- Email: [email protected]
Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer
Accepted Manuscript Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer R.Michael Tuttle, MD, Marcia S. Brose, MD, PhD, Enrique Grande, MD, Sun Wook Kim, MD, Makoto Tahara, MD, Mona M. Sabra, MD PII:
S1521-690X(17)30042-8
DOI:
10.1016/j.beem.2017.04.014
Reference:
YBEEM 1155
To appear in:
Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Tuttle RM, Brose MS, Grande E, Kim SW, Tahara M, Sabra MM, Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer, Best Practice & Research Clinical Endocrinology & Metabolism (2017), doi: 10.1016/ j.beem.2017.04.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine
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refractory differentiated thyroid cancer
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R Michael Tuttle, MD,1 Marcia S. Brose, MD, PhD,2 Enrique Grande, MD,3 Sun Wook Kim,
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MD,4 Makoto Tahara, MD,5 Mona M. Sabra, MD1
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Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA;
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Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the
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University of Pennsylvania, Philadelphia, PA, USA; 3Medical Oncology Department, Ramón y
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Cajal University Hospital, Madrid, Spain; 4Division of Endocrinology and Metabolism,
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Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of
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Medicine, Seoul, Korea; 5Department of Head and Neck Medical Oncology, National Cancer
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Center Hospital East, Kashiwa, Chiba, Japan
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Author Contact Information:
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R Michael Tuttle
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Endocrinology Service, Department of Medicine
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Memorial Sloan Kettering Cancer Center,
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New York, NY, USA
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Email: [email protected]
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Marcia S. Brose
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Director, Center for Rare Cancers and Personalized Therapy
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Abramson Cancer Center
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Associate Professor
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Department of Otorhinolaryngology: Head and Neck Surgery,
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Department of Medicine, Division of Hematology and Oncology,
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University of Pennsylvania, Perelman School of Medicine,
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Philadelphia, PA, USA
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Phone: 1-215-746-7344; Fax: 1-215-8982136; Email: [email protected]
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Enrique Grande
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Servicio de Oncología Médica,
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Hospital Universitario Ramón y Cajal de Madrid,
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28034-Madrid, SpainPhone: +34913368263; Fax: +34913369181; Email:
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[email protected]
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Sun Wook Kim
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Professor
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Thyroid Center
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Division of Endocrinology and Metabolism,
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Samsung Medical Center
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Sungkyunkwan University School of Medicine, Seoul, Korea
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Phone: +82-2-3410-1653; Fax: +82-2-6918-4653; Email: [email protected]
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Makoto Tahara
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Chief, Department of Head and Neck Medical Oncology,
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National Cancer Center hospital East
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6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
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Phone: +81-47133-1111; Fax: +81-4734-6957; Email: [email protected]
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Mona M. Sabra
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Endocrinology Service, Department of Medicine,
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Memorial Sloan Kettering Cancer Center,
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New York, NY, USA.
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Email: [email protected]
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ABSTRACT
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Multitargeted kinase inhibitors have been shown to improve progression-free survival in patients
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with structurally progressive, radioactive-iodine refractory differentiated thyroid cancer. While
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the inclusion criteria for phase 3 clinical trials and clinical practice guidelines provide guidance
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with regard to the minimal requirements that need to be met prior to initiation of a multitargeted
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kinase inhibitor, a better way to integrate the rate of structural disease progression with the size
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of the metastatic foci to more precisely define the optimal time to recommend initiation of
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therapy for individual patients is needed.
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assessments of tumor size and growth rates (structural disease doubling times) to define the
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critical point in time when the volume and rate of progression of metastatic structural disease
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merits consideration for initiation of systemic therapy (the inflection point).
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Keywords: inflection point, doubling time, growth curves, thyroid cancer
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In this manuscript we describe how to use
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Introduction
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A structural incomplete response to initial therapy (persistent or recurrent structural disease) is
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seen in up to 30% of patients with differentiated thyroid cancer who have been treated with total
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thyroidectomy and radioactive-iodine (RAI) remnant ablation (1-3). While the majority of
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structural incomplete responses will have persistent disease only in the neck, as many as 5% to
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10% may have distant metastasis at presentation, with an additional 5% to 10% developing
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distant metastases during follow-up (4). The majority of distant metastases are located in the
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lungs, with a smaller number located in the bones or in other sites (4). While many distant
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metastases remain asymptomatic, disease progression can be associated with a wide variety of
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symptoms, including pain and dyspnea on exertion.
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Although two-thirds of patients with metastatic disease demonstrate substantial uptake of RAI, only 42% demonstrate complete structural resolution of their disease, and fewer than 10%
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demonstrate complete resolution of both biochemical and structural evidence of disease (5-7).
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While 10-year survival rates of > 95% have been documented in young patients with distant
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metastases, a median 10-year overall survival rate of < 50% can be expected in older patients
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with either papillary or follicular thyroid cancer presenting with distant metastases (8, 9).
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Unfortunately, long-term overall survival drops to 10% when distant metastases are not
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responsive to RAI therapy (5). Further, overall survival is significantly worse in patients with
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bone or brain metastases (6, 10). While traditional chemotherapy is associated with short-term
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response rates of ≤ 25% (11), multitargeted kinase inhibitors have demonstrated much better
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results with documented improvements in progression-free survival associated with a tolerable
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side-effect profile (12-15).
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In a recently described cohort of 199 patients with pulmonary metastases, an increase in the size and/or number of metastatic foci was documented by Sabra and colleagues in 68% of
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patients despite repeated doses of RAI therapy (Figure 1) (6). For the entire cohort, the median
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time to progression was 3.7 years, with 17 % of patients progressing by the end of year 1, 35%
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by year 2, 55% by year 5, and 65% by year 10. However, disease progression occurred sooner
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and more often in RAI refractory patients (Table 1). Further, progression-free survival was
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significantly worse in patients with aggressive histologies (poorly differentiated thyroid cancer,
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hurthle cell cancer), fluorodeoxyglucose-positron emission tomography (FDG-PET) avid disease,
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metastatic lesions > 1 cm in diameter, bone metastasis, and in patients over 45 years of age at the
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time the metastatic disease was identified (6).
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With the approval of two oral multitargeted kinase inhibitors (lenvatinib and sorafenib)
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for the treatment of RAI refractory thyroid cancer, the clinician and the patients are now faced
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with the challenging decision of when to initiate multitargeted kinase inhibitor therapy. Both
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agents are approved for progressive or symptomatic RAI refractory thyroid cancer that is not
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amenable to localized therapies. However, in clinical practice, it is quite common to see patients
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with RAI refractory disease that is either stable or slowly progressive. Further, in some patients,
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the pace of clinical disease progression appears to increase as the metastatic lesions increase in
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size. Therefore, the precise time point in the clinical course of disease progression to initiate
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therapy for an individual patient can be difficult to identify. As such, treatment of advanced
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thyroid cancer is optimally undertaken in the context of a functional, integrated, disease-
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management team because management of these patients may require extensive surgery, external
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beam irradiation, radiofrequency ablation, embolization, or metastasectomy either in addition to
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or prior to starting other multitargeted kinase inhibitor therapies (16). Because oncologists and
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other specialists that give multitargeted inhibitors often will need to educate and establish a
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relationship with the patient prior to the initiation of treatment, the discussion below should be
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used to help all health care providers in anticipating when a patient may be approaching the need
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for multitargeted inhibitors and initiate timely referrals to the treating physicians.
