Clinical,Safety,and Economic Evidence in Radioactive Iodine–Refractory Differentiated Thyroid Cancer: A Systematic Literature Review

Abstract

Background:

Thyroid cancer is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising ∼93% of all thyroid cancers. While most cases of DTC are curable with the use of surgery and radioactive iodine (RAI) ablation of the remaining thyroid remnant, prognosis is dire and treatment options limited when DTC becomes RAI-refractory (RAI-R). Standard cytotoxic chemotherapy has limited efficacy, making enrollment in clinical trials of novel targeted therapies the preferred treatment approach. Thus, we conducted a comprehensive systematic review of the clinical trial scientific literature with a focus on efficacy, safety, and economics to identify all potential treatment options that have been or are currently being evaluated for the treatment of RAI-R DTC.

Methods:

Embase.com (including Medline), Medline In-Process and other nonindexed citations, the Cochrane Libraries, ClinicalTrials.gov, and relevant recent conference proceedings were searched using predefined search criteria. Important inclusion criteria included English language, randomized controlled studies or interventional single-arm studies only, and studies of drug therapies only. Search results were screened utilizing the discretion of multiple researchers, and key data were abstracted.

Results:

Forty-five unique trials (16 full-text, 4 conference abstracts, and 25 ClinicalTrials.gov entries) were included in the clinical review. No studies that met criteria for inclusion in the economic review were identified. Among 20 trials with results available, all were Phase II and only one was randomized. The most commonly studied drugs were tyrosine kinase inhibitors (TKIs); other drugs included celecoxib, doxorubicin with interferon alpha-2b, rosiglitazone, selumetinib (AZD6244), thalidomide, VEGF trap, and vorinostat. Overall, efficacy and safety profiles were specific to treatment regimen, with objective response rates (ORR) ranging from 0% on gefitinib, rosiglitazone, VEGF trap, and vorinostat to 50% on lenvatinib, a TKI.

Conclusions:

Limited clinical research and no economic research has been conducted in RAI-R DTC. Certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo-controlled trials are ongoing. New research on the economic and humanistic burden of RAI-R DTC must be paired with the clinical evidence currently in development to examine the existing burden and future promise in treating patients with RAI-R DTC.

Introduction

T hyroid cancer is the most common endocrine malignancy. In 2013, an estimated 60,220 Americans will be diagnosed with thyroid cancer, and the disease will account for approximately 1850 deaths (1). The vast majority (∼93%) of thyroid cancers are considered differentiated thyroid cancers (DTC), which include papillary (PTC), follicular (FTC), and Hürthle cell carcinoma (HCC) subtypes. A substantially smaller proportion of thyroid cancers are medullary (MTC) or anaplastic (ATC) thyroid cancers at ∼4% and ∼2% respectively (1). Thyroid cancer is usually asymptomatic and is often discovered incidentally (e.g., in the form of a thyroid nodule) during a routine examination; only 5% of nodules are malignant. Nevertheless, 3–15% of thyroid cancer patients present with distant metastases, and another 6–20% develop distant metastases during follow-up (2). Metastases are most common in the lungs and bones, yet can also be found in areas such as the brain and skin (2,3). Among patients with newly diagnosed metastatic thyroid cancer, it is estimated that healthcare costs can exceed $95,000 per patient in the first two years after diagnosis alone (4).

Differentiated thyroid tumors are highly treatable and usually curable, especially in patients younger than 40 years of age, without an extension beyond the thyroid. The goals of thyroid cancer treatment focus on removing the primary tumor and disease extending beyond the thyroid (if present), minimizing treatment-related morbidity, long-term surveillance, and minimizing the risk of disease recurrence (5). Most patients with DTC have an excellent outlook with the use of traditional therapies, including surgical resection, radioactive iodine (RAI) ablation of the remaining thyroid remnant, and thyrotropin suppression. Together these achieve a 10-year survival in >90% of cases, and complete remission in 60% of cases with local disease and in 30% of patients with distant metastases (6). Approximately 25% of patients with DTC develop locally advanced or metastatic disease and are candidates for RAI therapy (7). On average, about 25–50% of locally advanced/metastatic patients become refractory to RAI (RAI-R) (8). When RAI becomes ineffective against DTC, five-year survival is <50% (6) and 10-year survival is <10% (3). At this point in the disease, when standard therapies become ineffective, delaying disease progression and extending survival—often with systemic or targeted drug therapies—become crucial treatment goals.

