ORIGINAL E n d o c r i n e
ARTICLE C a r e
Role of Salvage Targeted Therapy in Differentiated Thyroid Cancer Patients Who Failed First-Line Sorafenib Ramona Dadu, Catherine Devine, Mike Hernandez, Steven G. Waguespack, Naifa L. Busaidy, Mimi I. Hu, Camilo Jimenez, Mouhammad A. Habra, Rena V. Sellin, Anita K. Ying, Gilbert J. Cote, Steven I. Sherman, and Maria E. Cabanillas Departments of Endocrine Neoplasia and Hormonal Disorders (R.D., S.G.W., N.L.B., M.I.H., C.J., M.A.H., R.V.S., A.K.Y., G.J.C., S.I.S., M.E.C.), Diagnostic Radiology (C.D.), and Biostatistics (M.H.), The University of Texas M. D. Anderson Cancer Center; and Department of Endocrinology, Diabetes, and Metabolism (R.D.), Baylor College of Medicine, Houston, Texas 77030
Context: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. Objective: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. Design: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. Patients: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). Patients who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). Outcome Measures: Progression-free survival, best response, and median OS were measured. Results: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P ⫽ .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n ⫽ 4), pazopanib (n ⫽ 3), cabozantinib (n ⫽ 4), lenvatinib (n ⫽ 3), and vemurafenib (n ⫽ 3). Conclusions: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy. (J Clin Endocrinol Metab 99: 2086 –2094, 2014)
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received September 24, 2013. Accepted February 27, 2014. First Published Online March 14, 2014
Abbreviations: CI, confidence interval; DTC, differentiated thyroid cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RAI, radioactive iodine; SD, stable disease; TKI, tyrosine kinase inhibitor.
For editorial see page 1995
2086
jcem.endojournals.org
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
doi: 10.1210/jc.2013-3588
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
ifferentiated thyroid cancer (DTC) is the most common endocrine cancer. Most patients with DTC are cured with standard primary treatments, including surgery, radioactive iodine (RAI), and thyroid-stimulating hormone suppression. However, once DTC metastasizes to distant sites and is no longer responsive to RAI therapy or surgery, expected survival declines rapidly (1–3). Despite effective standard treatments, 1850 patients are expected to die of thyroid cancer in 2013 (4); therefore, patients who develop RAI-refractory, rapidly progressive, and/or symptomatic disease require an effective treatment approach. Until November 2013, the only treatment approved by the US Food and Drug Administration for these patients was doxorubicin, but owing to low and shortlived response rates, this treatment is now considered a poor option. Sorafenib in now the first efficacious therapy approved for advanced DTC. The availability of tyrosine kinase inhibitors (TKIs) represents the first significant progress in treating patients with advanced DTC. A number of biological agents are being tested and have shown positive initial results (5). Sorafenib is an oral multikinase inhibitor whose targets includes vascular endothelial growth factor receptor, RET, BRAF, and c-KIT, and it is frequently the first-line treatment of choice for DTC. Several phase II studies (6 – 10) of sorafenib in DTC have shown promising results, which led to the development of a phase III placebo-controlled study (11). In this study, the investigators found a progression-free survival (PFS) advantage in the sorafenib group (11.8 months, compared with 5.8 months in the placebo group). This represents the first major breakthrough in treating metastatic DTC since the development of RAI. However, most patients eventually stop responding to sorafenib, and many patients must discontinue use of the drug because of its toxicity. Other systemic therapies are also used in clinical practice to treat DTC, either off label or as part of a clinical trial, and many have similar targets to sorafenib. It is unclear whether the similarities of drug targets in DTC would lead to complete cross-resistance or whether sequential application would be efficacious. In renal cell carcinoma, the sequential administration of sunitinib after first-line sorafenib failure has shown efficacy (12–16). In DTC, according to a few cases, clinical cross-resistance of TKIs may not be complete, and objective responses were observed when sunitinib or cabozantinib was used as second agent after sorafenib failure (17– 19). Although similar, systemic therapies have additional unique targets such as c-KIT, c-MET, or BRAF or different potencies, which may overcome the resistance to
D
jcem.endojournals.org
2087
sorafenib. In the present study, we sought to determine the efficacy of salvage therapy in patients with advanced DTC for whom first-line treatment with sorafenib failed.
Patients and Methods Study population After receiving institutional review board approval, we retrospectively collected data on adult patients with metastatic DTC who received first-line treatment with sorafenib between January 2005 and May 2013 at The University of Texas M. D. Anderson Cancer Center. Patient data collected included age, sex, histological findings, disease stage at diagnosis, cumulative I-131 activity, site of distant metastases, information about treatment with sorafenib (time from diagnosis to start of treatment, duration of treatment, dosage, reason for discontinuation, or changes to dosage), information about any salvage treatments received, tumor response, and follow-up time or date of death. For overall survival (OS) analysis, patients were assigned to one of two groups: patients in group 1 received first-line treatment with sorafenib only, and patients in group 2 received salvage treatment with another kinase inhibitor after initial treatment with sorafenib. Group 1 was included for OS analysis only. All patients were included for OS analysis of the entire cohort. For comparison between the two groups, we excluded from this analysis patients who died within 3 months of starting treatment with sorafenib because these patients were unable to receive salvage therapy (possibly skewing toward worse outcomes in group 1). We also excluded patients who developed a pathologically confirmed, unrelated malignancy during treatment with sorafenib, but we did not exclude patients with malignancies that occurred as an adverse event related to their treatment (such as squamous cell skin carcinomas). For PFS and best response analysis, we focused on the subset of patients who received salvage therapy after their initial treatment with sorafenib and who had a baseline and at least one follow-up imaging study during treatment with sorafenib and during salvage therapy. This group included patients treated with sorafenib outside a clinical trial. The drugs used as salvage therapy were administered either outside a clinical trial (sunitinib, pazopanib, and vemurafenib) or as part of a clinical trial (cabozantinib and lenvatinib). Patients receiving cabozantinib and lenvatinib were participating in phase I (NCT01100619) and phase II (NCT 00784303) clinical trials, respectively. We obtained approval from the sponsors of the studies to use these data.
Study objectives The primary end points in our analysis were PFS duration and best response with first-line sorafenib and salvage therapy. The secondary end point was OS duration in patients who received subsequent salvage therapy after sorafenib failure and in patients who received first-line treatment with sorafenib only.
Assessments and definitions Radiographic assessments were performed by a single radiologist (C.D.) using computed tomography or magnetic resonance imaging. Tumor response was categorized using Response Evaluation Criteria in Solid Tumors version 1.1 (20, 21), and
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2088
Dadu et al
Salvage Therapy in DTC
responses were defined as follows: progressive disease (PD): 20% or greater increase in total target lesions size or new metastatic lesion; stable disease (SD): any change in lesions size between a 19% increase and a 29% decrease; partial response (PR): 30% or greater decrease in target lesions size. Sorafenib failure was defined as disease progression or unacceptable toxicity leading to drug discontinuation. PFS was defined as the time from sorafenib or salvage therapy start until Response Evaluation Criteria in Solid Tumors progression determined from objective tumor measurements, clinical progression as determined by the treating physician, or death, whichever occurred first. Duration of treatment was defined as the time from the start of treatment until disease progression or unacceptable toxicity leading to drug discontinuation. OS was calculated from the date on which the treatment with sorafenib was started to the date of death. Patients who had not died at the time of analysis were censored at the time they were last known to be alive.
