evidence or prospective IRB approval [23,25,27,43] . The reasons for this change in clinical management are unknown. Instead of observing American patients with tumors under 1 cm, which would replicate the 1993 Kuma Hospital thyroid


Perspective

methodology, this institution began observing tumors larger than 1 cm, a practice that was outside and beyond the scope of the original Kuma Hospital studies as well as current Japanese guidelines for observation [19,22] . Notwithstanding, even if this institution were to merely replicate the Kuma studies of observing tumors under 1 cm, prospective IRB approval would still be necessary. But MSKCC authors have stated that they have been practicing observation without surgery for years [43,44] . They have not only published results of American patients with tumors or suspicious lymph nodes larger than 1 cm being ‘observed’ without surgery [27] but these were published as systematic retrospective studies in which patients were apparently offered ‘observation’ in a variety of settings when it was not the standard of care, or considered by other comparable experts, to be medically inappropriate. It is unclear whether these patients were aware of the novelty of the approach they were being offered. Two of the most alarming published studies echo uncomfortable observational protocols that were done in the preBelmont Report era; one involved observation of large, suspicious lymph nodes [27] when such withholding of treatment was not in accordance with the clinical practice guidelines [35] . Another published abstract reported that observation was presented to patients with tumors of 1.5 cm as an ‘alternative standard of care’ [23] when most would argue these patients were being offered nonstandard treatment. Patients at MSKCC were routinely consented to ‘observation alone’ as its ‘institutional standard of care’ [43] even though the USA courts have determined that there is no such thing as an ‘institutional standard of care’ [45] . The USA clinical practice guidelines in place during these American studies were published by the American Thyroid Association (ATA) in 2006 [46] and 2009 [11] respectively. According to both the 2006 and 2009 ATA guidelines, observation of even microcarcinomas was considered outside the standard of care, and certainly observation of tumors larger than 1 cm would only be considered acceptable practice if the patient had so many comorbidities that surgery would be considered prohibitively risky. There are no obvious ethically satisfactory explanations for why these practices persisted outside the standard of care, and even more questions about how such studies were published in prominent journals without ethical scrutiny. It appears that the


10.2217/ije-2017-0008

Perspective Rosenthal, Ain, Angelos, Hatanaka & Motojima authors of these studies have circumvented normal requirements for prospective IRB research: IRB review, and informed consent of the participants by reporting their data using IRB approval for a retrospective chart review. In turn, peer reviewers and journal editors seemingly failed to raise the appropriate questions about these methodologies, leading to their acceptance for publication. Moreover, journal editors may be overly reliant upon IRBs to raise the appropriate questions about study design. Like Japan, the USA does not have a central IRB system, and protocol review is institutionally based. Retrospective reviews get a much faster review because they are chart reviews that only involve analysis of existing data. The fatal flaw in both systems (Japan and the USA) are that IRBs are set up to depend upon the principal investigators to rigorously determine what treatments are standard of care and which are research, and IRBs do not routinely investigate applications independently. That may be a failing of the system, but in research, trust has always been an important element. IRBs do have the mechanism to investigate misconduct when brought to their attention, but that has so many consequences for ‘whistleblowers’ few are willing to do this. In a small subspecialty such as thyroid cancer, there is also the potential for personal conflicts of interest among journal editors, reviewers and the submitting authors. In this case, it seems clear that reviewers did not appreciate the significant methodological differences between the American and Japanese studies. Even by current ATA guidelines, such practices are not supported by the evidence. In 2015, revised clinical practice guidelines for differentiated thyroid cancer (DTC) were published [12] , which stated that there was not enough evidence to conclude that observation of microcarcinoma was beneficial, (Recommendation 101 (see: [D3].) Unfortunately, a confusing ‘discussion’ section citing the early Kuma Hospital studies, suggested that IRB-approved clinical studies in which observation of microcarcinoma is offered would be reasonable so that more data could be collected within the context of research. Notwithstanding this statement, the fact that routine observation of tumors larger than 1 cm outside of a prospective IRB trial remains outside of both Japanese and American guidelines does not seem to be understood, or publicly acknowledged, by US practitioners.