Possibly due to better prognosis and lower mortality rates among patients with thyroid cancer compared to other cancers, investigation into new treatments has been limited (9). The only systemic chemotherapy approved by the US Food and Drug Administration (FDA) that encompasses RAI-R DTC patients is doxorubicin (10). However, monotherapy or its combination with traditional agents such as cisplatin rarely yields a complete response (CR), and partial responses (PR) account for <40% (11) of cases and have limited durability (5) among RAI-R DTC patients when dosed appropriately. Furthermore, treatment with doxorubicin is associated with serious side effects such as cardiac and hematologic toxicities that are difficult to justify given doxorubicin's lack of significant efficacy (12,13). Treatment guidelines of medical organizations such as the National Comprehensive Cancer Network (14) and the American Thyroid Association (5) generally include one or more of four core recommendations for the treatment of RAI-R DTC: doxorubicin (with the caveats noted above), external beam radiation (primarily for palliative purposes), enrollment in clinical trials, or commercially available targeted molecular therapies such as tyrosine kinase inhibitors (TKIs), which act to halt tumor-cell proliferation and angiogenesis.

There is a clear unmet need for safe and effective treatments among the RAI-R DTC population, whose prognosis is not nearly as favorable as RAI-avid patients. Because evidence-based treatment recommendations by key medical societies prioritize inclusion in experimental clinical trials, we conducted a systematic review of the scientific literature to identify all potential treatment options that have been evaluated, or are currently being evaluated in Phase II trials or later, for the treatment of RAI-R DTC. Our review included a comprehensive view of the treatment landscape, with a focus on efficacy, safety, and also economic aspects of these novel treatments. The findings of this review are meant to help identify promising options for patients with RAI-R DTC, present evidence of safety and effectiveness among leading therapies, and delineate the remaining unmet needs as targets for future research.

Materials and Methods

Databases included in search

Literature searches were conducted in a number of databases. Embase.com was searched on July 2, 2012. The Embase database includes all Medline records produced by the National Library of Medicine (NLM), as well as more than five million records not covered on Medline (15). The Embase database also encompasses the Cochrane Database of Systematic Reviews (CDSR). Separate searches were conducted specifically for Medline In-Process and other nonindexed citations using the OvidSP interface on June 21, 2012, for clinical studies and on July 5, 2012, for economic studies. Because Embase includes only the CDSR, the remaining components of the Cochrane Libraries were searched using the Cochrane interface. In addition to the CDSR, the Cochrane Libraries include the Database of Abstracts of Reviews of Effects (DARE), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Methodology Register (CMR), the National Health Service Economic Evaluation Database (NHS EED), and the Health Technology Assessment Database (HTA). The Cochrane Libraries were searched on July 5, 2012.

In addition to the literature databases, the ClinicalTrials.gov registry (a service of the U.S. National Institutes of Health) was searched on June 18, 2012, for a list of all completed, recruiting, and ongoing clinical trials including patients with RAI-R DTC. “Gray literature” (i.e., source material available outside of peer-reviewed journals) was searched in the form of conference abstracts from recent relevant conferences, including the American Society of Clinical Oncology (2010–2012), the European Society for Medical Oncology (2010–2011), the American Thyroid Association (2009, 2011), the European Thyroid Association (2009, 2011), and the International Thyroid Congress (2010). Finally, the lists of references for all relevant systematic reviews identified in the literature searches were cross-checked to ensure continuity.

Search strategy

To target citations related to thyroid cancer in all Embase.com and Cochrane Libraries searches, controlled thesaurus indexing terms for the disease were used. The built-in Emtree thesaurus was utilized for the Embase.com searches, while the Cochrane Libraries interface utilizes the NLM MeSH thesaurus. For the Medline In-Process and other nonindexed citation searches, free-text terms for the disease were used, including “thyroid cancer,” “thyroid neoplasm,” “thyroid adenoma,” and “thyroid tumor.”

Separate searches were conducted for clinical trials and economic studies. To target clinical studies, searches in Embase.com included controlled thesaurus index terms specific to a comprehensive array of study types, while the Medline In-Process and other nonindexed citations searches used general free-text terms such as “trial” and “study.” Trial-related terms were not required for Cochrane Libraries searches, as the Cochrane databases are divided by study type. Finally, to target studies in an RAI-R population, the clinical trials searches also included free-text terms such as “radioiodine,” “iodine,” “refractory,” “advanced,” “iodine insensitive,” and “radioiodine unresponsive.”

To identify appropriate citations in the economic studies searches in Embase.com and Medline In-Process and other nonindexed citations, free-text terms such as “cost,” “effectiveness,” “economic,” and “utility” were utilized. Economic-related terms were not required for Cochrane Libraries searches, as the Cochrane databases are divided by study type, which include economic studies and health technology assessments.

As search interfaces for ClinicalTrials.gov and scientific conference proceedings are less targeted or specific than those of Embase.com and OvidSP, a broad search strategy for these sources was utilized, relying primarily on thyroid cancer–specific free-text terms noted previously.