Statistical analysis Descriptive statistics were used to summarize patient characteristics by group. Comparisons were made between groups to identify any significant imbalances in patient characteristics. An independent-samples t test was used to compare continuous variables and a 2 test was used to compare categorical variables. OS and PFS were illustrated using Kaplan-Meier plots. A log-rank test was used to compare survival distributions between groups. The best responses for individual patients, calculated using the percentage change in target lesion size compared with baseline (see above), were plotted graphically using a waterfall plot. Values were considered statistically significant at P ⬍ .05. Statistical analyses were performed using Stata version 12 software (StataCorp)and R version 3.0.2.
Results Study population Figure 1 depicts a flow chart of the patients who were included in our study. We identified 64 patients with metastatic DTC who received first-line treatment with sorafenib between January 2005 and May 2013. All patients were included for OS analysis of the entire cohort. Group 1 included 35 patients who received sorafenib only (no treatment followed after sorafenib failure or are still receiving sorafenib), and group 2 included 25 patients who received salvage therapy after sorafenib failure. Four patients (all in group 1) were excluded, one owing to early death within 3 months after starting treatment with sorafenib and three owing to other unrelated malignancies. One patient was diagnosed with diffuse large B cell lymphoma with leptomeningeal disease while on sorafenib for 77 weeks; the drug was discontinued for this reason and the patient died 27 weeks later. One patient had an intraductal papillary mucinous neoplasm (based on radiographic characteristics) prior to the sorafenib
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
First-Line Sorafenib in DTC (n=64)
Exclusion: Early E l ddeath h (n=1) ( 1) Other malignancies (n=3)
Group 2 Sorafenib followed by Salvage Therapy (n=25)
Group 1 Sorafenib Alone (n=35)
Exclusion: Missing radiographic assessments (n=8)
Study population for Best Response and PFS analysis (n=17) Figure 1. Patient population flow chart.
start, which was later diagnosed as pancreatic adenocarcinoma. This patient was on treatment with sorafenib for 71 weeks. Malignant transformation was noted on positron emission tomography/computed tomography 1 year after sorafenib discontinuation. One patient had history of metastatic colon cancer and non-small cell lung carcinoma prior to sorafenib initiation. For best response and PFS analyses, eight patients in group 2 were excluded owing to missing radiographic assessments, leaving 17 evaluable patients for these analyses. Two patients experienced toxicity with sorafenib that led to drug discontinuation before restaging; therefore, the response rate and PFS with sorafenib was reported for 15 patients. Overall survival analysis Patient characteristics The clinical characteristics of all 64 patients who received first-line treatment with sorafenib are summarized in Table 1 along with a comparison between groups. For all patients, the mean age at diagnosis was 54 years and 53% were male. Histological findings showed that 37 patients (58%) had papillary, 13 (20%) had follicular, and 14 (23%) had poorly differentiated carcinoma (papillarypoorly differentiated, follicular-insular, or poorly differ-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
jcem.endojournals.org
2089
Table 1. Patient Characteristics for the Whole Group (n ⫽ 64) and Comparison Between Group 1 (n ⫽ 35) and Group 2 (n ⫽ 25). n, % Characteristic Age at diagnosis, mean ⫾ SD Sex Female Male Histology Papillary-conventional Papillary-follicular Papillary-tall Papillary-poorly differentiated Follicular Follicular-Hurthle Follicular-insular Poorly differentiated-NOS Stage at diagnosis I II III IVA IVC Unknown Cumulative I131 activity, mean ⫾ SD Site of distant metastases at start of treatment with sorafenib Lung Bone Time from diagnosis to start of treatment with sorafenib, y, mean ⫾ SD Starting daily dose of sorafenib 200 mg 400 mg 800 mg Unknown Reason for sorafenib discontinuationd Progression Toxicity Sorafenib interruptione Sorafenib dose reductione Time to sorafenib failure, mo, median (95% CI)
All Patients (n ⴝ 64)
Group 1 (n ⴝ 35)
Group 2 (n ⴝ 25)
P Value
53.9 ⫾ 9.2
54.9 ⫾ 10.0
53.3 ⫾ 8.6
.519a
30 (47) 34 (53)
17 (49) 18 (51)
12 (48) 13 (52)
.965b
25 (39) 11 (17) 1 (2) 4 (6) 5 (8) 8 (13) 6 (9) 4 (6)
15 (43) 7 (20) 1 (3) 4 (11) 2 (6) 1 (3) 2 (6) 3 (9)
7 (28) 4 (16) 0 (0) 0 (0) 3 (12) 6 (24) 4 (16) 1 (4)
.07c
7 (11) 4 (6) 18 (28) 13 (20) 19 (30) 3 (5) 362 ⫾ 230
6 (17) 2 (6) 8 (23) 7 (20) 11 (31) 1 (3) 333 ⫾ 223
1 (4) 2 (8) 9 (36) 4 (16) 8 (32) 1 (4) 397 ⫾ 239
.646c
.337a
62 (97) 22 (34) 5.1 ⫾ 4.4
33 (94) 11 (31) 6.0 ⫾ 4.4
25 (100) 10 (40) 4.6 ⫾ 3.3
.506c .420b .192a
1 (2) 17 (27) 43 (67) 3 (5)
1 (3) 8 (23) 24 (69) 2 (6)
0 (0) 7 (28) 17 (68) 1 (4)
.817c
37/44 (84) 7/44 (16) 35/57 (61) 30/57 (53) 11 (5.4 –16.5)
12/17 (71) 5/17 (29) 18/31 (58) 17/31 (55) 10 (5.3–14.6)
23/24 (96) 1/24 (4) 15/22 (68) 12/22 (55) 14 (5.8 –22.1)
.066c .454b .984b .372f
Abbreviation: NOS, not otherwise specified. Percentages may not equal to 100% due to rounding error. a
P value based on an independent-samples t test.
b
P value based on a 2 test.
c
P value based on a Fisher’s exact test.
d
Evaluable in 44 patients.
e
Evaluable in 57 patients.
f
P value based on a log-rank test.