10.2217/ije-2017-0008


For example, many practitioners have misinterpreted the ‘discussion’ section in these latest guidelines as either permission or a ‘recommendation’ for observation only of tumors over 1 cm. Consequently, it appears that many practices now seem to offer observation routinely when it is still not evidenced-based [24] . Endocrine journals continue to publish studies promoting observation in the absence of evidence [26,47–50] . In one notable example, a 2016 paper from the Kuma Hospital [51] simply evaluated the surgical complications of patients who had surgery for microcarcinomas and concluded that thyroid patients who had surgery had more ‘unfavorable events’ (meaning surgical complications, including scarring) than thyroid patients who did not have surgery, even though those who did not have surgery were never fully assessed to see if any had developed metastatic disease to the lung or bones. Overall, we stress that the ethical problems lie with the American practitioners. Although Japan had no codified research ethics guidelines when observational studies were first performed in that country, the onus was on the Americans to ensure proper replication with prospective IRB approval and informed consent. It is important to emphasize, too, that no matter what research ethics guidelines exist in any country – studies without informed consent are ethically problematic based on international research ethics norms. Cultural & historical considerations The ethical standards in clinical research and in bedside encounters are different in Japan than in the USA. In Japan, medical history and health law evolved differently than in the USA. In Japan, physicians are respected socially, while its medical association has been politically influential historically. Its medical ethics council under MHLW has the authority to question or depose any doctor whose ethics are called into question, but has limited authority to impose any consequences or sanctions. Consequences are left up to each professional medical society, and the result is that ethical codes of behaviors are left up to each practitioner’s judgment. Resource allocation may also drive ethical standards in Japan for informed consent. In Japanese health law, each citizen must become a member of the national health insurance and the insurance fee is based on income. Japanese citizens can get equal access to medication regardless of income. Therefore, while access to


Problematic clinical trials in thyroid cancer: the issue of papillary carcinoma & observational approaches healthcare is greater in Japan than in the USA, meeting the demand is problematic. Japanese hospitals are typically crowded, and physicians feel pressed for time, which fosters a culture of paternalism as Japanese physicians may not have enough time to properly inform the patient of his/her condition, therapeutic options or a plan of care. Informed consent is sometimes obtained in a different context in Japan than in the USA. For example, Maria-Keiko Yasuoka, a Japanese medical anthropologist, has analyzed informed consent in the organ donation setting [52] and concludes that paternalism, and fears of ‘angering’ or disrespecting the physician, frequently lead patients into nonvoluntary consent. There are also cultural differences in the use of radioactive iodine in Japan, due to the events of the atomic bomb and fear of radioactive materials, resulting in very low usage in thyroid cancer treatment, and tight limits on which hospitals can legally use it [53] . This, too, creates a different clinical and cultural context for observation of microcarcinoma that is not transferable to the USA. In the USA, the patient autonomy movement arose from a few individual whistleblowers with moral distress who were concerned about human subject research abuses that seemed to violate the Nuremberg Code. The famous whistleblowing paper by Henry Beecher, which took considerable effort by the author to get published more than 50 years ago [54,55] , led to the 1979 Belmont Report guidelines [56] , which remain as the standard-bearer for ethical guidelines internationally. However, despite more rigid research ethics guidelines [57] , research misconduct in the USA continues to be problematic and education in bioethics is not mandatory in American medical schools. The American Association of Medical Colleges has noted these problems in medical school and residency training programs [58] . Practitioner knowledge about research ethics and clinical ethics concepts remains low in highly specialized fields and many clinical subspecialties. There does not appear to be an appreciation for the level of evidence needed to change the standard of care, versus merely justifying a clinical trial to replicate data from a different country and clinical context. Moreover, there is often no appreciation of differences between prospective and retrospective studies and the surgical culture in the USA still values