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Examining the time course of disease progression in individual patients with distant metastases
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In clinical practice, it is very apparent that the rate of disease progression and the
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likelihood that the metastatic disease will become life-threatening varies dramatically among
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individual patients with distant metastases. Several of the common patterns of disease
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progression are presented in Figure 2 where the volume of disease is plotted along the y-axis and
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the time from diagnosis presented along the x-axis. In this theoretical figure, patients
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demonstrating more rapid disease progression over time (Figure 2 curves A, B and C) can be
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expected to reach a lethal tumor burden more quickly than patients with slowly growing (Figure
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2 curve D) or stable disease (Figure 2 curves E and F).
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The biological basis for these theoretical volume of disease curves is the long-standing observation that human malignant tumors demonstrate a pattern of exponential growth
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(1248163262128 cells) that remains remarkably constant over time until large
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burdens of disease are achieved (17-19). It is important to remember that, because tumor growth
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is exponential, relatively small changes in tumor diameter are associated with much larger
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changes in tumor volume that often become clinically more problematic as the tumors exceed 1
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cm in diameter (Figure 3). Because of their near constant exponential growth pattern, the time
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required for a tumor to increase in diameter from 0.5 to 8 cm across a spectrum of doubling
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times can be demonstrated by graphing the diameter of the largest metastatic foci (in
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centimeters) versus follow-up time in years (Figure 4A). To facilitate the use of the growth
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curves as predictors of outcomes in clinical practice, it is easier to visualize exponential doubling
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time curves as straight lines by expressing them as semilog plots where the diameter is presented
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on a logarithmic scale on the y-axis with time on the standard x-axis linear scale (Figure 4B).
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The semilog curves make it easier to predict tumor diameters that can be expected in the future
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once the diameter doubling time has been established for particular metastatic foci.
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While the figures and tables in this manuscript largely describe doubling times in terms
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of change in diameter of individual metastatic lesions, it is important to note that eligibility for
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clinical trials allows for measurement of up to 5 metastatic foci in different organ locations, with
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preference given to the lesions with the greatest diameter that can be reproducibly measured with
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accuracy. Because of the potential for heterogeneity of growth rates among metastatic foci, it is
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likely that a doubling time calculated using the sum of diameters of multiple metastatic foci may
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more accurately reflect the clinical course of the disease than measurements of individual lesions.
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Identifying the clinical inflection point
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Rather than using “inflection point” in a strictly mathematical sense (the precise point at which a curve changes from convex to concave or vice versa), we are using the term in more of a
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general sense to designate a turning point or significant change in the clinical situation. From a
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clinical perspective, crossing over the 1-cm diameter threshold is an important boundary and
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represented the minimum size required for participation in most prospective therapeutic clinical
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trials. Even though the tumor size doubling time is constant as tumors increase in size, the
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clinical impact of increasing tumor diameter becomes much more significant as the tumor
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diameter exceeds 1 cm (See Figure 3). For tumor diameters < 1 cm, biomarker doubling times
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may provide a reliable estimate of tumor growth prior to the time when the volume of disease is
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large enough to be reliably measured with cross-sectional imaging (18, 20-22). The rapidity with which a tumor passes through the inflection point is dependent on the
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doubling time, with a far quicker transition in tumors demonstrating a 6-month diameter
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doubling time (6–12 months) compared with tumors demonstrating a 2 year diameter doubling
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time (2–4 years). Therefore, we picture the inflection point as a region on the growth curves that
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integrates both volume of disease and tumor growth rates (doubling times) as depicted by the
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grey triangle on Figure 4B.
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As illustrated in Figures 4A and 4B, the rate of disease progression (represented by the slope of the line or the actual doubling time ) will be the primary determinant in the development
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of a life-threatening mass of metastatic disease (18). If a treatment (or combination of
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treatments) significantly decreases the volume of disease and the growth rate remains stable, one
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could reasonably expect improved clinical outcomes even though asymptomatic small volume
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disease may continue to progress and eventually become clinically apparent at a time predicted
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by the underlying tumor doubling time. However, in the case of multitargeted kinase inhibitor
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treatments that decrease the growth rate (and prolong the diameter doubling time), it is possible
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that the time to the development of a lethal tumor mass may be delayed by months to years.
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As previously noted, the rate of change in either the tumor biomarkers or structurally
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evident disease usually remains quite constant over time in the absence of multitargeted kinase
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inhibitor therapies that might affect the secretion of these biomarkers (18-22). However,
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occasionally, the rate of disease progression will dramatically increase such that the rate of
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growth departs from the original predicted slope. In these cases, additional mutations acquired
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during follow up, or alternatively, upregulation of an already active pathway, may provide a
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growth advantage to a subclone of the thyroid cancer. This may occur in the case of the
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development of a new site of disease and is not accounted for in the above models. This subclone
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may define a new more rapid growth rate (and hence a new slope and doubling time) and is often
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associated with de-differentiation of the tumor histology and a shift toward markedly FDG PET
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avid disease (23). If a solitary site of disease such as this develops in the setting of slower
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growing disease, local therapy might be considered to restore the previously slower growth rate
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and allow a longer period prior to initiation of multitargeted kinase inhibitor therapy. Still, the
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vast majority of disease progression follows the initially predicted biochemical and structural
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growth curves for many years after diagnosis (18, 20-22, 24).
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Guidance from phase 3 trial entry criteria and cancer-management guidelines regarding
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initiation of multitargeted kinase inhibitor therapy in RAI refractory disease
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Inclusion criteria for the prospective, randomized, registration trials for sorafenib and
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lenvatinib required an increase of ≥ 20% in the sum of the longest diameters of target lesions
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defined by Response Evaluation Criteria in Solid Tumors (RECIST) over either a 13-month
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(lenvatinib) or 14-month (sorafenib) period (12, 15) or the identification of a new lesion. Based
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primarily on expert opinion, the 2015 American Thyroid Association thyroid cancer-
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management guidelines suggested that a 20% increase over a 6-month period should prompt
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consideration of multitargeted kinase inhibitor therapies (25). Similarly, a group of thyroid
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cancer experts also recommend using a minimum tumor volume (> 1 cm) with structural disease
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progression as defined by RECIST progression over < 12-14 months to define the time point to
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initiate systemic therapy in radioactive iodine refractory thyroid cancer (26). The National
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Comprehensive Cancer Network guidelines noted that the “pace of disease progression should be
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prompt initiation of kinase inhibitor therapy in patients with RAI refractory differentiated thyroid
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cancer or medullary thyroid cancer (27). While RECIST evaluations are the primary tool for
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evaluating changes in disease status in clinical trials, they are not used in clinical practice and
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can be a challenge to apply retrospectively. Therefore, we sought an alternative way to describe
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tumor growth rates that would be more accessible and understandable to clinicians and patients.
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Table 2 shows the relationship between the percentage increase per year in tumor
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diameter, which form the basis for current recommendations regarding initiation of multitargeted
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kinase inhibitor therapy, and tumor diameter doubling times for a hypothetical metastatic foci
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measured as 1 cm in maximal diameter at baseline. A 20% increase in metastatic foci diameter
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over a 12 to 14-month period would approximate a doubling time of 4 years. A 20% increase in
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tumor diameters over a 6-month period would correlate with a diameter doubling time of
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approximately 2 years (≈ 40% growth over 1 year).