Study inclusion and exclusion criteria

The review was restricted to peer-reviewed studies involving human research in the English language and published in the year 2000 or later. Studies published prior to 2000 were not included in the search because drug therapy for RAI-R DTC at that time primarily involved doxorubicin (11), which has been noted in more recent treatment guidelines as having limited effectiveness in treating advanced thyroid cancer (5,14). Table 1 lists complete a priori inclusion and exclusion criteria.

Table 1.

Inclusion/Exclusion Criteria

Inclusion criteria	Exclusion criteria
Clinical search	Clinical search
• Included an RAI-R population of which at least a subset had DTC	• Non-English language
• Randomized controlled trials with blinded or open-label design (crossover permitted)	• Published prior to 2000
• Interventional single-arm and open label studies	• Case reports, comments, letters, editorials, or reviews^a
• Patients received a drug therapy	• Animal, in vitro, genetic, or histochemical studies
	• Observational studies
	• Trials prior to Phase II
	• ≤10 patients per arm or follow-up duration of <2 weeks
	• Included patients <18 years of age
	• Did not include RAI-R patients with DTC
	• Did not evaluate a treatment of interest (i.e., studies evaluating surgery, imaging, diagnostic techniques, or treatment to restore responsiveness to RAI were not included in the review)
Economic search	Economic search
• Included an RAI-R population of which at least a subset had DTC	• All criteria of clinical search
• Addressed an economic issue	• Did not address an economic issue
• Pertained to a drug therapy

Citation lists in relevant review articles were later cross-checked with included trials to ensure no citations were overlooked.

DTC, differentiated thyroid cancer; RAI(-R), radioactive iodine(-refractory).

In the clinical trials searches, studies were deemed relevant and included in the review if they included an RAI-R population of which at least a subset had DTC. Only blinded and open-label randomized controlled studies (crossover permitted) and interventional single-arm open-label studies were included. Furthermore, only studies in which patients received a drug therapy were reviewed; studies of diagnostic tests or surgical techniques were not included in the review. In the economic studies searches, relevant citations involved an RAI-R population of which at least a subset had DTC, addressed an economic issue (e.g., cost-effectiveness, burden of illness), and pertained to drug therapies only.

Articles and abstracts were excluded from the clinical review if they were case reports, comments, letters, editorials, or reviews (although citation lists in relevant review articles were cross-checked); if they were classified as in vitro, genetic, or histochemical studies; if they pertained to observational studies; if they were trials prior to Phase II; if they had ≤10 patients per arm or a follow-up duration of <2 weeks; if they included patients <18 years of age; if they did not include RAI-R patients with DTC; or if they did not evaluate a treatment of interest (i.e., studies evaluating surgery, imaging, diagnostic techniques, or treatment to restore responsiveness to RAI were not included in the review). In the economic review, citations were further excluded if they did not address an economic issue.

Screening and data abstraction

Upon completion of the literature searches, a pilot sample containing 10% of the citation titles and abstracts were screened independently by two researchers based on the inclusion and exclusion criteria (V.T, R.F.), and results were compared to ensure consistency of review. A two-level review process was implemented. Upon consensus, all titles and abstracts were screened by one researcher (V.T.) based on the exclusion criteria (Level 1). Full-text articles for all potentially relevant citations satisfying Level 1 review were retrieved and were further reviewed by two researchers (V.T., R.F.) based on the inclusion criteria (Level 2). Any uncertainty in Level 2 screening was resolved by consensus among researchers (V.T., R.F., J.E.L.). Articles satisfying Level 2 screening were included in the review.

Relevant data were abstracted from the included articles, including treatment regimen, phase, country, number of patients enrolled/evaluable, baseline characteristics, overall survival (OS), progression free survival (PFS), response based on RECIST criteria, and grade 3–5 toxicities occurring in ≥5% of patients.

Results

Literature search and screening

Figure 1 illustrates the search and screening process of the systematic review. The clinical review search strategy identified 2269 potentially relevant citations in the Embase, Medline, and Cochrane databases, while the economic review strategy identified 208 potentially relevant citations. Level 1 screening of titles and abstracts resulted in 17 clinical and 6 economic full-text articles being reviewed in the Level 2 screening. Upon Level 2 screening, 15 clinical citations representing 15 unique clinical trials were included in the review, whereas no economic articles were deemed relevant. In addition to the published studies, the search of the ClinicalTrials.gov registry identified 40 clinical trials fulfilling the inclusion criteria, and the searches of professional conference proceedings identified 10 abstracts fulfilling the inclusion criteria. The clinical trial registry entries and conference abstracts were compared to each other and to the full-text articles, and duplicate studies were combined. One of the trials identified in the ClinicalTrials.gov registry search was published shortly after the literature searches had been conducted (16), and therefore the full-text publication was included in the literature review in place of the registry entry. Ultimately, four unique trials were included among the conference abstracts, and 25 unique trials were represented in ClinicalTrials.gov, yielding a total of 45 unique trials to be included in the clinical review. No relevant economic studies were identified in the form of conference abstracts. Thus, the systematic review of economic studies specific to RAI-R DTC yielded no results.