Perspective

‘innovation’. In the case of observation of thyroid tumors, all of these factors are at work, aggravated by misinterpretation of Japanese data. In keeping with American traditions of bioethicists ‘blowing whistles’ about serious clinical ethics problems, we believe this situation rises to that occasion. Discussion Based on published studies in the thyroidology literature, we estimate that a significant number of US patients have been offered observation instead of surgery outside of prospective IRBapproved trials [23,27,43–44] . Were these patients told that this option was potentially below and outside the standard of care? Since, some of the problematic US studies are ‘retrospective’ and are based on one-to-one clinical encounters, there is no record of what took place in any consent discussion, other than what might be in the patient’s medical chart. Given that the early Japanese studies were not IRB-approved, the USA practitioners should not have used its data to justify changing the USA standards of care, and would have needed to replicate these studies in prospective IRB-approved studies. This situation raises a variety of clinical ethics problems. First, are we repeating historic lapses in medical research in this situation? How similar are thyroid cancer observational protocols to the infamous syphilis observational protocols [59] or even the recent cervical cancer observational protocols in India, in which Pap smears were withheld in an attempt to lower healthcare costs [60–62] . Second, when we consider ethical problems with historical clinical research, what data should be discounted, and what data should be considered worthy of using or replicating? For example, the medical history of infectious disease involves many clinical trials that would not pass IRB approval today, including the Polio vaccine trials, in which the vaccine was tested on developmentally delayed children without informed consent [63,64] . There is little consensus about what to do with data that was collected without informed consent; however, there is wide consensus that data collected from medical experiments categorized as ‘war crimes’ should not be cited or used [65] . What seems to be a basic requirement, when there are any questions about informed consent, is to properly replicate a clinical trial with proper ethical oversight before universally and uncritically accepting its conclusions. In this clinical


10.2217/ije-2017-0008

Perspective Rosenthal, Ain, Angelos, Hatanaka & Motojima context, this has not occurred. First, not only have the 1990s Japanese studies been adopted uncritically in the USA before being properly replicated, but the Japanese methods have been changed and expanded by American practitioners without sufficient oversight. Given that the 1990s Japanese studies had methodological weaknesses, the observational trials intended for papillary cancer under 1 cm should be reexamined in a more rigorous clinical research trial setting, with proper ethical oversight before there is any contemplation of observing thyroid cancers over 1 cm. ●●Patient considerations

Finally, what would be reasonable and responsible clinical ethics recommendations for American and Japanese patients who may or may not have fully understood the nature of the nontraditional treatment plan they entered into? We propose different guidelines for different groups of patients. For American patients included in retrospective or other problematic observational studies, a ‘look back’ may be reasonable by the institution’s IRB. Given the excellent prognosis of most papillary thyroid cancer patients, it is likely that few have been harmed. However, the IRB may consider recontacting patients and revisiting what they were told, what the patients believed they were consenting to, and whether the patients should be re-evaluated by another practitioner not connected to the institution. For Japanese patients with thyroid nodules less than 1 cm, Japanese bioethicists worry they may have been subjected to unnecessary biopsies, based on American guidelines and international consensus. Therefore, more careful consideration is needed regarding biopsying nodules under a centimeter while second opinions may help patients understand the current status of their nodules. Japanese bioethicists also recommend that IRBs become more standardized to minimize variation of Japanese protocol reviews. Finally, Japanese bioethicists have major concerns about Americans overinterpreting Japanese clinical studies and expansion of microcarcinoma observation to larger tumors without proper ethical oversight. As for newly diagnosed American thyroid cancer patients with ‘low risk’, WDTC, we suggest goals of care discussions follow previously published recommendations in the International Journal of Endocrine Oncology [35] .

10.2217/ije-2017-0008


Conclusion There are distinct social, cultural, economic and clinical practice differences between Japan and Western countries that may have precipitated adoption of observation for micropapillary carcinoma as a standard of care in Japan, despite such sparse clinical research evidence. However, practices within this subspecialty have escaped real scrutiny by the bioethics community at large. Japanese bioethicists have concerns that Japanese patients may be subjected to unnecessary biopsies for thyroid nodules under 1 cm, and that the Japanese standard of care for microcarcinoma should follow the same standards as the USA: not to biopsy tumors under 1 cm unless they have other concerning features according to clinical practice guidelines. Both Japanese and American bioethicists concur that American thyroid oncologists have overinterpreted microcarcinoma data from Japan and used it to justify methodologically unsound research without proper ethical oversight by either country’s standards. With respect to observation of papillary microcarcinoma in the USA, observation of thyroid tumors outside of a prospective clinical trial is not ethically justified at this time. First, human subject research guidelines are different in each country, and the patient populations differ, requiring Americans to validate Japanese results by performing their own studies that follow American ethical guidelines for research. Second, since there are methodological concerns, even with the Japanese studies, the same methodological concerns need to be addressed by a prospective IRB-reviewed clinical trial. Finally, since there is no way to predict which thyroid papillary microcarcinoma will progress to a more aggressive cancer, it will take many years to demonstrate whether observation is better than the current standard of care. However, costs associated with observation (requiring multiple follow-ups with ultrasound, time-off for doctor’s appointments, and so forth) are often more onerous in the end than costs associated the current standard of care, which is already highly effective, even when surgical risk factors are taken into account. In addition, as noted concerning the Japanese studies, clinical ‘tunnel vision’ evaluating only neck ultrasounds without searching for distant disease remains problematic. Moreover, observation can lead to poorer outcomes as some tumors progress and become more difficult to treat.