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demonstrating a maximum diameter doubling time of < 2–4 years would meet the criteria for
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consideration for multitargeted kinase inhibitor therapy. Asymptomatic metastatic lesions in
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noncritical locations with tumor diameter doubling times longer than 4 years could be considered
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for active surveillance.
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A practical approach to using growth rates and the inflection point to guide clinical management An individualized assessment of the rate of structural disease progression is the cornerstone of critical decision-making in patients with advanced metastatic thyroid cancer. In its
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simplest form, patients with slow disease progression, manifest by longer tumor doubling times,
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can be followed with less frequent cross-sectional imaging and less aggressive treatment
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interventions than patients demonstrating more rapid structural disease progression. Tumor
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volume doubling times can be calculated using freely available online calculators from either the
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American Thyroid Association (http://www.thyroid.org/professionals/calculators/thyroid-with-
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nodules/) or from the Kuma Hospital (http://www.kuma-h.or.jp/english/about/doubling-time-
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progression-calculator/) web sites. When evaluating patients with thyroid cancer with
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structurally identifiable distant metastases, we find that the answers to 4 critical questions can
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provide valuable insights that can guide optimal management recommendations (Figure 5):
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1. Are the metastatic lesions RAI refractory?
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2. Is the patient symptomatic or at risk for developing symptoms because of the location of
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3. Is the rate of structural disease progression established?
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4. Has the tumor reached the 1- to 2-cm inflection point?
After determining whether the metastatic lesions are RAI avid and assessing the presence
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or likelihood of rapidly developing clinical symptoms, the key factors that guide the proper
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timing for initiation of other multitargeted kinase inhibitor therapies include tumor size and the
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rate of structural disease progression. Because the inflection-point concept integrates both tumor
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doubling time and volume of disease estimates, it can be used to guide decision- making with
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regard to when it would be appropriate to consider initiation of multitargeted kinase inhibitor
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therapy.
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Crossing the inflection point at approximately 1 cm in diameter is a minimal requirement for consideration of multitargeted kinase inhibitor therapies, based on the two phase 3 trials that
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have been completed. In our opinion, while patients with very rapid diameter doubling times (< 1
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year) should be considered for multitargeted kinase inhibitor therapy as their tumors approach 1
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cm in diameter, patients with longer doubling times (1–4 years) may not require initiation of
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therapy until tumors are in the 1.5- to 2-cm range depending on overall tumor volume, symptoms,
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location of disease and patient preference (Table 3). Graphically, the threshold to consider
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initiation of multitargeted kinase inhibitor therapy within each of the established diameter
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doubling time growth curves is depicted by a grey triangle in Figure 4B.
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Tumors with even longer doubling times (> 4 years) may not require multitargeted kinase inhibitor therapy for some time depending on the starting tumor volumes. In our view, though
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they are at risk for continued disease progression, asymptomatic patients with longer doubling
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times and subcentimeter metastases that have not passed through the inflection point should
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generally be followed with close observation. Active surveillance can allow these patients a
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prolonged period of symptom-free living without the side effects of the multitargeted kinase
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inhibitor therapies and, thus, can be pursued in these cases. Our recommended approach is,
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therefore, observation with serial imaging in the vast majority of asymptomatic patients with
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metastatic lesions demonstrating a doubling time greater than 4 years.
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Thus multitargeted kinase inhibitor therapy would be considered: (1) at the 1- to 2-cm
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inflection point, or possibly earlier, in patients with RAI refractory disease with doubling times
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< 2–4 years or (2) after passing through the inflection point, if ever, in patients with stable or
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very slowly progressive disease (doubling times > 4 years). It is important to emphasize that
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therapeutic interventions should be initiated without regard to the inflection point if the patient
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has (1) tumor associated symptoms such as dyspnea on exertion and cachexia, (2) lytic bone
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metastases that may benefit from bisphosphonate or rank ligand inhibitor therapy, (3) metastatic
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disease likely to cause local symptoms that can be treated with a directed therapy such as
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surgical resection, EBRT, embolization, or radiofrequency ablation, or (4) patients with a very
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high overall tumor volume despite smaller sized lesions (e.g. multiple lesions that may only have
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a maximal tumor volume of 1 cm, but overall due to high number represent a greater risk of
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symptomatic progression).
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progression through the 1- to 2-cm inflection point is not a requirement for additional RAI
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therapies as these treatments work best in low volume (5). Continued decrease in tumor volume
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in response to previous treatments may prompt additional RAI treatments depending on the age
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of the patient, the volume of residual disease, the rate of disease progression, the cumulative
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administered activity of RAI, side-effect profile for individual patients, and patient desires/goals.
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However, because fewer than 10% of RAI avid patients will achieve complete remission,
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observation is usually recommended for patients with persistent, stable small-volume disease or
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patients with only biochemical evidence of persistent disease (6).
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In addition to using the doubling time curves as one of the key indicators for initiation of
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multitargeted kinase inhibitor therapy, they can also be used to evaluate the efficacy (or failure)
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of ongoing treatments. Traditionally, a multitargeted inhibitor is discontinued once the patient
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documents clinically significant structural disease progression, which may be required as part of
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the clinical trial design. However, we would argue that an agent may still be having a clinically
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significant effect if treatment is associated with a clinically significant increase in doubling time,
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even if structural disease progression eventually develops. Rather than using disease stability as
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the only indicator of treatment success, a paradigm that emphasizes the impact of drug treatment
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on increasing the doubling time would identify patients in whom even slowly growing disease
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would still be considered evidence of treatment efficacy if the doubling rate has been decreased
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enough to predict a likely improvement in progression-free survival or overall survival. In this
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approach, a switch to another agent would be delayed until there was evidence not only of
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disease progression, but progression with a rapid doubling time indicative of a lack of efficacy of
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the current drug. Using this approach, tumor doubling time could be used to evaluate both the
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appropriateness of initiating multitargeted kinase inhibitor therapy and the interpretation of the
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efficacy of ongoing therapy.
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Summary
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Optimal management of patients with metastatic differentiated thyroid cancer requires careful consideration of multiple tumor-associated and patient-related factors within the context
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of an experienced multidisciplinary team. Because our current multitargeted kinase inhibitor
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therapy options are seldom curative, either in the RAI refractory or RAI responsive disease
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setting, proper selection of patients for intervention with treatment options that are either
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palliative or designed to slow disease progression is critical. Optimal decision-making with
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regard to when to initiate multitargeted kinase inhibitor therapy in the metastatic disease setting
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requires the clinician and the patient to thoughtfully integrate an understanding of the patient’s
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symptom burden, tumor progression, and potential tolerance of treatment-related side effects.
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Practice Points
Multi-targeted kinase inhibitors have demonstrated improvement in progression free survival in patients with structurally progressive, radioactive iodine refractory thyroid
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cancer.
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mortality in radioactive iodine refractory thyroid cancer.
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Tumor burden, location and growth rates are the primary determinates of morbidity and
Increases in tumor size are remarkably consistent over time and follow classical
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exponential growth curves with distinct structural doubling times.
Relatively small increases in tumor diameter are associated with much larger increases in
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tumor volume which often becomes clinically significant as the tumor diameter exceeds 1
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cm.
By integrating tumor size (maximal diameter) with the rate of structural disease
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progression (tumor diameter doubling times), it is possible to identify a period of time
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(the inflection point) where the structural disease progression is becoming clinically
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significant.