FIG. 1.

Summary of literature search and study selection. ASCO, American Society of Clinical Oncology; ATA, American Thyroid Association; CDSR, Cochrane Database of Systematic Reviews; CENTRAL, Cochrane Central Register of Controlled Trials; DARE, Database of Abstracts of Reviews of Effects; ETA, European Thyroid Association; HTAD, Health Technology Assessment Database; ITC, International Thyroid Congress; NHSEED, National Health Service Economic Evaluation Database.

Citations were mostly excluded from the clinical search for not pertaining to interventional clinical trials, not involving RAI-R disease, and not evaluating interventions of interest. Commonly excluded interventions included surgical and diagnostic techniques (e.g., scintigraphy or positron emission tomography). The most common reasons for exclusion in the economic search were not being economic studies and not evaluating interventions of interest. Of note, one study by Chen et al. (17) evaluating sorafenib in the treatment of Chinese patients with RAI-R DTC (100% PTC population) was excluded from the review for having fewer than 10 patients in the trial (n=9) when it would have been included otherwise. This is the only instance where a citation was excluded solely on the basis of population size.

Characteristics of included clinical trials

Twenty unique clinical trials with reported results were included in the literature review (see Appendix) (12,16,18 –37). Despite the searches going back to the year 2000, all identified trials were published between 2006 and 2012. All trials were conducted at centers in North America (United States or Canada) or Europe, and all were conducted among a predominantly (≥78%) white patient population. The most commonly studied drugs were TKIs, including axitinib, gefitinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitinib, and vandetanib. Other drugs evaluated in RAI-R DTC patients included celecoxib, doxorubicin+interferon alpha-2b, rosiglitazone, selumetinib, thalidomide, VEGF trap, and vorinostat. All trials were Phase II; 19 were single-arm trials with enrollment of between 11 (20) and 93 (28) patients, and one was a randomized controlled trial of 145 patients (16). Ten trials consisted of exclusively DTC patients (16,20,22,27 –29,32 –34,36) (based upon a definition of non-MTC, non-ATC, but including poorly differentiated thyroid cancer), while the remaining studies consisted of mixed thyroid cancer populations. The median age of patients ranged from 55 (18) to 69 (12). Performance status, as measured by Eastern Cooperative Oncology Group (ECOG) grade (38), was predominantly between 0 and 1. Of the trials that reported patients with ECOG grade 2 or higher, the proportion of patients in this category was ≤10%. Patients enrolled in the trials were primarily described as having advanced metastatic disease. Besides RAI, the most commonly cited prior therapies among patients were radiation and, generally to a lesser extent, chemotherapy.

Table 2 describes the 25 recruiting, ongoing, or completed clinical trials identified in the ClinicalTrials.gov registry for which results have not been published. Overall, everolimus (an mTOR inhibitor), sorafenib, and sunitinib were the most commonly studied drugs, involved in five (39 –43), three (41,44,45), and three (46 –48) trials respectively. Two ongoing Phase III trials, both involving TKIs, were identified among exclusively RAI-R DTC populations, one evaluating sorafenib versus placebo (44) and the other evaluating lenvatinib versus placebo (49). The remaining trials were single-arm Phase II trials.

Table 2.

Completed, Recruiting, and Ongoing Trials Identified in ClinicalTrials.gov Registry