Problematic clinical trials in thyroid cancer: the issue of papillary carcinoma & observational approaches Future perspective As thyroid cancer incidence continues to rise, observation protocols should not be offered in the USA without sufficient data to ethically justify such approaches. Inconclusive research remains surrounding the frequency of imaging for observation, use of molecular markers to risk stratify, and whether decision making aids can improve informed consent in this context. Until there is clear data demonstrating that observation maximizes benefit and minimizes harm, patients need to be informed that it is nonstandard therapy, and the risk of poorer outcomes associated with nonintervention in biopsy-confirmed thyroid cancer.

References 1

2

3

4

5

6

7

8

Howlader N, Noone AM, Krapcho M et al. SEER cancer statistics review, 1975–2013. National Cancer Institute MD, USA (2015). https://seer.cancer.gov/csr/1975_2014 Ain KB. Management of undifferentiated thyroid cancer. Baillieres Best Pract. Res. Clin. Endocrinol. Metab. 14(4), 615–629 (2000). Smallridge RC, Ain KB, Asa SL et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22(11), 1104–1139 (2012). Nixon IJ, Whitcher MM, Palmer FL et al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. Thyroid 22(9), 884–889 (2012). Sabra MM, Dominguez JM, Grewal RK et al. Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases. J. Clin. Endocrinol. Metab. 98(5), e829–e836 (2013). Klubo-Gwiezdzinska J, Van Nostrand D, Atkins F et al. Efficacy of dosimetric versus empiric prescribed activity of 131i for therapy of differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 96(10), 3217–3225 (2011). Samuel AM, Rajashekharrao B, Shah DH. Pulmonary metastases in children and adolescents with well-differentiated thyroid cancer. J. Nucl. Med. 39(9), 1531–1536 (1998). Ain KB. Anaplastic thyroid carcinoma: behavior, biology, and therapeutic approaches. Thyroid 8(8), 715–726 (1998).


9

Perspective

Disclaimer The opinions expressed in this perspective are those of the authors and do not necessarily reflect the views of Future Medicine Ltd.

Financial & competing interests disclosure KB Ain (spouse of MS Rosenthal) has received consulting fees from Jubilant DraxImage Inc. MS Rosenthal has provided unpaid independent bioethics opinions to Jublilant DraxImage Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat. Rev. Endocrinol. 7(10), 569–580 (2011).

10 Turajlic S, Swanton C. Metastasis as an

evolutionary process. Science 352(6282), 169–175 (2016). 11 Cooper DS, Doherty GM, Haugen BR et al.

Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19(11), 1167–1214 (2009). 12 Haugen BR, Alexander EK, Bible KC et al.

2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26(1), 1–133 (2016). 13 Bilimoria KY, Bentrem DJ, Ko CY et al.

Extent of surgery affects survival for papillary thyroid cancer. Ann. Surg. 246(3), 375–384 (2007). 14 Haugen BR. Patients with differentiated

thyroid carcinoma benefit from radioiodine remnant ablation. J. Clin. Endocrinol. Metab. 89(8), 3665–3667 (2004). 15 Ain KB. Radioiodine-remnant ablation in

low-risk differentiated thyroid cancer: pros. Endocrine 50(1), 61–66 (2015). 16 Ain KB. Pathobiology of antineoplastic

therapy in undifferentiated thyroid cancer. In: Molecular Basis of Thyroid Cancer. Farid NR (Ed.). Kluwer Academic, MA, USA, 357–367 (2004). 17 Bible KC, Ain KB, Rosenthal MS. Protein

kinase inhibitor therapy in advanced thyroid cancer: ethical challenges and potential

solutions. Int. J. Endocrine Oncol. 1(2), 145–151 (2014). 18 Ito Y, Uruno T, Nakano K et al. An

observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 13(4), 381–387 (2003). 19 Sugitani I, Toda K, Yamada K, Yamamoto N,

Ikenaga M, Fujimoto Y. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World J. Surg. 34(6), 1222–1231 (2010). 20 Ito Y, Miyauchi A. Nonoperative

management of low-risk differentiated thyroid carcinoma. Curr. Opin. Oncol. 27(1), 15–20 (2015). 21 Sugitani I, Fujimoto Y. Management of

low-risk papillary thyroid carcinoma: unique conventional policy in Japan and our efforts to improve the level of evidence. Surg. Today 40(3), 199–215 (2010). 22 Takami H, Ito Y, Okamoto T, Yoshida A.