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The inflection point should identify the earliest time point that consideration should be
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given for the initiation of multi-targeted kinase inhibitors in otherwise asymptomatic patients.
Prolongation of structural disease doubling time, even if associated with slow disease
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progression, would demonstrate a favorable therapeutic effect of multi-targeted kinase
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inhibitor therapy.
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Research Agenda
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Trials are needed that specifically examine the effectiveness of multi-targeted kinase inhibitors based on tumor size and structural disease doubling times.
Trials are needed to determine if initiating multi-targeted kinase inhibitors at the time
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of clinically significant disease progression (the inflection point) is better or worse
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than starting treatment either before or after that time point.
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Further research is needed to determine if improvements in structural disease
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doubling times, despite some degree of structural disease progression, is indicative of
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continued therapeutic effectiveness.
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Acknowledgements
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This study was funded by Eisai Inc. Editorial assistance was provided by Oxford PharmaGenesis
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Inc. and was funded by Eisai Inc.
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Author Disclosure Statement
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RMT has served as a paid consultant for Eisai and Bayer.
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MB has served as a paid consultant for Eisai and Bayer.
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EG has served as a paid consultant for Eisai and Bayer.
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SWK has served as a paid consultant for Eisai and Bayer.
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MT has received grants and research support from Eisai, MSD, Boehringer Ingelheim,
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AstraZeneca, Ono, Novartis, Bayer, NanoCarrier, Pfizer and has served as paid consultant for
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Merck Serono, MSD, BMS, Bayer, Eisai, Otsuka, Astra Zeneca and Pfizer
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MS Nothing to disclose
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Address correspondence to:
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R Michael Tuttle, MD
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Endocrinology Service, Department of Medicine
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Memorial Sloan Kettering Cancer Center
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1275 York Avenue, New York, NY, USA 10021
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Email: [email protected]
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*17. *18. 19.
Vaisman F, Momesso D, Bulzico D, et al. Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy. Clin Endocrinol (Oxf) 2012; 77: 132-138. Vaisman F, Tala H, Grewal R, et al. In differentiated thyroid cancer, an incomplete structural response to therapy is associated with significantly worse clinical outcomes than only an incomplete thyroglobulin response. Thyroid 2011; 21: 1317-22. Haugen BR and Sherman SI. Evolving approaches to patients with advanced differentiated thyroid cancer. Endocr Rev 2013; 34: 439-55. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91: 2892-9. Sabra M, Ghossein R, and Tuttle M. Time course and predictors of structural disease progression in pulmonary metastases arising from follicular cell derived thyroid cancer. Thyroid 2015: In press. 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 2013; 98: E829-36. Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer 1998; 83: 2638-48. Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006; 16: 1229-42. Henriques de Figueiredo B, Godbert Y, Soubeyran I, et al. Brain metastases from thyroid carcinoma: a retrospective study of 21 patients. Thyroid 2014; 24: 270-6. Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am 2008; 37: 511-24, xi. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014; 384: 319-28. Marotta V, Sciammarella C, Vitale M, et al. The evolving field of kinase inhibitors in thyroid cancer. Crit Rev Oncol Hematol 2015; 93: 60-73. Schlumberger M and Leboulleux S. Treatment of distant metastases from follicular cellderived thyroid cancer. F1000Prime Rep 2015; 7: 22. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodinerefractory thyroid cancer. N Engl J Med 2015; 372: 621-30. Carty SE, Doherty GM, Inabnet WB, 3rd, et al. American Thyroid Association statement on the essential elements of interdisciplinary communication of perioperative information for patients undergoing thyroid cancer surgery. Thyroid 2012; 22: 395-9. Collins VP, Loeffler RK, and Tivey H. Observations on growth rates of human tumors. Am J Roentgenol Radium Ther Nucl Med 1956; 76: 988-1000. Friberg S and Mattson S. On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol 1997; 65: 284-97. Norton L, Simon R, Brereton HD, et al. Predicting the course of Gompertzian growth. Nature 1976; 264: 542-5.
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Barbet J, Campion L, Kraeber-Bodere F, et al. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 2005; 90: 6077-84. Miyauchi A, Kudo T, Miya A, et al. Prognostic impact of serum thyroglobulin doublingtime under TSH suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy. Thyroid 2011; 7: 707-716. Miyauchi A, Onishi T, Morimoto S, et al. Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma. Ann Surg 1984; 199: 461-6. Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res 2009; 69: 4885-93. Sabra M, Sherman E, and Tuttle M. Tumor volume doubling time of the pulmonary metastases predicts overall survival and can guide the initiation of multi-kinase inhibitor therapy in metastatic follicular cell derived thyroid carcinoma. Cancer 2017; Apr 3. doi: 10.1002/cncr.30690. [Epub ahead of print]. 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 2016; 26: 1-133. Schlumberger M, Brose M, Elisei R, et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol 2014; 2: 3568. Network NCC. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma version 1.2016. 2016 [cited 2016 November 12].
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TABLES TABLE 1. CUMULATIVE PERCENTAGE OF PATIENTS DEMONSTRATING DISEASE
446
PROGRESSION OVER TIME
447
RAI avid disease
RAI refractory disease
1
17
12
29
2
35
5
55
10
65
RAI, radioactive iodine.
448
452 453 454 455
41
83
53
91
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451
53
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450
26
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449
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Entire cohort
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Year, %
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456 457
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TABLE 2. RELATIONSHIP BETWEEN PERCENTAGE INCREASE IN LARGEST TUMOR DIAMETER AND
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CORRESPONDING DIAMETER DOUBLING TIME
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Increase in largest tumor diameter per year, %
Size of metastatic focus, cm
Corresponding diameter doubling time, years
(1 cm in diameter at baseline)
20% 30% 40%
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50%
461 462 463 464
1.3
2.7
1.4
2.1
1.5
1.7
1.8
1.2
2.0
1.0
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3.8
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100%
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75%
1.2
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TABLE 3. DIAMETER DOUBLING TIMES AND TUMOR DIAMETERS THAT SHOULD PROMPT CONSIDERATION FOR
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MULTITARGETED KINASE INHIBITOR THERAPY Diameter doubling time, years
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Corresponding increase in
Diameter of metastatic focus that should
maximum diameter per year, %
prompt consideration for initiation of
Corresponding tumor volume, mL
multitargeted kinase inhibitor therapy, cm
469 470 471 472
40–100
2–4
20–40
>4
< 20
0.5
1.0–1.5
0.5–1.8
1.5–2.0
1.8–4.2
Usually not indicated
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100
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<1
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FIGURE TITLES AND LEGENDS
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FIG 1. Overall survival and progression-free survival in a cohort of 199 patients with pulmonary
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metastases from nonanaplastic follicular cell-derived thyroid cancer.
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CI, confidence interval.
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477
FIG 2. Theoretical growth curves representing the most common patterns observed in clinical
479
practice in patients with metastatic disease that continues to be RAI responsive or becomes RAI
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refractory.
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RAI, radioactive iodine.
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FIG 3. Relationship between tumor diameter and tumor volume demonstrating dramatic
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increases in tumor volume, with relatively small changes in tumor diameter.
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FIG 4. Growth curves for a tumor growing from 0.5 to 8 cm in maximal diameter with a
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doubling time of 6 months, 1 year, 2 years, and 4 years plotted as (A) the diameter of the lesion
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versus time or (B) the log of the lesion diameter versus time (semilog).