Intervention [ClinicalTrials.gov identifier]	# of trials	Phase	Histology	Status (as of December 3, 2012)
Axitinib (AG-013736/AG-6013736) [NCT00176748; NCT00389441]	2	II (both)	Any (both)	(1) Completed June 2009(2) Completed September 2012
Bortezomib [NCT00104871]	1	II	PTC, FTC, HCC	Unknown
Cediranib maleate±lenalidomide [NCT01208051]	1	I/II	PTC, FTC, HCC	Recruiting
Decitabine [NCT00085293]	1	II	PTC, FTC	Ongoing, not recruiting
Everolimus (RAD001) [NCT00936858; NCT01164176; NCT01118065]	3	II (all)	(1) MTC, DTC, ATC (2) Any(3) MTC, DTC, ATC	(1) Recruiting(2) Recruiting(3) Unknown
Everolimus (RAD001)+sorafenib [NCT01141309]	1	II	Non ATC	Recruiting
Irofulven+capecitabine [NCT00124527]	1	II	MTC, DTC, ATC	Completed (date NR)
Lenalidomide [NCT00287287]	1	II	PTC, FTC, HCC	Ongoing, not recruiting
Lenvatinib (E7080) alone (Phase II) and vs. placebo (Phase III) [NCT00784303; NCT01321554]	2	(1) II(2) III	(1) MTC, DTC(2) PTC, FTC, HCC	(1) Ongoing, not recruiting(2) Ongoing, not recruiting
Panobinostat (LBH589) [NCT01013597]	1	II	MTC, DTC	Recruiting
Pasireotide, everolimus (RAD001), pasireotide+everolimus [NCT01270321]	1	II	MTC, PTC, FTC, HCC	Recruiting
Romidepsin (FR901228) [NCT00098813]	1	II	PTC, FTC, HCC	Completed July 2012
Sorafenib vs. placebo [NCT00984282]	1	III	PTC, FTC, HCC	Ongoing, not recruiting
Sunitinib [NCT00510640; NCT00381641; NCT00668811]	3	II (all)	(1) Any(2) PTC, FTC, HCC, MTC(3) PTC, FTC	(1) Unknown(2) Ongoing, not recruiting(3) Recruiting
Tanespimycin (17-AAG) [NCT00118248]	1	II	DTC, MTC	Ongoing, not recruiting
Temsirolimus+sorafenib [NCT01025453]	1	II	PTC, FTC, HCC, ATC	Ongoing, not recruiting
Valproic acid [NCT01182285]	1	II	DTC	Recruiting
VB-111 [NCT01229865]	1	II	PTC, FTC, HCC	Ongoing, not recruiting
Vemurafenib (RO5185426) [NCT01286753]	1	II	PTC	Recruiting

ATC, anaplastic thyroid cancer; FTC, follicular thyroid cancer; HCC, Hürthle cell carcinoma; MTC, medullary thyroid cancer; NR, not reported; PTC, papillary thyroid cancer.

Clinical and safety results of the included clinical trials

Detailed summaries of the 20 trials with published results are provided in the Appendix. The most commonly studied drug was sorafenib, with five unique trials in monotherapy (18 –22) (Appendix A) and one trial in combination therapy with temsirolimus, an mTOR inhibitor (31). Sorafenib monotherapy displayed clinical activity with PR rates ranging from 13% among a population of PTC patients who had received prior chemotherapy (19) to 38% among patients with DTC and poorly differentiated thyroid cancers (21,24). No CRs were reported. With respect to survival, treatment with sorafenib resulted in median PFS estimates up to 96 weeks [95% confidence interval (CI) 75.1–135.4 weeks] in a population with DTC and poorly differentiated thyroid cancer (21,24) and median OS estimates up to 37.5 months (∼161 weeks) among a population of PTC patients who had received prior chemotherapy (19). The proportion of patients discontinuing sorafenib therapy due to adverse events was between 6% and 25% in studies by Ahmed et al. (18) and Kloos et al. (19) respectively. For studies of sorafenib monotherapy, patients began at a dose of 400 mg twice daily. A 2012 conference abstract by Sherman et al. evaluated a regimen of sorafenib 200 mg twice daily in combination with weekly temsirolimus via infusion in RAI-R DTC and ATC (31). In this study, there was no CR, yet PR rates among evaluable patients were as high as 38%.

Objective response rates of up to 50% were observed among other TKIs, all of which were administered once daily (Appendix B). Sunitinib demonstrated a CR of 3% and a PR of 28% in a population consisting of 80% DTC patients and 20% MTC patients (30). No other CRs were observed among other TKIs, but PR rates were observed among 14% of patients on motesanib (DTC patients only) (28), 49% of patients on pazopanib (DTC patients only) (29), 50% of patients on lenvatinib (DTC patients only) (27), 8% of patients on vandetanib (DTC patients only) (16), and 30% of patients on axitinib (mixed DTC, MTC, and ATC patients) (25). Gefitinib 250 mg elicited neither a CR nor a PR among a mixed histology population (26). Median PFS ranged from 3.7 months (∼16 weeks) for gefitinib (26) to 18.1 months (∼78 weeks) for axitinib (25). Median OS was only reported for gefitinib, and was 17.5 months (∼75 weeks) among the entire trial population and 27.4 months (∼118 weeks) among only the well-differentiated thyroid cancer population (26). Leboulleux et al. evaluated vandetanib versus placebo in a randomized double-blind trial (the only such trial identified in the review) (16). In this trial, vandetanib significantly improved PFS versus placebo (11.1 months vs. 5.9 months; hazard ratio (HR) 0.63; p=0.017). Median OS was not reported, but no significant difference was observed between treatment arms (HR 0.83; p=0.42). The rate of treatment discontinuation due to adverse events was as high as 33% for patients receiving vandetanib (16). This value was 23% for lenvatinib (27), similar to values seen in the sorafenib trials. Rates of discontinuation due to adverse events among axitinib, motesanib, sunitinib, and gefitinib were lower at 13%, 13%, 11%, and 7% respectively (25,26,28,30). Only 5% of patients receiving pazopanib discontinued due to adverse events (29).