Therapeutic strategy for differentiated thyroid carcinoma in Japan based on a newly established guideline managed by Japanese Society of Thyroid Surgeons and Japanese Association of Endocrine Surgeons. World J. Surg. 35(1), 111–121 (2011). 23 Pace MD, Fagin JA, Bach A et al. Properly

selected patients with papillary thyroid cancer readily accept active surveillance when offered as a standard of care alternative to immediate surgery. Presented at: 83rd Annual Meeting of the American Thyroid Association. San Juan, Puerto Rico, 16–20 October 2013. 24 Haser GC, Tuttle RM, Su HK et al. Active

surveillance for papillary thyroid microcarcinoma: new challenges and


10.2217/ije-2017-0008

Perspective Rosenthal, Ain, Angelos, Hatanaka & Motojima opportunities for the health care system. Endocr. Pract. 22(5), 602–611 (2016). 25 Leboulleux S, Tuttle RM, Pacini F,

Schlumberger M. Papillary thyroid microcarcinoma: time to shift from surgery to active surveillance? Lancet Diabetes Endocrinol. 4(11), 933–942 (2016). 26 Stack BC Jr, Angelos P. The ethics of

disclosure and counseling of patients with thyroid cancer. JAMA Otolaryngol. Head Neck Surg. 141(11), 957–958 (2015). 27 Robenshtok E, Fish S, Bach A,

Dominguez JM, Shaha A, Tuttle RM. Suspicious cervical lymph nodes detected after thyroidectomy for papillary thyroid cancer usually remain stable over years in properly selected patients. J. Clin. Endocrinol. Metab. 97(8), 2706–2713 (2012). 28 Brito JP, Hay ID, Morris JC. Low risk

papillary thyroid cancer. BMJ 348, g3045 (2014). 29 Davies L, Welch HG. Current thyroid cancer

trends in the United States. JAMA Otolaryngol. Head Neck Surg. 140(4), 317–322 (2014). 30 Chong PY. Thyroid carcinomas in Singapore

autopsies. Pathology 26(1), 20–22 (1994). 31 Martinez-Tello FJ, Martinez-Cabruja R,

Fernandez-Martin J, Lasso-Oria C, BallestinCarcavilla C. Occult carcinoma of the thyroid. Cancer 71(12), 4022–4029 (1993). 32 Yamamoto Y, Maeda T, Izumi K, Otsuka H.

Occult papillary carcinoma of the thyroid: a study of 408 autopsy cases. Cancer 65(5), 1173–1179 (1990). 33 Corthay A. Does the immune system

naturally protect against cancer? Front. Immunol. 5, 197 (2014). 34 Cheung KJ, Ewald AJ. A collective route to

metastasis: seeding by tumor cell clusters. Science 352(6282), 167–169 (2016). 35 Rosenthal MS, Angelos P, Bible KC et al.

Informed consent for low-risk thyroid cancer. Int. J. Endocr. Oncol. 3(2), 131–142 (2016). 36 Ain KB. Management of thyroid cancer. In:

Diseases of the Thyroid. Braverman L (Ed.). Humana Press, NJ, USA, 287–317 (1997). 37 Freedman B. Equipoise and the ethics of

clinical research. N. Engl. J. Med. 317(3), 141–145 (1987). 38 Ito Y, Miyauchi A, Inoue H et al. An

observational trial for papillary thyroid microcarcinoma in Japanese patients. World J. Surg. 34(1), 28–35 (2010).