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The inflection point (indicated by the grey triangle in panel B) is critical point in time when the
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volume and rate of progression of metastatic structural disease merits consideration for initiation
498
of systemic therapy.
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FIG 5. Therapeutic decision-making in metastatic thyroid cancer.
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RAI, radioactive iodine.
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S1521-690X(17)30042-8
DOI:
10.1016/j.beem.2017.04.014
Reference:
YBEEM 1155
To appear in:
Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Tuttle RM, Brose MS, Grande E, Kim SW, Tahara M, Sabra MM, Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer, Best Practice & Research Clinical Endocrinology & Metabolism (2017), doi: 10.1016/ j.beem.2017.04.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine
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refractory differentiated thyroid cancer
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R Michael Tuttle, MD,1 Marcia S. Brose, MD, PhD,2 Enrique Grande, MD,3 Sun Wook Kim,
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MD,4 Makoto Tahara, MD,5 Mona M. Sabra, MD1
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Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA;
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Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the
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University of Pennsylvania, Philadelphia, PA, USA; 3Medical Oncology Department, Ramón y
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Cajal University Hospital, Madrid, Spain; 4Division of Endocrinology and Metabolism,
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Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of
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Medicine, Seoul, Korea; 5Department of Head and Neck Medical Oncology, National Cancer
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Center Hospital East, Kashiwa, Chiba, Japan
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Author Contact Information:
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R Michael Tuttle
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Endocrinology Service, Department of Medicine
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Memorial Sloan Kettering Cancer Center,
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New York, NY, USA
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Email: [email protected]
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Marcia S. Brose
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Director, Center for Rare Cancers and Personalized Therapy
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Abramson Cancer Center
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Associate Professor
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Department of Otorhinolaryngology: Head and Neck Surgery,
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Department of Medicine, Division of Hematology and Oncology,
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University of Pennsylvania, Perelman School of Medicine,
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Philadelphia, PA, USA
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Phone: 1-215-746-7344; Fax: 1-215-8982136; Email: [email protected]
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Enrique Grande
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Servicio de Oncología Médica,
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Hospital Universitario Ramón y Cajal de Madrid,
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28034-Madrid, SpainPhone: +34913368263; Fax: +34913369181; Email:
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[email protected]
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Sun Wook Kim
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Professor
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Thyroid Center
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Division of Endocrinology and Metabolism,
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Samsung Medical Center
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Sungkyunkwan University School of Medicine, Seoul, Korea
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Phone: +82-2-3410-1653; Fax: +82-2-6918-4653; Email: [email protected]
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Makoto Tahara
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Chief, Department of Head and Neck Medical Oncology,
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National Cancer Center hospital East
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6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
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Phone: +81-47133-1111; Fax: +81-4734-6957; Email: [email protected]
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Mona M. Sabra
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Endocrinology Service, Department of Medicine,
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Memorial Sloan Kettering Cancer Center,
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New York, NY, USA.
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Email: [email protected]
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ABSTRACT
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Multitargeted kinase inhibitors have been shown to improve progression-free survival in patients
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with structurally progressive, radioactive-iodine refractory differentiated thyroid cancer. While
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the inclusion criteria for phase 3 clinical trials and clinical practice guidelines provide guidance
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with regard to the minimal requirements that need to be met prior to initiation of a multitargeted
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kinase inhibitor, a better way to integrate the rate of structural disease progression with the size
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of the metastatic foci to more precisely define the optimal time to recommend initiation of
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therapy for individual patients is needed.
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assessments of tumor size and growth rates (structural disease doubling times) to define the
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critical point in time when the volume and rate of progression of metastatic structural disease
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merits consideration for initiation of systemic therapy (the inflection point).
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Keywords: inflection point, doubling time, growth curves, thyroid cancer
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In this manuscript we describe how to use
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Introduction
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A structural incomplete response to initial therapy (persistent or recurrent structural disease) is
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seen in up to 30% of patients with differentiated thyroid cancer who have been treated with total
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thyroidectomy and radioactive-iodine (RAI) remnant ablation (1-3). While the majority of
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structural incomplete responses will have persistent disease only in the neck, as many as 5% to
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10% may have distant metastasis at presentation, with an additional 5% to 10% developing
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distant metastases during follow-up (4). The majority of distant metastases are located in the
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lungs, with a smaller number located in the bones or in other sites (4). While many distant
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metastases remain asymptomatic, disease progression can be associated with a wide variety of
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symptoms, including pain and dyspnea on exertion.
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Although two-thirds of patients with metastatic disease demonstrate substantial uptake of RAI, only 42% demonstrate complete structural resolution of their disease, and fewer than 10%
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demonstrate complete resolution of both biochemical and structural evidence of disease (5-7).
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While 10-year survival rates of > 95% have been documented in young patients with distant
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metastases, a median 10-year overall survival rate of < 50% can be expected in older patients
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with either papillary or follicular thyroid cancer presenting with distant metastases (8, 9).
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Unfortunately, long-term overall survival drops to 10% when distant metastases are not
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responsive to RAI therapy (5). Further, overall survival is significantly worse in patients with
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bone or brain metastases (6, 10). While traditional chemotherapy is associated with short-term
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response rates of ≤ 25% (11), multitargeted kinase inhibitors have demonstrated much better
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results with documented improvements in progression-free survival associated with a tolerable
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side-effect profile (12-15).
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In a recently described cohort of 199 patients with pulmonary metastases, an increase in the size and/or number of metastatic foci was documented by Sabra and colleagues in 68% of
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patients despite repeated doses of RAI therapy (Figure 1) (6). For the entire cohort, the median
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time to progression was 3.7 years, with 17 % of patients progressing by the end of year 1, 35%
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by year 2, 55% by year 5, and 65% by year 10. However, disease progression occurred sooner
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and more often in RAI refractory patients (Table 1). Further, progression-free survival was
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significantly worse in patients with aggressive histologies (poorly differentiated thyroid cancer,
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hurthle cell cancer), fluorodeoxyglucose-positron emission tomography (FDG-PET) avid disease,
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metastatic lesions > 1 cm in diameter, bone metastasis, and in patients over 45 years of age at the
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time the metastatic disease was identified (6).
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With the approval of two oral multitargeted kinase inhibitors (lenvatinib and sorafenib)
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for the treatment of RAI refractory thyroid cancer, the clinician and the patients are now faced
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with the challenging decision of when to initiate multitargeted kinase inhibitor therapy. Both
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agents are approved for progressive or symptomatic RAI refractory thyroid cancer that is not
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amenable to localized therapies. However, in clinical practice, it is quite common to see patients
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with RAI refractory disease that is either stable or slowly progressive. Further, in some patients,
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the pace of clinical disease progression appears to increase as the metastatic lesions increase in
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size. Therefore, the precise time point in the clinical course of disease progression to initiate
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therapy for an individual patient can be difficult to identify. As such, treatment of advanced
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thyroid cancer is optimally undertaken in the context of a functional, integrated, disease-
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management team because management of these patients may require extensive surgery, external
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beam irradiation, radiofrequency ablation, embolization, or metastasectomy either in addition to
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or prior to starting other multitargeted kinase inhibitor therapies (16). Because oncologists and
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other specialists that give multitargeted inhibitors often will need to educate and establish a
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relationship with the patient prior to the initiation of treatment, the discussion below should be
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used to help all health care providers in anticipating when a patient may be approaching the need
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for multitargeted inhibitors and initiate timely referrals to the treating physicians.
