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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 84-91

Hypothyroidism post-chemoradiation on outcomes in head-and-neck cancer


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Centre for Cancer Epidemiology, The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication17-May-2019

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_17_18

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  Abstract 


Background: Hypothyroidism is a known side effect of head-and-neck cancer treatment and might improve outcomes. However, whether the development of hypothyroidism or maintaining a hypothyroid state remains a factor is unclear.
Methods: Once-a-week versus once-every-3-weeks cisplatin chemoradiation in locally advanced head and neck cancer was a Phase III open-label, noninferiority randomized study conducted by our group in the Medical Oncology Department of Tata Memorial Hospital, Mumbai, India. The database of this study was assessed for this analysis. Hypothyroidism was defined as a serum thyroid-stimulating hormone (TSH) level of above 5 uIU/ml. Duration of hypothyroidism was defined as cumulative duration in days postrandomization that the patient spent in hypothyroid state before progression. The relationship between duration of hypothyroidism (continuous variable) and peak TSH values and outcomes (locoregional failure [LRF] rate, progression-free survival [PFS], and overall survival [OS]) were analyzed.
Results: Higher duration of time spent in a hypothyroid state had a favorable impact on PFS (HR: 0.996, 95% CI: 0.994–0.999, P = 0.007), and OS (HR: 0.995, 95% CI: 0.991–0.999, P = 0.016). This favorable impact on LRF (HR: 0.963, 95% CI: 0.929–0.997, P = 0.034), PFS (HR: 0.996, 95% CI: 0.993–0.999, P = 0.005), and OS (HR: 0.993, 95% CI: 0.987–0.999, P = 0.022) was confirmed on multivariate analysis too. Peak TSH value between 30 and 40 uIU/ml provided the maximum benefit for LRF with HR of 4.76 (standard error (SE) of HR as 0.627, P = 0.01).
Conclusion: A longer duration and higher state of hypothyroidism (TSH – 30–40 Iu/ml) provided the maximum improvement in outcomes, this is an interesting hypothesis which needs to be confirmed with more studies.

Keywords: Chemoradiation, head-and-neck cancer, hypothyroidism, survival, thyroid


How to cite this article:
Patil VM, Noronha V, Joshi A, Mandal TK, Bhattacharjee A, Goel A, Talreja V, Chandrasekharan A, Pande N, Ramaswamy A, Prabhash K. Hypothyroidism post-chemoradiation on outcomes in head-and-neck cancer. Cancer Res Stat Treat 2018;1:84-91

How to cite this URL:
Patil VM, Noronha V, Joshi A, Mandal TK, Bhattacharjee A, Goel A, Talreja V, Chandrasekharan A, Pande N, Ramaswamy A, Prabhash K. Hypothyroidism post-chemoradiation on outcomes in head-and-neck cancer. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Aug 24];1:84-91. Available from: http://www.crstonline.com/text.asp?2018/1/2/84/258535




  Introduction Top


Hypothyroidism is a known complication in patients treated with irradiation for head-and-neck cancer.[1],[2],[3],[4] The reported incidence varies between 6% and 74%.[5] The incidence is impacted by multiple factors such as age, site of primary, radiation dose to thyroid, and duration of follow-up.[2], 3, [6],[7],[8],[9] Radiation-induced hypothyroidism is frequently detected anywhere between 6 months and 2 years postradiation completion with some patients having a delayed onset up to 20 years post-treatment.[3],[5],[9] Clinical hypothyroidism results in a myriad of cardiovascular, metabolic, and gastrointestinal syndromes that may significantly hamper the quality of life.[4] Such systemic effects may further hamper survival outcomes post-treatment of primary cancer. The current literature consistently recommends thyroid function testing at 6-monthly intervals post-chemoradiation for 3–5 years and then annually for at least 10 years.[5]

Development of treatment-induced hypothyroidism in few cancers, associated with improvement in progression-free survival (PFS) and overall survival (OS). Sunitinib- and sorafenib-induced hypothyroidism in the treatment of renal cell carcinoma (RCC) are associated with improved OS.[10],[11],[12],[13] In a Phase II study of recurrent glioblastoma multiforme, medically induced hypothyroidism led to an improvement in PFS and OS.[14],[15] Similar observational data also exist for other solid tumors.[16],[17] The occurrence of such a phenomenon in head-and-neck cancers has not been previously evaluated. We recently reported the outcomes of once-a-week versus once-every-3-weeks cisplatin (W3W study) as concurrent chemotherapy along with radiation in head-and-neck cancer.[18] The prospective nature of this study allowed us to evaluate the incidence, extent, relationship of hypothyroidism, and thyroid-stimulating hormone (TSH) levels with cancer-related outcomes.


  Methods Top


Study conduct

W3W was a Phase III open-label, noninferiority randomized study conducted by our group in the Medical Oncology department of Tata Memorial Hospital, Mumbai, India. The protocol of this study was approved by the institutional ethics committee, and it was registered with Clinical Trials Registry of India (CTRI/2012/10/003062). The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. It was funded by the Tata Memorial Centre Research Administration Council.