entiated-not otherwise specified), and most patients had stage III or IV disease at diagnosis. All patients had RAIrefractory disease. At the time that treatment with sorafenib was started, 62 patients (97%) had distant metastases in the lung and 22 patients (34%) had distant metastases in the bone. Data regarding sorafenib discontinuation were available in 44 patients: 37 (85%) discontinued sorafenib owing to progression and seven (16%) owing to toxicity. Information concerning sorafenib dose reduction and drug interruption was available in 57 pa-
tients: drug interruption was needed in 35 patients (61%) and dose reduction was needed in 30 patients (53%). No statistical differences were observed between the two groups, but group 1 (sorafenib only) contained more patients with papillary thyroid cancer (64%) and group 2 (salvage therapy) contained more patients with follicular thyroid cancer (52%). In group 1, 11 patients were still receiving sorafenib at the time of this analysis. In group 2, nine patients were still receiving second-line treatment and six patients had received more than two lines of treatment.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2090
Dadu et al
Salvage Therapy in DTC
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
Salvage treatments included sunitinib (n ⫽ 10), pazopanib (n ⫽ 4), cabozantinib (n ⫽ 4), lenvatinib (n ⫽ 4), and vemurafenib (n ⫽ 3). Patients receiving cabozantinib and lenvatinib were part of a clinical trial. Overall survival The median OS of all 64 patients treated with first-line sorafenib was 36.6 months [95% confidence interval (CI) 30.4-NA] (Figure 2A). The median OS in group 2 (the salvage therapy group) was 58.4 months (95% CI 33.4 –NA [not reached]), which was significantly longer than the median OS in group 1 (the sorafenib-only group) (28.8; 95% CI 16.1–NA); P ⫽ .013; Figure 2B). Median OS did not differ on the basis of sex, histological findings, stage at diagnosis, discontinuation owing to toxicity or progression, dose reduction, or drug interruptions. Nineteen patients in group 1 (54%) and 15 patients in group 2 (60%) were still alive at the time of this analysis. The median follow-up time was 36.6 months (95% CI 30.4 – NA) in all patients, 26.2 months (95% CI 22.7– 42.4)
Overall Survival With First line Sorafenib
0.4 0.2
20
40
60
80
100
Months
B Overall Survival
1.0
Sorafenib followed by Salvage Therapy (Group 2) Sorafenib Alone (Group 1)
0.2
0.4
0.6
0.8
Group 1 (N = 35) Group 2 (N = 25)
Group 1 versus Group 2 p-value = 0.013
0.0
Survival Probability
Patient characteristics The baseline characteristics of the subgroup of patients included in this analysis are shown in Table 2. The mean age at diagnosis was 52 years, and 53% of patients were male. Histological findings showed that nine patients had papillary (six conventional and three follicular) and seven patients had follicular thyroid cancer (four Hurthle cell carcinoma, two insular type, and one poorly differentiated cancer). T3 and T4 tumors were present in 16 patients (94%), and seven (41%) had metastatic disease at the time
Table 2. Baseline Characteristics of the Subgroup of Patients Included in the Best Response and PFS Analysis (n ⫽ 17)
0
• •
Efficacy analysis of salvage therapy
0.6 0
0.8
All Patients (N = 64)
0.0
Survival Prob bability
1.0
A
in group 1, and 46.6 months (95% CI 35.7– 66.4) in group 2. When all patients were included in group 1 (n ⫽ 39), the median OS was 24.2 months (95% CI 17.8 –NA). The OS in this group remains significantly shorter when compared with group 2 [58.4 months (95% CI 34.0-NA); P ⫽ .007]. To evaluate the effect of salvage therapy on survival, a second OS analysis was performed using sorafenib end as the start date for OS analysis. To date, 42 patients failed first-line sorafenib, of which 17 were in group 1 and 25 in group 2. Using this definition, the median OS was still significantly longer with salvage treatment compared with sorafenib alone (4.25 vs 42 months, P ⬍ .001).
0
20
40
60
80
100
Months
Figure 2. A, Median OS from the start of treatment with sorafenib for all 64 patients was 36.6 months. B, Median OS from start of sorafenib in group 1 (sorafenib alone) compared with group 2 (sorafenib followed by salvage therapy) was 58.4 vs 28.8 months (P ⫽ .013).
Characteristic
n, %
Age at diagnosis, y, mean ⫾ SD Sex Female Male Histology Papillary, all variants Follicular, all variants Poorly differentiated TNM stage at diagnosis T3, T4 M1 Site of distant metastases Lung Bone Reason for sorafenib discontinuation Progressive disease Toxicity Salvage therapy Sunitinib Cabozantinib Pazopanib Lenvatinib Vemurafenib
52.5 ⫾ 8.8 8 (47) 9 (53) 9 (53) 7 (41) 1 (6) 16 (94) 7 (41) 17 (100) 6 (35) 15 (88) 2 (12) 4 4 3 3 3
Abbreviation: TNM, tumor node metastasis. Percentages may not equal to 100% due to rounding error.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
jcem.endojournals.org
of diagnosis. Seven of 17 evaluable patients receiving salvage therapy were still on treatment with a second agent at the time of this analysis. Ten patients discontinued the drug due to progression. To date, there were no discontinuations due to toxicity during treatment with salvage therapy, although most patients needed dose adjustment to manage side effects. Best response and PFS Two patients experienced toxicity with sorafenib that led to drug discontinuation before restaging (mucositis and hand foot syndrome). In the remaining 15 patients, best responses with first-line sorafenib were PR in two (13%), SD in 10 (67%), and PD in three (20%) patients (Figure 3A). In all 17 patients, best responses with salvage therapy were PR in seven (41%) and SD in 10 (59%) patients (Figure 3B). No PD was observed with salvage therapy as the best response. All three patients who had PD
A
Best Response with First-Line Sorafenib
Chan nge in sum of target lesions l (%)
60
SD 67%
PD 20%
PR 13%
40 20 0
**
-20 40 -40 -60
Assessable patients (n=15)
*2 stopped due to toxicity
B
Best Response with Salvage Therapy
Change in n sum of target lesion ns (%)
60 SD 59%
PR 41%
40 20 0
-20 -40 -60 Assessable patients (n=17)
Figure 3. Best response with sorafenib (A) and with salvage therapy (B) in 17 patients whose first-line treatment with sorafenib failed. In panel A, two patients were excluded owing to sorafenib toxicity. Note that patients are not shown in the same order in panels A and B.
2091
during treatment with sorafenib achieved PR with the second drug (⬎55% tumor size reduction). Two patients discontinued sorafenib owing to toxicity in less than 1 month but tolerated and responded to second-line treatment with sunitinib. One of these patients achieved SD with tumor regression (15% reduction) for 16 months. The second patient achieved PR (61% reduction) and is still receiving sunitinib after 30 months. Tumor responses in individual patients are shown in Figure 4. The median PFS was 7.4 months (95% CI 3.1–11.3) with first-line sorafenib and 11.3 months (95% CI 5.3– 24.4) with salvage therapy.
Discussion Our results suggest that other molecular targeted agents can be effective as salvage therapies after sorafenib failure in patients with metastatic DTC. Salvage therapy after sorafenib failure is used in clinical practice because responses are not durable and nearly 20% of patients do not tolerate sorafenib (11). Several trials of TKIs for the treatment of DTC have included patients who received prior treatment with other TKIs, but information regarding the efficacy of such an approach is limited. The results of a small phase I study of cabozantinib showed that patients with thyroid cancer in whom treatment with first-line TKIs failed, continued to respond to cabozantinib. Of 14 evaluable patients, eight received sorafenib prior to cabozantinib, and five of these patients achieved PR with cabozantinib (17). In the phase II sunitinib trial, two patients were treated with sorafenib and had the drug discontinued due to toxicity. After starting sunitinib, one patient had 29% reduction of tumor and was on therapy for 12 months (18). Our study is the first to examine the efficacy of salvage therapy in patients with metastatic, RAI-refractory DTC whose first-line treatment with sorafenib failed. Inevitably, all patients treated with sorafenib develop disease progression or toxicity leading to discontinuation, and it is not clear whether salvage therapy is advantageous. The results of our study suggest that salvage treatment with drugs that have similar mechanisms of action to those of sorafenib can be beneficial. We have shown that patients continued to respond to second-line treatment after firstline sorafenib failure. PR occurred in 41% and SD in 59% of the patients receiving salvage therapy. PFS with a second-line TKI therapy was 11.4 months. This is similar to the PFS durations and response rates reported in phase II trials with various TKIs, such as sunitinib, pazopanib, vandetanib, cabozantinib, and lenvatinib (17, 18, 22–24). Three patients in our study who had PD as the best re-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2092
Dadu et al
Salvage Therapy in DTC
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