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Examining the time course of disease progression in individual patients with distant metastases
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In clinical practice, it is very apparent that the rate of disease progression and the
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likelihood that the metastatic disease will become life-threatening varies dramatically among
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individual patients with distant metastases. Several of the common patterns of disease
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progression are presented in Figure 2 where the volume of disease is plotted along the y-axis and
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the time from diagnosis presented along the x-axis. In this theoretical figure, patients
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demonstrating more rapid disease progression over time (Figure 2 curves A, B and C) can be
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expected to reach a lethal tumor burden more quickly than patients with slowly growing (Figure
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2 curve D) or stable disease (Figure 2 curves E and F).
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The biological basis for these theoretical volume of disease curves is the long-standing observation that human malignant tumors demonstrate a pattern of exponential growth
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(1248163262128 cells) that remains remarkably constant over time until large
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burdens of disease are achieved (17-19). It is important to remember that, because tumor growth
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is exponential, relatively small changes in tumor diameter are associated with much larger
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changes in tumor volume that often become clinically more problematic as the tumors exceed 1
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cm in diameter (Figure 3). Because of their near constant exponential growth pattern, the time
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required for a tumor to increase in diameter from 0.5 to 8 cm across a spectrum of doubling
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times can be demonstrated by graphing the diameter of the largest metastatic foci (in
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centimeters) versus follow-up time in years (Figure 4A). To facilitate the use of the growth
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curves as predictors of outcomes in clinical practice, it is easier to visualize exponential doubling
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time curves as straight lines by expressing them as semilog plots where the diameter is presented
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on a logarithmic scale on the y-axis with time on the standard x-axis linear scale (Figure 4B).
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The semilog curves make it easier to predict tumor diameters that can be expected in the future
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once the diameter doubling time has been established for particular metastatic foci.
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While the figures and tables in this manuscript largely describe doubling times in terms
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of change in diameter of individual metastatic lesions, it is important to note that eligibility for
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clinical trials allows for measurement of up to 5 metastatic foci in different organ locations, with
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preference given to the lesions with the greatest diameter that can be reproducibly measured with
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accuracy. Because of the potential for heterogeneity of growth rates among metastatic foci, it is
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likely that a doubling time calculated using the sum of diameters of multiple metastatic foci may
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more accurately reflect the clinical course of the disease than measurements of individual lesions.
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Identifying the clinical inflection point
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Rather than using “inflection point” in a strictly mathematical sense (the precise point at which a curve changes from convex to concave or vice versa), we are using the term in more of a
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general sense to designate a turning point or significant change in the clinical situation. From a
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clinical perspective, crossing over the 1-cm diameter threshold is an important boundary and
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represented the minimum size required for participation in most prospective therapeutic clinical
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trials. Even though the tumor size doubling time is constant as tumors increase in size, the
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clinical impact of increasing tumor diameter becomes much more significant as the tumor
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diameter exceeds 1 cm (See Figure 3). For tumor diameters < 1 cm, biomarker doubling times
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may provide a reliable estimate of tumor growth prior to the time when the volume of disease is
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large enough to be reliably measured with cross-sectional imaging (18, 20-22). The rapidity with which a tumor passes through the inflection point is dependent on the
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doubling time, with a far quicker transition in tumors demonstrating a 6-month diameter
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doubling time (6–12 months) compared with tumors demonstrating a 2 year diameter doubling
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time (2–4 years). Therefore, we picture the inflection point as a region on the growth curves that
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integrates both volume of disease and tumor growth rates (doubling times) as depicted by the
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grey triangle on Figure 4B.
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As illustrated in Figures 4A and 4B, the rate of disease progression (represented by the slope of the line or the actual doubling time ) will be the primary determinant in the development
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of a life-threatening mass of metastatic disease (18). If a treatment (or combination of
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treatments) significantly decreases the volume of disease and the growth rate remains stable, one
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could reasonably expect improved clinical outcomes even though asymptomatic small volume
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disease may continue to progress and eventually become clinically apparent at a time predicted
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by the underlying tumor doubling time. However, in the case of multitargeted kinase inhibitor
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treatments that decrease the growth rate (and prolong the diameter doubling time), it is possible
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that the time to the development of a lethal tumor mass may be delayed by months to years.
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As previously noted, the rate of change in either the tumor biomarkers or structurally
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evident disease usually remains quite constant over time in the absence of multitargeted kinase
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inhibitor therapies that might affect the secretion of these biomarkers (18-22). However,
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occasionally, the rate of disease progression will dramatically increase such that the rate of
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growth departs from the original predicted slope. In these cases, additional mutations acquired
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during follow up, or alternatively, upregulation of an already active pathway, may provide a
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growth advantage to a subclone of the thyroid cancer. This may occur in the case of the
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development of a new site of disease and is not accounted for in the above models. This subclone
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may define a new more rapid growth rate (and hence a new slope and doubling time) and is often
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associated with de-differentiation of the tumor histology and a shift toward markedly FDG PET
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avid disease (23). If a solitary site of disease such as this develops in the setting of slower
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growing disease, local therapy might be considered to restore the previously slower growth rate
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and allow a longer period prior to initiation of multitargeted kinase inhibitor therapy. Still, the
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vast majority of disease progression follows the initially predicted biochemical and structural
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growth curves for many years after diagnosis (18, 20-22, 24).
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Guidance from phase 3 trial entry criteria and cancer-management guidelines regarding
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initiation of multitargeted kinase inhibitor therapy in RAI refractory disease
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Inclusion criteria for the prospective, randomized, registration trials for sorafenib and
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lenvatinib required an increase of ≥ 20% in the sum of the longest diameters of target lesions
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defined by Response Evaluation Criteria in Solid Tumors (RECIST) over either a 13-month
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(lenvatinib) or 14-month (sorafenib) period (12, 15) or the identification of a new lesion. Based
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primarily on expert opinion, the 2015 American Thyroid Association thyroid cancer-
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management guidelines suggested that a 20% increase over a 6-month period should prompt
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consideration of multitargeted kinase inhibitor therapies (25). Similarly, a group of thyroid
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cancer experts also recommend using a minimum tumor volume (> 1 cm) with structural disease
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progression as defined by RECIST progression over < 12-14 months to define the time point to
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initiate systemic therapy in radioactive iodine refractory thyroid cancer (26). The National
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Comprehensive Cancer Network guidelines noted that the “pace of disease progression should be
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prompt initiation of kinase inhibitor therapy in patients with RAI refractory differentiated thyroid
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cancer or medullary thyroid cancer (27). While RECIST evaluations are the primary tool for
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evaluating changes in disease status in clinical trials, they are not used in clinical practice and
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can be a challenge to apply retrospectively. Therefore, we sought an alternative way to describe
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tumor growth rates that would be more accessible and understandable to clinicians and patients.
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Table 2 shows the relationship between the percentage increase per year in tumor
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diameter, which form the basis for current recommendations regarding initiation of multitargeted
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kinase inhibitor therapy, and tumor diameter doubling times for a hypothetical metastatic foci
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measured as 1 cm in maximal diameter at baseline. A 20% increase in metastatic foci diameter
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over a 12 to 14-month period would approximate a doubling time of 4 years. A 20% increase in
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tumor diameters over a 6-month period would correlate with a diameter doubling time of
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approximately 2 years (≈ 40% growth over 1 year).