Doxorubicin treatment, currently the only FDA-approved treatment for thyroid cancer that encompasses RAI-R DTC, was reported in only one clinical trial within the parameters of the systematic review (12) (Appendix C). This Phase II single-arm trial evaluated interferon alpha-2b given on days 1–5 and doxorubicin given on day 3 in 28-day cycles among a mixed DTC and ATC population. This regimen resulted in no CRs and a 6% PR rate. Median time to progression (TTP) was 5.9 months (∼25 weeks [CI 4.9–7.0 months]), and median OS was 26.4 months (∼114 weeks [CI 6.7–46.1 months]). Interferon alpha-2b+doxorubicin resulted in a high degree of grade 3–5 toxicity (Appendix C). While discontinuation due to adverse events was not reported, 41% of patients required doxorubicin dose reduction and 12% required interferon alpha-2b dose reduction due to prolonged myelotoxicity.

Aside from TKIs and doxorubicin, several other drug therapies were identified in this systematic review (Appendix C). Studies of VEGF trap (36), rosiglitazone (33), and vorinostat (37) showed no CR or PR, while PR rates for thalidomide, celecoxib, and selumetinib ranged from 3% for selumetinib (34) and celecoxib (32) to 18% on thalidomide (35). In the trial of twice-daily selumetinib among a DTC (exclusively PTC) population, 15% of patients discontinued treatment due to adverse events (34). In the Phase II study of twice-daily celecoxib in a population consisting of exclusively DTC patients, 9% of patients discontinued treatment due to adverse events (32). When once-daily thalidomide was administered to a mixed RAI-R population consisting of DTC, MTC, and insular histologies, 10 of 36 enrolled patients (28%) discontinued treatment due to adverse events (35).

Discussion

While the spectrum of drug therapies available for patients with RAI-R DTC has been recently described in detail (50 –53), to our knowledge this report represents the first systematic literature review performed to identify all relevant clinical and economic studies pertaining to such therapies and to provide a detailed summary of the studies' results. Our findings confirm the unmet need in RAI-R DTC for evidence on the use of optimal or effective therapeutic regimens and their benefit to patients in terms of tumor response, tolerability, patient burden, and cost. Most of the evidence on clinical and safety outcomes for novel RAI-R DTC treatments in the literature reviewed comes from single-arm Phase II nonrandomized trials and highlights the need for more rigorous trial design to establish alternatives to doxorubicin definitively. Another important finding was that our systematic review turned up no economic analyses on RAI-R DTC drug therapies. While this is not surprising at this relatively early point in clinical research investigating targeted therapies in advanced thyroid cancer, it confirms the paucity of information regarding financial burden of illness, impact of cost, and interplay between economic, clinical, and health-related quality of life (HRQoL) outcomes commonly assessed in economic studies.

Our review suggests that within the last decade, targeted molecular therapies, such as TKIs, are emerging as promising treatment options for patients affected with RAI-R DTC based upon Phase II clinical activity. Evidence on toxicity profiles for new therapies is highly variable across trials, but appears to be similar to levels observed for other cancer treatments in other tumor types. Sorafenib is the most studied TKI agent for this patient population in the literature accessed for this review. Unfortunately, head-to-head comparisons among targeted molecular therapies and with older therapies (e.g., doxorubicin) are not available, hampering an ability to discern optimal treatments. However, results of a Phase II randomized controlled trial of vandetanib versus placebo among an advanced or metastatic RAI-R DTC population were very recently published in which vandetanib conferred a statistically significant PFS advantage of 5.2 months, although no significant OS difference was observed (16). While this trial represents the only randomized double-blind clinical trial among RAI-R DTC published since 2000, TKIs are the lead agents being investigated in ongoing research based on review of the CinicalTrials.gov registry (involved in 11 of the 25 trials identified), with notably two Phase III randomized placebo-controlled trials underway: one each for sorafenib (44) and lenvatinib (49).