tage in the sorafenib arm (10.8 months compared with 5.8 months 1 Line Sorafenib CABO: cabozantinib (n=4) LEN: lenvatinib (n=3) in the placebo arm). The PR rate was 50 Salvage Therapy PAZ: pazopanib (n=3) 12.2% with sorafenib compared SUN: sunitinib (n=4) VEM: vemurafenib (n=3) 30 with 0.5% with placebo, and no PAZ complete responses were observed. PAZ Sorafenib LEN Toxicity 10 SD of 6 or more months was present SUN SUN in 42% of patients receiving -10 sorafenib. The discontinuation rate VEM SUN CABO owing to toxicity was 19%. -30 To date, data reporting median VEM PAZ CABO VEM OS duration in treatment-naive pa-50 tients with DTC receiving first-line LEN CABO CABO treatment with sorafenib are limited. SUN LEN -70 Our study, which included a rela1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 tively large number of patients, is the Assessable patients (n=17) first to report a median OS of 37 Figure 4. Best responses in individual patients whose first-line treatment with sorafenib failed months in patients with TKI naive (n ⫽ 17). DTC treated with first-line sorafenib. In the phase III clinical sponse to sorafenib achieved impressive responses (more trial, the median OS has not been reached in either arm than 55% tumor reduction) with a second-line TKI (two (11). Two phase II studies that included a smaller number cabozantinib and one lenvatinib). The rest of the patients of patients and a different patient population reached a continued to have prolonged SD or PR with the secondmedian OS. Schneider et al (9) reported an estimated meline treatment despite PD with sorafenib. Furthermore, dian OS of 34.5 months in 31 patients with DTC receiving two patients developed severe toxicity with sorafenib, sorafenib, but these patients were not all TKI-naive. For a leading to drug discontinuation early in the treatment but subgroup of 33 patients with papillary thyroid cancer responded to and tolerated another TKI (sunitinib) with a treated with first-line sorafenib, Kloos et al (6) reported a similar toxicity profile. median OS of 23 months. Because patients responded to the salvage therapy, disAnother important finding of our study is the longer ease progression or toxicity with sorafenib should not exsurvival we observed in patients who were able to receive clude use of another TKI. To address this issue in a prospective fashion, a phase II trial of cabozantinib in patients salvage therapy. Our study is the first to show that patients with DTC that progressed during treatment with first-line who are able to receive salvage therapy may survive longer treatment with antiangiogenic TKIs is currently underway than those treated with sorafenib followed by no salvage (clinicaltrials.gov, NCT identifier 1811212). Whether the treatment. The median OS was 58 months for those who differences in response between first-line and salvage ther- received salvage therapy compared with 28 months in apy are caused by inhibition of different vascular endo- those treated with sorafenib alone. The two groups were thelial growth factor receptors, inhibition of other targets similar in terms of baseline characteristics, including age, such as RET, c-KIT, c-MET, or BRAF, or different poten- sex, stage at diagnosis, site of distant metastases, time from cies of each compound (IC50 concentrations) (Supplemen- diagnosis to the start of treatment with sorafenib, and duration of treatment with sorafenib. More patients had tal Table 1) needs to be determined. In our study, the efficacy and tolerability with sorafenib papillary thyroid cancer in the group receiving sorafenib are similar to those reported in the phase III trial (11). The alone and more patients had follicular thyroid cancer in best response to first-line treatment with sorafenib was the group receiving salvage therapy, although these dif13% PR and 67% SD, PFS was 7.4 months, and discon- ferences were not statistically significant. Because of this, tinuation rate owing to toxicity was 15%. PFS presented the two groups are not directly comparable on the basis of in our study is slightly shorter than previously reported, histological findings, although one would expect a worse possibly due to inclusion of more aggressive histologies, outcome in the group with more follicular thyroid cancer. namely poorly differentiated thyroid cancer and more pa- The difference in OS between the two groups may also be tients with metastasis to bone. Results of the phase III explained by differences in performance status; the group placebo-controlled trial with TKI-naive patients with of patients who did not receive salvage therapy after DTC demonstrated a statistically significant PFS advan- sorafenib may have been much sicker. Because of the retBest Response in Individual Patients
Change in sum of target lesions (%)
St
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
rospective nature of the study, we were unable to assess the performance status of our patients. To the best of our knowledge, patients did not receive second-line therapy for several reasons: 1) limited knowledge regarding the efficacy of salvage therapy during the first years in which targeted therapies were in use, therefore preventing the treating physician from offering this as an option; 2) unavailability of other therapies; 3) patient refusal; and 4) palliative treatment offered instead owing to poor performance status. Furthermore, several patients were still receiving sorafenib at the time of this analysis and likely will be offered salvage therapy in the event of disease progression. This study contains several limitations resulting from its retrospective design, including missing information regarding patient performance status, lack of a clear reason for not receiving salvage therapy, and lack of conclusive evidence that all patients had progressive disease before the start of treatment with sorafenib. Because advanced thyroid cancer is rare and TKIs are a fairly new treatment approach, the subgroup of patients in our study population who received salvage therapy was small, and they received a variety of different drugs. Therefore, a comparison between different drugs used as salvage therapy was not feasible. In summary, sorafenib failure did not predict response to salvage treatment with other drugs despite similar mechanisms of action. Although the groups in our study are not directly comparable, our findings indicate that patients who are able to receive salvage therapy after sorafenib failure benefit from this approach, and the current standard should be to offer targeted therapy as a salvage treatment to these patients. Future directions of study include elucidating the mechanism of resistance with targeted therapies, determining the best order of targeted therapy use, and analysis of combination and additive therapies.
Acknowledgments Address all correspondence and requests for reprints to: Maria E. Cabanillas, MD, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1461, Houston, TX 77030. E-mail: [email protected]. This work was supported by the National Institutes of Health/National Cancer Institute under Award P30CA016672. Disclosure Summary: R.D., C.D., M.H., S.G.W., M.I.H., C.J., M.A.H., R.V.S., A.K.Y., and G.J.C. have nothing to disclose. N.L.B. has received research funding from Bayer/Onyx. S.I.S. is a consultant to Bayer, Eisai, and Exelixis. M.E.C. has received research funding from Roche, Eisai, and Exelixis and has served on the advisory boards for Eisai and Exelixis.
jcem.endojournals.org
2093
References 1. Ruegemer JJ, Hay ID, Bergstralh EJ, Ryan JJ, Offord KP, Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab. 1988;67:501–508. 2. Shoup M, Stojadinovic A, Nissan A, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg. 2003;197:191–197. 3. 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;91:2892–2899. 4. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10 –29. 5. Dadu R, Cabanillas ME. Optimizing therapy for radioactive iodinerefractory differentiated thyroid cancer: current state of the art and future directions. Minerva Endocrinol. 2012;37:335–356. 6. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27:1675–1684. 7. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714 – 4719. 8. Hoftijzer H, Heemstra KA, Morreau H, et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol. 2009;161:923–931. 9. Schneider T, Abdulrahman R, Corssmit EP, Morreau H, Smit JW, Kapiteijn E. Long term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol. 2012; 167:643– 650. 10. Ahmed M, Barbachano Y, Riddell A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol. 2011;165:315–322. 11. Brose M, Nuyying C, Jarzab B, et al. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. J Clin Oncol. 2013;31:abstract 4. 12. Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology. 2009;76:350 –354. 13. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115:61– 67. 14. Porta C, Procopio G, Carteni G, et al. Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (rcc): an Italian multicentre retrospective analysis of 189 patient cases. BJU Int. 2011; 108:E250 –E257. 15. Procopio G, Verzoni E, Iacovelli R, Guadalupi V, Gelsomino F, Buzzoni R. Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience. Expert Rev Anticancer Ther. 2011;11:1631–1640. 16. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29 –34. 17. Cabanillas ME, Brose M, Lee Y, Miles D, Sherman SI. Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC). J Clin Oncol Vol. 2012;30: abstract 5547. 18. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260 – 5268. 19. Cabanillas ME, Waguespack SG, Bronstein Y, et al. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab. 2010;95:2588 –2595.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2094
Dadu et al
Salvage Therapy in DTC
20. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. 21. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228 –247. 22. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. 23. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905. 24. Sherman SI, Jarzab B, Cabanillas ME, et al. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol. 2011;29:Abstract 5503.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
ARTICLE C a r e
Role of Salvage Targeted Therapy in Differentiated Thyroid Cancer Patients Who Failed First-Line Sorafenib Ramona Dadu, Catherine Devine, Mike Hernandez, Steven G. Waguespack, Naifa L. Busaidy, Mimi I. Hu, Camilo Jimenez, Mouhammad A. Habra, Rena V. Sellin, Anita K. Ying, Gilbert J. Cote, Steven I. Sherman, and Maria E. Cabanillas Departments of Endocrine Neoplasia and Hormonal Disorders (R.D., S.G.W., N.L.B., M.I.H., C.J., M.A.H., R.V.S., A.K.Y., G.J.C., S.I.S., M.E.C.), Diagnostic Radiology (C.D.), and Biostatistics (M.H.), The University of Texas M. D. Anderson Cancer Center; and Department of Endocrinology, Diabetes, and Metabolism (R.D.), Baylor College of Medicine, Houston, Texas 77030
Context: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. Objective: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. Design: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. Patients: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). Patients who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). Outcome Measures: Progression-free survival, best response, and median OS were measured. Results: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P ⫽ .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n ⫽ 4), pazopanib (n ⫽ 3), cabozantinib (n ⫽ 4), lenvatinib (n ⫽ 3), and vemurafenib (n ⫽ 3). Conclusions: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy. (J Clin Endocrinol Metab 99: 2086 –2094, 2014)
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received September 24, 2013. Accepted February 27, 2014. First Published Online March 14, 2014
Abbreviations: CI, confidence interval; DTC, differentiated thyroid cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RAI, radioactive iodine; SD, stable disease; TKI, tyrosine kinase inhibitor.