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demonstrating a maximum diameter doubling time of < 2–4 years would meet the criteria for
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consideration for multitargeted kinase inhibitor therapy. Asymptomatic metastatic lesions in
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noncritical locations with tumor diameter doubling times longer than 4 years could be considered
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for active surveillance.
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A practical approach to using growth rates and the inflection point to guide clinical management An individualized assessment of the rate of structural disease progression is the cornerstone of critical decision-making in patients with advanced metastatic thyroid cancer. In its
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simplest form, patients with slow disease progression, manifest by longer tumor doubling times,
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can be followed with less frequent cross-sectional imaging and less aggressive treatment
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interventions than patients demonstrating more rapid structural disease progression. Tumor
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volume doubling times can be calculated using freely available online calculators from either the
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American Thyroid Association (http://www.thyroid.org/professionals/calculators/thyroid-with-
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nodules/) or from the Kuma Hospital (http://www.kuma-h.or.jp/english/about/doubling-time-
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progression-calculator/) web sites. When evaluating patients with thyroid cancer with
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structurally identifiable distant metastases, we find that the answers to 4 critical questions can
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provide valuable insights that can guide optimal management recommendations (Figure 5):
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1. Are the metastatic lesions RAI refractory?
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2. Is the patient symptomatic or at risk for developing symptoms because of the location of
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3. Is the rate of structural disease progression established?
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4. Has the tumor reached the 1- to 2-cm inflection point?
After determining whether the metastatic lesions are RAI avid and assessing the presence
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or likelihood of rapidly developing clinical symptoms, the key factors that guide the proper
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timing for initiation of other multitargeted kinase inhibitor therapies include tumor size and the
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rate of structural disease progression. Because the inflection-point concept integrates both tumor
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doubling time and volume of disease estimates, it can be used to guide decision- making with
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regard to when it would be appropriate to consider initiation of multitargeted kinase inhibitor
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therapy.
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Crossing the inflection point at approximately 1 cm in diameter is a minimal requirement for consideration of multitargeted kinase inhibitor therapies, based on the two phase 3 trials that
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have been completed. In our opinion, while patients with very rapid diameter doubling times (< 1
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year) should be considered for multitargeted kinase inhibitor therapy as their tumors approach 1
254
cm in diameter, patients with longer doubling times (1–4 years) may not require initiation of
255
therapy until tumors are in the 1.5- to 2-cm range depending on overall tumor volume, symptoms,
256
location of disease and patient preference (Table 3). Graphically, the threshold to consider
257
initiation of multitargeted kinase inhibitor therapy within each of the established diameter
258
doubling time growth curves is depicted by a grey triangle in Figure 4B.
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Tumors with even longer doubling times (> 4 years) may not require multitargeted kinase inhibitor therapy for some time depending on the starting tumor volumes. In our view, though
261
they are at risk for continued disease progression, asymptomatic patients with longer doubling
262
times and subcentimeter metastases that have not passed through the inflection point should
263
generally be followed with close observation. Active surveillance can allow these patients a
264
prolonged period of symptom-free living without the side effects of the multitargeted kinase
265
inhibitor therapies and, thus, can be pursued in these cases. Our recommended approach is,
266
therefore, observation with serial imaging in the vast majority of asymptomatic patients with
267
metastatic lesions demonstrating a doubling time greater than 4 years.
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Thus multitargeted kinase inhibitor therapy would be considered: (1) at the 1- to 2-cm
269
inflection point, or possibly earlier, in patients with RAI refractory disease with doubling times
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< 2–4 years or (2) after passing through the inflection point, if ever, in patients with stable or
271
very slowly progressive disease (doubling times > 4 years). It is important to emphasize that
272
therapeutic interventions should be initiated without regard to the inflection point if the patient
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has (1) tumor associated symptoms such as dyspnea on exertion and cachexia, (2) lytic bone
274
metastases that may benefit from bisphosphonate or rank ligand inhibitor therapy, (3) metastatic
275
disease likely to cause local symptoms that can be treated with a directed therapy such as
276
surgical resection, EBRT, embolization, or radiofrequency ablation, or (4) patients with a very
277
high overall tumor volume despite smaller sized lesions (e.g. multiple lesions that may only have
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a maximal tumor volume of 1 cm, but overall due to high number represent a greater risk of
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symptomatic progression).
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In metastatic disease that continues to be responsive to radioactive iodine administration,
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progression through the 1- to 2-cm inflection point is not a requirement for additional RAI
282
therapies as these treatments work best in low volume (5). Continued decrease in tumor volume
283
in response to previous treatments may prompt additional RAI treatments depending on the age
284
of the patient, the volume of residual disease, the rate of disease progression, the cumulative
285
administered activity of RAI, side-effect profile for individual patients, and patient desires/goals.
286
However, because fewer than 10% of RAI avid patients will achieve complete remission,
287
observation is usually recommended for patients with persistent, stable small-volume disease or
288
patients with only biochemical evidence of persistent disease (6).
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In addition to using the doubling time curves as one of the key indicators for initiation of
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multitargeted kinase inhibitor therapy, they can also be used to evaluate the efficacy (or failure)
291
of ongoing treatments. Traditionally, a multitargeted inhibitor is discontinued once the patient
292
documents clinically significant structural disease progression, which may be required as part of
293
the clinical trial design. However, we would argue that an agent may still be having a clinically
294
significant effect if treatment is associated with a clinically significant increase in doubling time,
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even if structural disease progression eventually develops. Rather than using disease stability as
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the only indicator of treatment success, a paradigm that emphasizes the impact of drug treatment
297
on increasing the doubling time would identify patients in whom even slowly growing disease
298
would still be considered evidence of treatment efficacy if the doubling rate has been decreased
299
enough to predict a likely improvement in progression-free survival or overall survival. In this
300
approach, a switch to another agent would be delayed until there was evidence not only of
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disease progression, but progression with a rapid doubling time indicative of a lack of efficacy of
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the current drug. Using this approach, tumor doubling time could be used to evaluate both the
303
appropriateness of initiating multitargeted kinase inhibitor therapy and the interpretation of the
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efficacy of ongoing therapy.
305
Summary
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Optimal management of patients with metastatic differentiated thyroid cancer requires careful consideration of multiple tumor-associated and patient-related factors within the context
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of an experienced multidisciplinary team. Because our current multitargeted kinase inhibitor
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therapy options are seldom curative, either in the RAI refractory or RAI responsive disease
310
setting, proper selection of patients for intervention with treatment options that are either
311
palliative or designed to slow disease progression is critical. Optimal decision-making with
312
regard to when to initiate multitargeted kinase inhibitor therapy in the metastatic disease setting
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requires the clinician and the patient to thoughtfully integrate an understanding of the patient’s
314
symptom burden, tumor progression, and potential tolerance of treatment-related side effects.
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Practice Points
Multi-targeted kinase inhibitors have demonstrated improvement in progression free survival in patients with structurally progressive, radioactive iodine refractory thyroid
319
cancer.
321
mortality in radioactive iodine refractory thyroid cancer.
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Tumor burden, location and growth rates are the primary determinates of morbidity and
Increases in tumor size are remarkably consistent over time and follow classical
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exponential growth curves with distinct structural doubling times.