The findings of our systematic review highlight a number of areas where further research related to RAI-R DTC is required to form a more complete understanding of burden of illness and viable treatment options. First, while we identified 16 unique experimental treatments with published results, all but one (vandetanib) were investigated in Phase II single-arm studies, offering no comparison of the relative efficacy to other treatment. In addition, patient entry criteria varied amongst the Phase II studies, making comparison between agents even more challenging. Comparative evidence within a homogenous patient population is critical in making an informed assessment of effectiveness. As noted, the ongoing randomized placebo-controlled trials investigating sorafenib and lenvatinib in RAI-R DTC will provide the first Phase III data in the TKI era. Phase III studies like these may also give a better perspective on PFS and OS differences between active treatment and placebo, especially as OS may be confounded by subsequent treatments available in clinical practice. Second, advances in genetic profiling of RAI-R DTC patients may help to predict response to a given treatment, allowing a patient to receive the treatment to which he or she is most likely to respond, thus making care more efficient. For example, in their Phase II study of lenvatinib in RAI-R DTC, Ball et al. evaluated tumor genotype as a predictor of response (54). They found that tumors harboring a mutation in KRAS or NRAS were significantly associated with maximum tumor shrinkage (p=0.022) and response rate (p=0.007), as well as a longer PFS versus wild-type tumors (p=0.027; HR 0.20 [CI 0.04–0.95]). This is a potentially valuable finding considering that RAS mutations have been shown to be present in up to 57% of FTCs and significantly associated with poor overall patient survival (55). While more research is needed, such findings reinforce the potential benefit of genetic profiling prior to treatment and predict a shift toward “personalized medicine.” A third area where research is warranted is the merging of clinical efficacy data with economic and HRQoL data to assess burden of illness, cost-effectiveness, or budget impact of the various treatments for RAI-R DTC. With the fairly significant potential impact on HRQoL by TKI treatment, as evidenced by the frequency of adverse events and treatment discontinuation rates reported in clinical trials, coupled with the relatively long treatment periods and lengthy survival of the RAI-R thyroid cancer population, it is critical to put the burden of illness, treatment impact on HRQoL, and cost into perspective. Such research can provide important data on patient burden and help articulate the respective overall impacts of treatments as they become available to patients, payers, and society.

Finally, two important limitations to our study are worth noting. First, the randomized controlled trial of vandetanib versus placebo reported by Leboulleux et al. (16) was added to the review in full-text format after the systematic review had been performed. While this study was initially captured in our ClinicalTrials.gov registry search and is important to the review as it represents the only randomized controlled trial published thus far in RAI-R DTC, we cannot be sure that there are no other recently published studies that could also have been included in the time between the literature searches and publication. Second, there is another goal of drug therapy in the treatment of RAI-R DTC, which is to restore response to RAI. For example, a 2012 conference abstract describes a study of selumetinib among RAI-R DTC patients (56,57), in which selumetinib increased RAI uptake in 12 of 20 evaluable patients, eight to the point where RAI therapy was again possible. While this goal of treatment was not included in the inclusion criteria of our review, it represents an intriguing treatment option, as restoring sensitivity to RAI can minimize time that patients receive other systemic therapies and spare patients troublesome side effects and expense.

Conclusion

In conclusion, RAI-R DTC is a burdensome illness with poor prognosis compared to other thyroid cancers, limited treatment options, and has no true standard of care. Based on the results of our systematic literature review, we conclude that limited clinical research has been conducted among this patient population, with 19 Phase II single-arm trials and one Phase II randomized controlled trial identified over the past 12 years. Furthermore, economic and HRQoL research is lacking. Nevertheless, certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo controlled trials are ongoing. Other treatment modalities that may have promise include genetic profiling for predictive markers and treatment to restore sensitivity to RAI. Finally, new research on economic and humanistic burden of RAI-R DTC that integrates clinical efficacy, cost of care, and HRQoL must be paired with the robust clinical evidence currently in development to highlight both existing burden and future promise in treating patients with this dire illness.

Footnotes

Acknowledgments

The authors would like to thank Victoria Szydlowski and Noemi Kiss, both of Oxford Outcomes, for their assistance with the literature searches, screening, data abstraction, and fact checking in conjunction with this research project. The authors would also like to thank Rachael Fleurence, Director at Oxford Outcomes, for her contributions to study design and leadership.

Author Disclosure Statement

This project was funded by Bayer Healthcare Pharmaceuticals. J.E.L. and V.T. were paid consultants to Bayer Healthcare Pharmaceuticals for this project. R.A. reports no compensation for the role of authorship of this manuscript; he serves as a paid consultant to Bayer Pharma AG relating to patient-reported outcomes assessments. L.J.W. reports no compensation for the role of authorship of this manuscript; she serves as a paid consultant to Bayer Pharma AG and Exelexis. K.K. is an employee of Bayer Healthcare Pharmaceuticals.

Appendix C.