10.2217/ije-2017-0008

39 Motojima M, Ichikawa I. The impact of

recent revisions in the Japanese ethical guidelines for clinical research. Asian Bioethics Review 1(4), 329–341 (2009). 40 Miyauchi A. Clinical trials of active

surveillance of papillary microcarcinoma of the thyroid. World J. Surg. 40(3), 516–522 (2016). 41 Katashima R, Sato C, Kinoshita S,

Kawashima S, Yanagawa H. Present status of Japanese ethics committees: a survey in Tokushima Prefecture. J. Med. Invest. 61(3–4), 399–403 (2014). 42 Ministry of Health Labour and Welfare of

Japan. Correspondence and Recurrence Prevention as Response for Clinical Research Case of Hypertension Medicine. Committee on Clinical Research Cases on Hypertension Medicine (2013). 43 Morris LG, Wong RJ, Tuttle RM. Ethical

considerations when counseling patients with thyroid cancer about surgery vs observation. JAMA Otolaryngol. Head Neck Surg. 142(4), 406–407 (2016). 44 Leboulleux S, Tuttle RM, Pacini F,

Schlumberger M. Papillary thyroid microcarcinoma and active surveillance – authors’ reply. Lancet Diabetes Endocrinol. 4(12), 976–977 (2016). 45 Catalano v. Moreland, 299 AD 2d 881 (N.Y.

2002). 46 Singer PA, Cooper DS, Levy EG et al.

52 Yasuoka MK. Organ Donation in Japan : a

Medical Anthropological Study. Lexington Books, MD, USA (2015). 53 Tominaga T, Yokoyama N, Nagataki S et al.

International differences in approaches to 131I therapy for Graves’ disease: case selection and restrictions recommended to patients in Japan, Korea, and China. Thyroid 7(2), 217–220 (1997). 54 Beecher HK. Ethics and clinical research.

N. Engl. J. Med. 274(24), 1354–1360 (1966). 55 Jones DS, Grady C, Lederer SE. “Ethics and

clinical research” – the 50th anniversary of Beecher’s bombshell. N. Engl. J. Med. 374(24), 2393–2398 (2016). 56 National Commisson for the Protection of

Human Subjects of Biomedical and Behavioral Research. Belmont report: ethical principles and guidelines for the protection of human subjects of research. Federal Register 44(76), 23192–23197 (1979). 57 Code of Federal Regulations - Title 45 Public

Welfare CFR 46.116(a). US Department of Health and Human Services, Washington DC, USA (2009). 58 Saltzburg L. Is the current state of medical

ethics education having an impact on medical students? Online J. Health Ethics 10(2), (2014). 59 Rockwell DH, Yobs AR, Moore MB Jr. The

Tuskegee study of untreated syphilis; the 30th year of observation. Arch. Intern. Med. 114, 792–798 (1964).

Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA 273(10), 808–812 (1995).

60 Nagarajani R. Row over clinical trial as 254

47 Angelos P. Papillary thyroid microcarcinoma

61 Suba EJ. Eleven questions regarding cervical

and active surveillance. Lancet Diabetes Endocrinol. 4(12), 975–976 (2016). 48 Liu Z, Huang T. Papillary thyroid

microcarcinoma and active surveillance. Lancet Diabetes Endocrinol. 4(12), 974–975 (2016). 49 Tulchinsky M. Papillary thyroid

microcarcinoma and active surveillance. Lancet Diabetes Endocrinol. 4(12), 974 (2016). 50 Viola D. Papillary thyroid microcarcinoma

and active surveillance. Lancet Diabetes Endocrinol. 4(12), 975 (2016). 51 Oda H, Miyauchi A, Ito Y et al. Incidences of

unfavorable events in the management of low-risk papillary microcarcinoma of the thyroid by active surveillance versus immediate surgery. Thyroid 26(1), 150–155 (2016).


Indian women die. The Times of India, 21st April (2014). cancer prevention in India. J. Cancer Res. Ther. 10(3), 459–460 (2014). 62 Suba EJ. India cervical cancer testing is

Tuskegee 2.0. Alabama Media Group, 17th June (2015). 63 Hornblum AM, Newman JL, Dober GJ.

Against Their Will: The Secret History of Medical Experimentation on Children in Cold War America. Palgrave Macmillan, London, UK (2013). 64 Wellner KL. Polio and historical inquiry.

OAH Mag. Hist. 19(5), 54–58 (2005). 65 Berger RL. Nazi science – the Dachau

hypothermia experiments. N. Engl. J. Med. 322(20), 1435–1440 (1990).