Relatively small increases in tumor diameter are associated with much larger increases in
325
tumor volume which often becomes clinically significant as the tumor diameter exceeds 1
326
cm.
By integrating tumor size (maximal diameter) with the rate of structural disease
D
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progression (tumor diameter doubling times), it is possible to identify a period of time
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(the inflection point) where the structural disease progression is becoming clinically
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significant.
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The inflection point should identify the earliest time point that consideration should be
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given for the initiation of multi-targeted kinase inhibitors in otherwise asymptomatic patients.
Prolongation of structural disease doubling time, even if associated with slow disease
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progression, would demonstrate a favorable therapeutic effect of multi-targeted kinase
336
inhibitor therapy.
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339
341
Research Agenda
342
Trials are needed that specifically examine the effectiveness of multi-targeted kinase inhibitors based on tumor size and structural disease doubling times.
Trials are needed to determine if initiating multi-targeted kinase inhibitors at the time
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of clinically significant disease progression (the inflection point) is better or worse
345
than starting treatment either before or after that time point.
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Further research is needed to determine if improvements in structural disease
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doubling times, despite some degree of structural disease progression, is indicative of
348
continued therapeutic effectiveness.
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Acknowledgements
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This study was funded by Eisai Inc. Editorial assistance was provided by Oxford PharmaGenesis
352
Inc. and was funded by Eisai Inc.
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Author Disclosure Statement
354
RMT has served as a paid consultant for Eisai and Bayer.
355
MB has served as a paid consultant for Eisai and Bayer.
356
EG has served as a paid consultant for Eisai and Bayer.
357
SWK has served as a paid consultant for Eisai and Bayer.
358
MT has received grants and research support from Eisai, MSD, Boehringer Ingelheim,
359
AstraZeneca, Ono, Novartis, Bayer, NanoCarrier, Pfizer and has served as paid consultant for
360
Merck Serono, MSD, BMS, Bayer, Eisai, Otsuka, Astra Zeneca and Pfizer
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MS Nothing to disclose
362
Address correspondence to:
363
R Michael Tuttle, MD
364
Endocrinology Service, Department of Medicine
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Memorial Sloan Kettering Cancer Center
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1275 York Avenue, New York, NY, USA 10021
367
Email: [email protected]
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References
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Vaisman F, Momesso D, Bulzico D, et al. Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy. Clin Endocrinol (Oxf) 2012; 77: 132-138. Vaisman F, Tala H, Grewal R, et al. In differentiated thyroid cancer, an incomplete structural response to therapy is associated with significantly worse clinical outcomes than only an incomplete thyroglobulin response. Thyroid 2011; 21: 1317-22. Haugen BR and Sherman SI. Evolving approaches to patients with advanced differentiated thyroid cancer. Endocr Rev 2013; 34: 439-55. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91: 2892-9. Sabra M, Ghossein R, and Tuttle M. Time course and predictors of structural disease progression in pulmonary metastases arising from follicular cell derived thyroid cancer. Thyroid 2015: In press. 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 2013; 98: E829-36. Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer 1998; 83: 2638-48. Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006; 16: 1229-42. Henriques de Figueiredo B, Godbert Y, Soubeyran I, et al. Brain metastases from thyroid carcinoma: a retrospective study of 21 patients. Thyroid 2014; 24: 270-6. Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am 2008; 37: 511-24, xi. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014; 384: 319-28. Marotta V, Sciammarella C, Vitale M, et al. The evolving field of kinase inhibitors in thyroid cancer. Crit Rev Oncol Hematol 2015; 93: 60-73. Schlumberger M and Leboulleux S. Treatment of distant metastases from follicular cellderived thyroid cancer. F1000Prime Rep 2015; 7: 22. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodinerefractory thyroid cancer. N Engl J Med 2015; 372: 621-30. Carty SE, Doherty GM, Inabnet WB, 3rd, et al. American Thyroid Association statement on the essential elements of interdisciplinary communication of perioperative information for patients undergoing thyroid cancer surgery. Thyroid 2012; 22: 395-9. Collins VP, Loeffler RK, and Tivey H. Observations on growth rates of human tumors. Am J Roentgenol Radium Ther Nucl Med 1956; 76: 988-1000. Friberg S and Mattson S. On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol 1997; 65: 284-97. Norton L, Simon R, Brereton HD, et al. Predicting the course of Gompertzian growth. Nature 1976; 264: 542-5.
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TABLES TABLE 1. CUMULATIVE PERCENTAGE OF PATIENTS DEMONSTRATING DISEASE
446
PROGRESSION OVER TIME
447
RAI avid disease
RAI refractory disease
1
17
12
29
2
35
5
55
10
65
RAI, radioactive iodine.
448
452 453 454 455
41
83
53
91
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451
53
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450
26
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449
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Entire cohort
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Year, %
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445
456 457
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TABLE 2. RELATIONSHIP BETWEEN PERCENTAGE INCREASE IN LARGEST TUMOR DIAMETER AND
459
CORRESPONDING DIAMETER DOUBLING TIME
M AN US C
458
Increase in largest tumor diameter per year, %
Size of metastatic focus, cm
Corresponding diameter doubling time, years
(1 cm in diameter at baseline)
20% 30% 40%
D
50%
461 462 463 464
1.3
2.7
1.4
2.1
1.5
1.7
1.8
1.2
2.0
1.0
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460
3.8
EP
100%
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75%
1.2
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TABLE 3. DIAMETER DOUBLING TIMES AND TUMOR DIAMETERS THAT SHOULD PROMPT CONSIDERATION FOR
466
MULTITARGETED KINASE INHIBITOR THERAPY Diameter doubling time, years
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465
Corresponding increase in
Diameter of metastatic focus that should
maximum diameter per year, %
prompt consideration for initiation of
Corresponding tumor volume, mL
multitargeted kinase inhibitor therapy, cm
469 470 471 472
40–100
2–4
20–40
>4
< 20
0.5
1.0–1.5
0.5–1.8
1.5–2.0
1.8–4.2
Usually not indicated
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1–2
≈ 1.0
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468
100
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467
<1
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FIGURE TITLES AND LEGENDS
474
FIG 1. Overall survival and progression-free survival in a cohort of 199 patients with pulmonary
475
metastases from nonanaplastic follicular cell-derived thyroid cancer.
476
CI, confidence interval.
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473
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477
FIG 2. Theoretical growth curves representing the most common patterns observed in clinical
479
practice in patients with metastatic disease that continues to be RAI responsive or becomes RAI
480
refractory.
481
RAI, radioactive iodine.
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478
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FIG 3. Relationship between tumor diameter and tumor volume demonstrating dramatic
484
increases in tumor volume, with relatively small changes in tumor diameter.
487 488 489
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490 491 492
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FIG 4. Growth curves for a tumor growing from 0.5 to 8 cm in maximal diameter with a
494
doubling time of 6 months, 1 year, 2 years, and 4 years plotted as (A) the diameter of the lesion
495
versus time or (B) the log of the lesion diameter versus time (semilog).
496
The inflection point (indicated by the grey triangle in panel B) is critical point in time when the
497
volume and rate of progression of metastatic structural disease merits consideration for initiation
498
of systemic therapy.
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493
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499 500
FIG 5. Therapeutic decision-making in metastatic thyroid cancer.
501
RAI, radioactive iodine.
502
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503
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