Summary of Published Trials of Other Treatments

	Mrozek et al., 2006 (32)	Argiris et al., 2008 (12)	Kebebew et al., 2009 (33)	Hayes et al., 2012 (34)
Treatment regimen	Celecoxib 400 mg orally twice daily	Doxorubicin 40 mg/m² IV on day 3 + Interferon alpha-2b 12 million units/m² SQ on days 1–5, every 28 days	Rosiglitazone 4 mg orally daily for one week, 8 mg daily for seven weeks	Selumetinib (AZD6244; ARRY-142886) 100 mg orally twice daily
n ^b; % male	n = 32; 41% male	n = 17; 47% male	n = 21; 55% male	n = 39; 67% male
Histology^c	PTC: 66% FTC: 22% HCC: 9% Insular: 3%	FTC: 41% PTC: 29% HCC: 18% ATC: 12%	Classic PTC: 80% HCC: 10% PTC, follicular variant: 5% FTC: 5%	PTC: 100%
Prior therapies	NR	Surgery: 94% RAI: 82% Radiation: 59% Doxorubicin: 18%	NR	Systemic: 23%
Overall survival (median)	NR	26.4 mo. [CI 6.7–46.1]	NR	NR
Progression-free survival or time to progression (median)	NR	TTP = 5.9 mo. [CI 4.9–7.0]	NR	PFS = 32 wk. [CI 8.4–56]
Response rates^d	CR = 0% PR_9m = 3% SD = 38% PD = 59%	CR = 0% PR = 6% SD = 63% PD = 31%	CR_3m = 0% PR_3m = 0%	CR = 0% PR = 3% SD = 66% PD = 31%
Grade 3–5 toxicities occurring in ≥5% of patients	Infection: 9%	Neutropenia: 77% Fatigue: 41% Nausea/vomiting, anorexia: 29% Mucositis: 24% Chills/rigors, visual disturbances, motor neuropathy: 18% Thrombocytopenia, hyponatremia, fever, cardiac: 6%	None	Rash: 18% Fatigue: 8% Diarrhea, peripheral edema: 5%

	Ain et al., 2007 (35)	Sherman et al., 2011 (36) ^a	Woyach et al., 2009 (37)
Treatment regimen	Thalidomide 200 mg orally once daily for two weeks, gradually increasing to 800 mg once daily	VEGF trap 4 mg/kg IV every 14 days	Vorinostat 200 mg orally twice daily for two weeks, one week off treatment, in three-week cycles; dose increase to 300 mg if tolerated
n ^b; % male	n = 36; 67% male	n = 41; 48% male	DTC: n = 16; 31% male	MTC: n = 3; 67% male
Histology^c	Classic PTC: 31% HCC: 22% MTC: 19% Classic FTC: 11% Insular: 11% Tall-cell variant: 6%	PTC: 60% HCC: 28% Poorly diff.: 8% FTC: 5%	DTC: Classic PTC: 75% PTC, follicular variant: 13% FTC: 6% HCC: 6%
Prior therapies	Non-MTC: all patients previously treated with RAI but not cytotoxic chemo. MTC: no patients were previously treated with RAI or systemic agents.	NR	DTC: RAI: 100%Surgery: 94%Radiation: 38%Chemo: 38%	MTC: Surgery: 100%Radiation: 67%Chemo: 67%
Overall survival (median)	17 mo.	NR	NR
Progression-free survival or time to progression (median)	NR	NR	NR
Response rates^d	CR = 0%PR = 18% [CI 6–37%]SD = 32% [CI 12–42%]PD = 50%	CR = 0%PR = 0%SD = 83%PD = 18%	DTC: CR = 0%PR = 0%SD = 56%PD_<12w = 19%PD_12w = 6%PD_24w = 6%PD_36w = 6%	MTC: CR = 0%PR = 0%SD = 0%PD_24w = 33%
Grade 3–5 toxicities occurring in ≥5% of patients	Infection without neutropenia: 11%Fatigue/somnolence: 8%Peripheral neuropathy: 6%	Grade 4 proteinuria: 8%	Fatigue, thrombocytopenia: 26%Dehydration, bronchitis/pneumonia, high PT/INR, low calcium: 11%Ataxia, bruising/hematoma, deep vein thrombosis, arterial thrombosis, neutropenia, lymphopenia, hyperglycemia: 5%

Abstract.

Refers to the number enrolled in each study. The number enrolled or randomized is sometimes slightly different from the number evaluable for patient characteristics, efficacy, or safety in each trial.

Due to rounding, percentages may not sum to 100%.

According to RECIST. Unless otherwise noted, time frame not specified for evaluation of response rates. Subscript numbers represent time frame in months (m) or weeks (w).

PT/INR, prothrombin time/international normalized ratio; SQ, subcutaneous.

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