For editorial see page 1995
2086
jcem.endojournals.org
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
doi: 10.1210/jc.2013-3588
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
ifferentiated thyroid cancer (DTC) is the most common endocrine cancer. Most patients with DTC are cured with standard primary treatments, including surgery, radioactive iodine (RAI), and thyroid-stimulating hormone suppression. However, once DTC metastasizes to distant sites and is no longer responsive to RAI therapy or surgery, expected survival declines rapidly (1–3). Despite effective standard treatments, 1850 patients are expected to die of thyroid cancer in 2013 (4); therefore, patients who develop RAI-refractory, rapidly progressive, and/or symptomatic disease require an effective treatment approach. Until November 2013, the only treatment approved by the US Food and Drug Administration for these patients was doxorubicin, but owing to low and shortlived response rates, this treatment is now considered a poor option. Sorafenib in now the first efficacious therapy approved for advanced DTC. The availability of tyrosine kinase inhibitors (TKIs) represents the first significant progress in treating patients with advanced DTC. A number of biological agents are being tested and have shown positive initial results (5). Sorafenib is an oral multikinase inhibitor whose targets includes vascular endothelial growth factor receptor, RET, BRAF, and c-KIT, and it is frequently the first-line treatment of choice for DTC. Several phase II studies (6 – 10) of sorafenib in DTC have shown promising results, which led to the development of a phase III placebo-controlled study (11). In this study, the investigators found a progression-free survival (PFS) advantage in the sorafenib group (11.8 months, compared with 5.8 months in the placebo group). This represents the first major breakthrough in treating metastatic DTC since the development of RAI. However, most patients eventually stop responding to sorafenib, and many patients must discontinue use of the drug because of its toxicity. Other systemic therapies are also used in clinical practice to treat DTC, either off label or as part of a clinical trial, and many have similar targets to sorafenib. It is unclear whether the similarities of drug targets in DTC would lead to complete cross-resistance or whether sequential application would be efficacious. In renal cell carcinoma, the sequential administration of sunitinib after first-line sorafenib failure has shown efficacy (12–16). In DTC, according to a few cases, clinical cross-resistance of TKIs may not be complete, and objective responses were observed when sunitinib or cabozantinib was used as second agent after sorafenib failure (17– 19). Although similar, systemic therapies have additional unique targets such as c-KIT, c-MET, or BRAF or different potencies, which may overcome the resistance to
D
jcem.endojournals.org
2087
sorafenib. In the present study, we sought to determine the efficacy of salvage therapy in patients with advanced DTC for whom first-line treatment with sorafenib failed.
Patients and Methods Study population After receiving institutional review board approval, we retrospectively collected data on adult patients with metastatic DTC who received first-line treatment with sorafenib between January 2005 and May 2013 at The University of Texas M. D. Anderson Cancer Center. Patient data collected included age, sex, histological findings, disease stage at diagnosis, cumulative I-131 activity, site of distant metastases, information about treatment with sorafenib (time from diagnosis to start of treatment, duration of treatment, dosage, reason for discontinuation, or changes to dosage), information about any salvage treatments received, tumor response, and follow-up time or date of death. For overall survival (OS) analysis, patients were assigned to one of two groups: patients in group 1 received first-line treatment with sorafenib only, and patients in group 2 received salvage treatment with another kinase inhibitor after initial treatment with sorafenib. Group 1 was included for OS analysis only. All patients were included for OS analysis of the entire cohort. For comparison between the two groups, we excluded from this analysis patients who died within 3 months of starting treatment with sorafenib because these patients were unable to receive salvage therapy (possibly skewing toward worse outcomes in group 1). We also excluded patients who developed a pathologically confirmed, unrelated malignancy during treatment with sorafenib, but we did not exclude patients with malignancies that occurred as an adverse event related to their treatment (such as squamous cell skin carcinomas). For PFS and best response analysis, we focused on the subset of patients who received salvage therapy after their initial treatment with sorafenib and who had a baseline and at least one follow-up imaging study during treatment with sorafenib and during salvage therapy. This group included patients treated with sorafenib outside a clinical trial. The drugs used as salvage therapy were administered either outside a clinical trial (sunitinib, pazopanib, and vemurafenib) or as part of a clinical trial (cabozantinib and lenvatinib). Patients receiving cabozantinib and lenvatinib were participating in phase I (NCT01100619) and phase II (NCT 00784303) clinical trials, respectively. We obtained approval from the sponsors of the studies to use these data.
Study objectives The primary end points in our analysis were PFS duration and best response with first-line sorafenib and salvage therapy. The secondary end point was OS duration in patients who received subsequent salvage therapy after sorafenib failure and in patients who received first-line treatment with sorafenib only.
Assessments and definitions Radiographic assessments were performed by a single radiologist (C.D.) using computed tomography or magnetic resonance imaging. Tumor response was categorized using Response Evaluation Criteria in Solid Tumors version 1.1 (20, 21), and
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2088
Dadu et al
Salvage Therapy in DTC
responses were defined as follows: progressive disease (PD): 20% or greater increase in total target lesions size or new metastatic lesion; stable disease (SD): any change in lesions size between a 19% increase and a 29% decrease; partial response (PR): 30% or greater decrease in target lesions size. Sorafenib failure was defined as disease progression or unacceptable toxicity leading to drug discontinuation. PFS was defined as the time from sorafenib or salvage therapy start until Response Evaluation Criteria in Solid Tumors progression determined from objective tumor measurements, clinical progression as determined by the treating physician, or death, whichever occurred first. Duration of treatment was defined as the time from the start of treatment until disease progression or unacceptable toxicity leading to drug discontinuation. OS was calculated from the date on which the treatment with sorafenib was started to the date of death. Patients who had not died at the time of analysis were censored at the time they were last known to be alive.
Statistical analysis Descriptive statistics were used to summarize patient characteristics by group. Comparisons were made between groups to identify any significant imbalances in patient characteristics. An independent-samples t test was used to compare continuous variables and a 2 test was used to compare categorical variables. OS and PFS were illustrated using Kaplan-Meier plots. A log-rank test was used to compare survival distributions between groups. The best responses for individual patients, calculated using the percentage change in target lesion size compared with baseline (see above), were plotted graphically using a waterfall plot. Values were considered statistically significant at P ⬍ .05. Statistical analyses were performed using Stata version 12 software (StataCorp)and R version 3.0.2.
Results Study population Figure 1 depicts a flow chart of the patients who were included in our study. We identified 64 patients with metastatic DTC who received first-line treatment with sorafenib between January 2005 and May 2013. All patients were included for OS analysis of the entire cohort. Group 1 included 35 patients who received sorafenib only (no treatment followed after sorafenib failure or are still receiving sorafenib), and group 2 included 25 patients who received salvage therapy after sorafenib failure. Four patients (all in group 1) were excluded, one owing to early death within 3 months after starting treatment with sorafenib and three owing to other unrelated malignancies. One patient was diagnosed with diffuse large B cell lymphoma with leptomeningeal disease while on sorafenib for 77 weeks; the drug was discontinued for this reason and the patient died 27 weeks later. One patient had an intraductal papillary mucinous neoplasm (based on radiographic characteristics) prior to the sorafenib
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
First-Line Sorafenib in DTC (n=64)
Exclusion: Early E l ddeath h (n=1) ( 1) Other malignancies (n=3)
Group 2 Sorafenib followed by Salvage Therapy (n=25)
Group 1 Sorafenib Alone (n=35)
Exclusion: Missing radiographic assessments (n=8)
Study population for Best Response and PFS analysis (n=17) Figure 1. Patient population flow chart.
start, which was later diagnosed as pancreatic adenocarcinoma. This patient was on treatment with sorafenib for 71 weeks. Malignant transformation was noted on positron emission tomography/computed tomography 1 year after sorafenib discontinuation. One patient had history of metastatic colon cancer and non-small cell lung carcinoma prior to sorafenib initiation. For best response and PFS analyses, eight patients in group 2 were excluded owing to missing radiographic assessments, leaving 17 evaluable patients for these analyses. Two patients experienced toxicity with sorafenib that led to drug discontinuation before restaging; therefore, the response rate and PFS with sorafenib was reported for 15 patients. Overall survival analysis Patient characteristics The clinical characteristics of all 64 patients who received first-line treatment with sorafenib are summarized in Table 1 along with a comparison between groups. For all patients, the mean age at diagnosis was 54 years and 53% were male. Histological findings showed that 37 patients (58%) had papillary, 13 (20%) had follicular, and 14 (23%) had poorly differentiated carcinoma (papillarypoorly differentiated, follicular-insular, or poorly differ-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
jcem.endojournals.org
2089
Table 1. Patient Characteristics for the Whole Group (n ⫽ 64) and Comparison Between Group 1 (n ⫽ 35) and Group 2 (n ⫽ 25). n, % Characteristic Age at diagnosis, mean ⫾ SD Sex Female Male Histology Papillary-conventional Papillary-follicular Papillary-tall Papillary-poorly differentiated Follicular Follicular-Hurthle Follicular-insular Poorly differentiated-NOS Stage at diagnosis I II III IVA IVC Unknown Cumulative I131 activity, mean ⫾ SD Site of distant metastases at start of treatment with sorafenib Lung Bone Time from diagnosis to start of treatment with sorafenib, y, mean ⫾ SD Starting daily dose of sorafenib 200 mg 400 mg 800 mg Unknown Reason for sorafenib discontinuationd Progression Toxicity Sorafenib interruptione Sorafenib dose reductione Time to sorafenib failure, mo, median (95% CI)
All Patients (n ⴝ 64)
Group 1 (n ⴝ 35)
Group 2 (n ⴝ 25)
P Value
53.9 ⫾ 9.2
54.9 ⫾ 10.0
53.3 ⫾ 8.6
.519a
30 (47) 34 (53)
17 (49) 18 (51)
12 (48) 13 (52)
.965b
25 (39) 11 (17) 1 (2) 4 (6) 5 (8) 8 (13) 6 (9) 4 (6)
15 (43) 7 (20) 1 (3) 4 (11) 2 (6) 1 (3) 2 (6) 3 (9)
7 (28) 4 (16) 0 (0) 0 (0) 3 (12) 6 (24) 4 (16) 1 (4)
.07c
7 (11) 4 (6) 18 (28) 13 (20) 19 (30) 3 (5) 362 ⫾ 230
6 (17) 2 (6) 8 (23) 7 (20) 11 (31) 1 (3) 333 ⫾ 223
1 (4) 2 (8) 9 (36) 4 (16) 8 (32) 1 (4) 397 ⫾ 239
.646c
.337a
62 (97) 22 (34) 5.1 ⫾ 4.4
33 (94) 11 (31) 6.0 ⫾ 4.4
25 (100) 10 (40) 4.6 ⫾ 3.3
.506c .420b .192a
1 (2) 17 (27) 43 (67) 3 (5)
1 (3) 8 (23) 24 (69) 2 (6)
0 (0) 7 (28) 17 (68) 1 (4)
.817c
37/44 (84) 7/44 (16) 35/57 (61) 30/57 (53) 11 (5.4 –16.5)
12/17 (71) 5/17 (29) 18/31 (58) 17/31 (55) 10 (5.3–14.6)
23/24 (96) 1/24 (4) 15/22 (68) 12/22 (55) 14 (5.8 –22.1)
.066c .454b .984b .372f
Abbreviation: NOS, not otherwise specified. Percentages may not equal to 100% due to rounding error. a
P value based on an independent-samples t test.
b
P value based on a 2 test.
c
P value based on a Fisher’s exact test.
d
Evaluable in 44 patients.
e
Evaluable in 57 patients.
f
P value based on a log-rank test.
entiated-not otherwise specified), and most patients had stage III or IV disease at diagnosis. All patients had RAIrefractory disease. At the time that treatment with sorafenib was started, 62 patients (97%) had distant metastases in the lung and 22 patients (34%) had distant metastases in the bone. Data regarding sorafenib discontinuation were available in 44 patients: 37 (85%) discontinued sorafenib owing to progression and seven (16%) owing to toxicity. Information concerning sorafenib dose reduction and drug interruption was available in 57 pa-
tients: drug interruption was needed in 35 patients (61%) and dose reduction was needed in 30 patients (53%). No statistical differences were observed between the two groups, but group 1 (sorafenib only) contained more patients with papillary thyroid cancer (64%) and group 2 (salvage therapy) contained more patients with follicular thyroid cancer (52%). In group 1, 11 patients were still receiving sorafenib at the time of this analysis. In group 2, nine patients were still receiving second-line treatment and six patients had received more than two lines of treatment.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2090
Dadu et al
Salvage Therapy in DTC
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
Salvage treatments included sunitinib (n ⫽ 10), pazopanib (n ⫽ 4), cabozantinib (n ⫽ 4), lenvatinib (n ⫽ 4), and vemurafenib (n ⫽ 3). Patients receiving cabozantinib and lenvatinib were part of a clinical trial. Overall survival The median OS of all 64 patients treated with first-line sorafenib was 36.6 months [95% confidence interval (CI) 30.4-NA] (Figure 2A). The median OS in group 2 (the salvage therapy group) was 58.4 months (95% CI 33.4 –NA [not reached]), which was significantly longer than the median OS in group 1 (the sorafenib-only group) (28.8; 95% CI 16.1–NA); P ⫽ .013; Figure 2B). Median OS did not differ on the basis of sex, histological findings, stage at diagnosis, discontinuation owing to toxicity or progression, dose reduction, or drug interruptions. Nineteen patients in group 1 (54%) and 15 patients in group 2 (60%) were still alive at the time of this analysis. The median follow-up time was 36.6 months (95% CI 30.4 – NA) in all patients, 26.2 months (95% CI 22.7– 42.4)
Overall Survival With First line Sorafenib
0.4 0.2
20
40
60
80
100
Months
B Overall Survival
1.0
Sorafenib followed by Salvage Therapy (Group 2) Sorafenib Alone (Group 1)
0.2
0.4
0.6
0.8
Group 1 (N = 35) Group 2 (N = 25)
Group 1 versus Group 2 p-value = 0.013
0.0
Survival Probability
Patient characteristics The baseline characteristics of the subgroup of patients included in this analysis are shown in Table 2. The mean age at diagnosis was 52 years, and 53% of patients were male. Histological findings showed that nine patients had papillary (six conventional and three follicular) and seven patients had follicular thyroid cancer (four Hurthle cell carcinoma, two insular type, and one poorly differentiated cancer). T3 and T4 tumors were present in 16 patients (94%), and seven (41%) had metastatic disease at the time
Table 2. Baseline Characteristics of the Subgroup of Patients Included in the Best Response and PFS Analysis (n ⫽ 17)
0
• •
Efficacy analysis of salvage therapy
0.6 0
0.8
All Patients (N = 64)
0.0
Survival Prob bability
1.0
A
in group 1, and 46.6 months (95% CI 35.7– 66.4) in group 2. When all patients were included in group 1 (n ⫽ 39), the median OS was 24.2 months (95% CI 17.8 –NA). The OS in this group remains significantly shorter when compared with group 2 [58.4 months (95% CI 34.0-NA); P ⫽ .007]. To evaluate the effect of salvage therapy on survival, a second OS analysis was performed using sorafenib end as the start date for OS analysis. To date, 42 patients failed first-line sorafenib, of which 17 were in group 1 and 25 in group 2. Using this definition, the median OS was still significantly longer with salvage treatment compared with sorafenib alone (4.25 vs 42 months, P ⬍ .001).
0
20
40
60
80
100
Months
Figure 2. A, Median OS from the start of treatment with sorafenib for all 64 patients was 36.6 months. B, Median OS from start of sorafenib in group 1 (sorafenib alone) compared with group 2 (sorafenib followed by salvage therapy) was 58.4 vs 28.8 months (P ⫽ .013).
Characteristic
n, %
Age at diagnosis, y, mean ⫾ SD Sex Female Male Histology Papillary, all variants Follicular, all variants Poorly differentiated TNM stage at diagnosis T3, T4 M1 Site of distant metastases Lung Bone Reason for sorafenib discontinuation Progressive disease Toxicity Salvage therapy Sunitinib Cabozantinib Pazopanib Lenvatinib Vemurafenib
52.5 ⫾ 8.8 8 (47) 9 (53) 9 (53) 7 (41) 1 (6) 16 (94) 7 (41) 17 (100) 6 (35) 15 (88) 2 (12) 4 4 3 3 3
Abbreviation: TNM, tumor node metastasis. Percentages may not equal to 100% due to rounding error.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
jcem.endojournals.org
of diagnosis. Seven of 17 evaluable patients receiving salvage therapy were still on treatment with a second agent at the time of this analysis. Ten patients discontinued the drug due to progression. To date, there were no discontinuations due to toxicity during treatment with salvage therapy, although most patients needed dose adjustment to manage side effects. Best response and PFS Two patients experienced toxicity with sorafenib that led to drug discontinuation before restaging (mucositis and hand foot syndrome). In the remaining 15 patients, best responses with first-line sorafenib were PR in two (13%), SD in 10 (67%), and PD in three (20%) patients (Figure 3A). In all 17 patients, best responses with salvage therapy were PR in seven (41%) and SD in 10 (59%) patients (Figure 3B). No PD was observed with salvage therapy as the best response. All three patients who had PD
A
Best Response with First-Line Sorafenib
Chan nge in sum of target lesions l (%)
60
SD 67%
PD 20%
PR 13%
40 20 0
**
-20 40 -40 -60
Assessable patients (n=15)
*2 stopped due to toxicity
B
Best Response with Salvage Therapy
Change in n sum of target lesion ns (%)
60 SD 59%
PR 41%
40 20 0
-20 -40 -60 Assessable patients (n=17)
Figure 3. Best response with sorafenib (A) and with salvage therapy (B) in 17 patients whose first-line treatment with sorafenib failed. In panel A, two patients were excluded owing to sorafenib toxicity. Note that patients are not shown in the same order in panels A and B.
2091
during treatment with sorafenib achieved PR with the second drug (⬎55% tumor size reduction). Two patients discontinued sorafenib owing to toxicity in less than 1 month but tolerated and responded to second-line treatment with sunitinib. One of these patients achieved SD with tumor regression (15% reduction) for 16 months. The second patient achieved PR (61% reduction) and is still receiving sunitinib after 30 months. Tumor responses in individual patients are shown in Figure 4. The median PFS was 7.4 months (95% CI 3.1–11.3) with first-line sorafenib and 11.3 months (95% CI 5.3– 24.4) with salvage therapy.
Discussion Our results suggest that other molecular targeted agents can be effective as salvage therapies after sorafenib failure in patients with metastatic DTC. Salvage therapy after sorafenib failure is used in clinical practice because responses are not durable and nearly 20% of patients do not tolerate sorafenib (11). Several trials of TKIs for the treatment of DTC have included patients who received prior treatment with other TKIs, but information regarding the efficacy of such an approach is limited. The results of a small phase I study of cabozantinib showed that patients with thyroid cancer in whom treatment with first-line TKIs failed, continued to respond to cabozantinib. Of 14 evaluable patients, eight received sorafenib prior to cabozantinib, and five of these patients achieved PR with cabozantinib (17). In the phase II sunitinib trial, two patients were treated with sorafenib and had the drug discontinued due to toxicity. After starting sunitinib, one patient had 29% reduction of tumor and was on therapy for 12 months (18). Our study is the first to examine the efficacy of salvage therapy in patients with metastatic, RAI-refractory DTC whose first-line treatment with sorafenib failed. Inevitably, all patients treated with sorafenib develop disease progression or toxicity leading to discontinuation, and it is not clear whether salvage therapy is advantageous. The results of our study suggest that salvage treatment with drugs that have similar mechanisms of action to those of sorafenib can be beneficial. We have shown that patients continued to respond to second-line treatment after firstline sorafenib failure. PR occurred in 41% and SD in 59% of the patients receiving salvage therapy. PFS with a second-line TKI therapy was 11.4 months. This is similar to the PFS durations and response rates reported in phase II trials with various TKIs, such as sunitinib, pazopanib, vandetanib, cabozantinib, and lenvatinib (17, 18, 22–24). Three patients in our study who had PD as the best re-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2092
Dadu et al
Salvage Therapy in DTC
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
tage in the sorafenib arm (10.8 months compared with 5.8 months 1 Line Sorafenib CABO: cabozantinib (n=4) LEN: lenvatinib (n=3) in the placebo arm). The PR rate was 50 Salvage Therapy PAZ: pazopanib (n=3) 12.2% with sorafenib compared SUN: sunitinib (n=4) VEM: vemurafenib (n=3) 30 with 0.5% with placebo, and no PAZ complete responses were observed. PAZ Sorafenib LEN Toxicity 10 SD of 6 or more months was present SUN SUN in 42% of patients receiving -10 sorafenib. The discontinuation rate VEM SUN CABO owing to toxicity was 19%. -30 To date, data reporting median VEM PAZ CABO VEM OS duration in treatment-naive pa-50 tients with DTC receiving first-line LEN CABO CABO treatment with sorafenib are limited. SUN LEN -70 Our study, which included a rela1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 tively large number of patients, is the Assessable patients (n=17) first to report a median OS of 37 Figure 4. Best responses in individual patients whose first-line treatment with sorafenib failed months in patients with TKI naive (n ⫽ 17). DTC treated with first-line sorafenib. In the phase III clinical sponse to sorafenib achieved impressive responses (more trial, the median OS has not been reached in either arm than 55% tumor reduction) with a second-line TKI (two (11). Two phase II studies that included a smaller number cabozantinib and one lenvatinib). The rest of the patients of patients and a different patient population reached a continued to have prolonged SD or PR with the secondmedian OS. Schneider et al (9) reported an estimated meline treatment despite PD with sorafenib. Furthermore, dian OS of 34.5 months in 31 patients with DTC receiving two patients developed severe toxicity with sorafenib, sorafenib, but these patients were not all TKI-naive. For a leading to drug discontinuation early in the treatment but subgroup of 33 patients with papillary thyroid cancer responded to and tolerated another TKI (sunitinib) with a treated with first-line sorafenib, Kloos et al (6) reported a similar toxicity profile. median OS of 23 months. Because patients responded to the salvage therapy, disAnother important finding of our study is the longer ease progression or toxicity with sorafenib should not exsurvival we observed in patients who were able to receive clude use of another TKI. To address this issue in a prospective fashion, a phase II trial of cabozantinib in patients salvage therapy. Our study is the first to show that patients with DTC that progressed during treatment with first-line who are able to receive salvage therapy may survive longer treatment with antiangiogenic TKIs is currently underway than those treated with sorafenib followed by no salvage (clinicaltrials.gov, NCT identifier 1811212). Whether the treatment. The median OS was 58 months for those who differences in response between first-line and salvage ther- received salvage therapy compared with 28 months in apy are caused by inhibition of different vascular endo- those treated with sorafenib alone. The two groups were thelial growth factor receptors, inhibition of other targets similar in terms of baseline characteristics, including age, such as RET, c-KIT, c-MET, or BRAF, or different poten- sex, stage at diagnosis, site of distant metastases, time from cies of each compound (IC50 concentrations) (Supplemen- diagnosis to the start of treatment with sorafenib, and duration of treatment with sorafenib. More patients had tal Table 1) needs to be determined. In our study, the efficacy and tolerability with sorafenib papillary thyroid cancer in the group receiving sorafenib are similar to those reported in the phase III trial (11). The alone and more patients had follicular thyroid cancer in best response to first-line treatment with sorafenib was the group receiving salvage therapy, although these dif13% PR and 67% SD, PFS was 7.4 months, and discon- ferences were not statistically significant. Because of this, tinuation rate owing to toxicity was 15%. PFS presented the two groups are not directly comparable on the basis of in our study is slightly shorter than previously reported, histological findings, although one would expect a worse possibly due to inclusion of more aggressive histologies, outcome in the group with more follicular thyroid cancer. namely poorly differentiated thyroid cancer and more pa- The difference in OS between the two groups may also be tients with metastasis to bone. Results of the phase III explained by differences in performance status; the group placebo-controlled trial with TKI-naive patients with of patients who did not receive salvage therapy after DTC demonstrated a statistically significant PFS advan- sorafenib may have been much sicker. Because of the retBest Response in Individual Patients
Change in sum of target lesions (%)
St
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3588
rospective nature of the study, we were unable to assess the performance status of our patients. To the best of our knowledge, patients did not receive second-line therapy for several reasons: 1) limited knowledge regarding the efficacy of salvage therapy during the first years in which targeted therapies were in use, therefore preventing the treating physician from offering this as an option; 2) unavailability of other therapies; 3) patient refusal; and 4) palliative treatment offered instead owing to poor performance status. Furthermore, several patients were still receiving sorafenib at the time of this analysis and likely will be offered salvage therapy in the event of disease progression. This study contains several limitations resulting from its retrospective design, including missing information regarding patient performance status, lack of a clear reason for not receiving salvage therapy, and lack of conclusive evidence that all patients had progressive disease before the start of treatment with sorafenib. Because advanced thyroid cancer is rare and TKIs are a fairly new treatment approach, the subgroup of patients in our study population who received salvage therapy was small, and they received a variety of different drugs. Therefore, a comparison between different drugs used as salvage therapy was not feasible. In summary, sorafenib failure did not predict response to salvage treatment with other drugs despite similar mechanisms of action. Although the groups in our study are not directly comparable, our findings indicate that patients who are able to receive salvage therapy after sorafenib failure benefit from this approach, and the current standard should be to offer targeted therapy as a salvage treatment to these patients. Future directions of study include elucidating the mechanism of resistance with targeted therapies, determining the best order of targeted therapy use, and analysis of combination and additive therapies.
Acknowledgments Address all correspondence and requests for reprints to: Maria E. Cabanillas, MD, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1461, Houston, TX 77030. E-mail: [email protected]. This work was supported by the National Institutes of Health/National Cancer Institute under Award P30CA016672. Disclosure Summary: R.D., C.D., M.H., S.G.W., M.I.H., C.J., M.A.H., R.V.S., A.K.Y., and G.J.C. have nothing to disclose. N.L.B. has received research funding from Bayer/Onyx. S.I.S. is a consultant to Bayer, Eisai, and Exelixis. M.E.C. has received research funding from Roche, Eisai, and Exelixis and has served on the advisory boards for Eisai and Exelixis.
jcem.endojournals.org
2093
References 1. Ruegemer JJ, Hay ID, Bergstralh EJ, Ryan JJ, Offord KP, Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab. 1988;67:501–508. 2. Shoup M, Stojadinovic A, Nissan A, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg. 2003;197:191–197. 3. 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;91:2892–2899. 4. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10 –29. 5. Dadu R, Cabanillas ME. Optimizing therapy for radioactive iodinerefractory differentiated thyroid cancer: current state of the art and future directions. Minerva Endocrinol. 2012;37:335–356. 6. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27:1675–1684. 7. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714 – 4719. 8. Hoftijzer H, Heemstra KA, Morreau H, et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol. 2009;161:923–931. 9. Schneider T, Abdulrahman R, Corssmit EP, Morreau H, Smit JW, Kapiteijn E. Long term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol. 2012; 167:643– 650. 10. Ahmed M, Barbachano Y, Riddell A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol. 2011;165:315–322. 11. Brose M, Nuyying C, Jarzab B, et al. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. J Clin Oncol. 2013;31:abstract 4. 12. Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology. 2009;76:350 –354. 13. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115:61– 67. 14. Porta C, Procopio G, Carteni G, et al. Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (rcc): an Italian multicentre retrospective analysis of 189 patient cases. BJU Int. 2011; 108:E250 –E257. 15. Procopio G, Verzoni E, Iacovelli R, Guadalupi V, Gelsomino F, Buzzoni R. Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience. Expert Rev Anticancer Ther. 2011;11:1631–1640. 16. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29 –34. 17. Cabanillas ME, Brose M, Lee Y, Miles D, Sherman SI. Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC). J Clin Oncol Vol. 2012;30: abstract 5547. 18. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260 – 5268. 19. Cabanillas ME, Waguespack SG, Bronstein Y, et al. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab. 2010;95:2588 –2595.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
2094
Dadu et al
Salvage Therapy in DTC
20. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. 21. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228 –247. 22. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in
J Clin Endocrinol Metab, June 2014, 99(6):2086 –2094
progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. 23. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905. 24. Sherman SI, Jarzab B, Cabanillas ME, et al. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol. 2011;29:Abstract 5503.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2014. at 04:33 For personal use only. No other uses without permission. . All rights reserved.