Study population

Head-and-neck cancer patients with locally advanced cancer who had primary in the oral cavity, oropharynx, larynx, and hypopharynx or had a neck node with unknown primary were enrolled in this study. The indications for receiving chemoradiation were either in the radical setting (upfront for unresectable disease or as organ preservation strategy) or as adjuvant in the high-risk postoperative setting. The other eligibility criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) <3, normal organ functions, and no previous chemotherapy. The detailed eligibility criteria have been previously published.[18]

Study methodology

Patients post-consenting underwent a block-stratified computerized randomization by an independent statistician. They were randomized in 1:1 fashion to either the once-in-3-weeks cisplatin (100 mg/m2) arm or once-a-week cisplatin (30 mg/m2) arm. The chemotherapy was administered concurrently with radiotherapy as per standard protocols. The dose of radiation was 6000 cGy over 6 weeks with daily fraction size of 200 cGy in the adjuvant setting and 7000 cGy over 7 weeks in the radical setting. Post-completion of chemoradiation, patients were followed up at 3-monthly intervals for the first 2 years and then every 6 months, subsequently. At each visit, complete history, relevant physical examination, and testing of blood parameters were done, including serum T3, T4, and TSH levels (thyroid function test [TFT]). The detailed methodology of the study including details of planning, quality assurance, delivery of radiation, chemotherapy details, and dose modifications are published already.

Statistical analysis

R version 3.4.2 (R Core Team, Vienna, Austria) was used for analysis. Hypothyroidism was defined as a serum TSH level of above 5 uIU/ml (Duntas 2016). The time to development of hypothyroidism was defined as time in months from the date of randomization to the first occurrence of hypothyroidism. The cumulative incidence curve of hypothyroidism was then plotted. Those patients who had not developed hypothyroidism were censored at their last follow-up. Patients who had either progressed or died before the first visit (when TFT was tested) were used as a competing event when plotting the cumulative incidence curve.

Previously suggested factors predicting the development of hypothyroidism were evaluated. These were age (as a continuous variable), gender (male or female), site of primary (hypopharynx or larynx versus non-hypopharynx or larynx), nodal stage (N0–1 vs. N2–3), T stage (T0–T2 vs. T3–4), cumulative radiotherapy dose (as a continuous variable), and cumulative cisplatin dose (as a continuous variable). The binary logistic regression analysis was used for this analysis. Patients who had either progressed or died before the first visit (when TFT was tested) were excluded from this analysis [Supplementary Appendix Figure 1]. P =0.05 or below was considered as statistically significant. The odds ratio with its 95% confidence interval (CI) for the development of hypothyroidism was calculated.

The impact of the development of hypothyroidism on outcomes was studied [Supplementary Appendix Figure 1]. The outcomes tested were locoregional failure (LRF), PFS, and OS. LRF was defined as time in months from the date of randomization to LRF. LRF was considered as recurrence of tumor in local or regional area. In definitive setting, those patients who did not have complete disappearance of malignancy at the first-evaluation visit were considered as failed at the first-evaluation visit. PFS was defined as time in months from the date of randomization to any kind of failure or death due to any cause, whichever occurred earlier. OS was defined as time in months from date of randomization to death due to any cause. Kaplan–Meier method was used to estimate these periods (PFS and OS) and log-rank test was used to compare these durations between patients developing hypothyroidism and not developing hypothyroidism. As the development of hypothyroidism was a time-dependent covariate, Cox proportional hazard regression with time-varying covariate was used for calculation of hazard ratio (HR), with time to onset of hypothyroidism being considered as the time-varying covariate. This was used to test whether the development of hypothyroidism was an independent prognostic factor or not.

The duration of hypothyroidism was defined as cumulative duration in days post-randomization that the patient spent in hypothyroid state before progression. The patients who had developed a TSH >5 uIU/ml but were asymptomatic were not treated with thyroxine but were kept under close observation until the values of TSH was >10 uIU/ml. The relationship between duration of hypothyroidism (continuous variable) and outcomes (LRF rate [LRFR], PFS, and OS) was analyzed. Cox regression analysis was used to test whether the duration of hypothyroidism (tested as a continuous variable) was an independent prognostic factor or not. Patients who had not developed hypothyroidism were excluded from this analysis.

The relationship between TSH level and outcomes were studied. The missing values of TSH for this analysis were imputed using multiple imputations using the Multivariate Imputation via Chained Equations package 2.46.0 for intermediate missing observations. The imputation of TSH was carried with reference to patient's follow-up periods. There was a maximum of six occasions where TSH value was measured; months 3, 6, 9, 12, 18, and 24. The imputed and repeatedly observed values were considered to generate the weighted mean average value of TSH. The six time points weighted mean average was considered if the patients followed/censored till or after 24 months. Alternatively, five, four, three, and two-time points weighted the mean average was considered if the patients were followed or censored till 18, 12, 9, 6, and 3 months, respectively. The relationship between TSH levels (as a time varying repeated measure) and outcomes (LRFR, PFS, and OS) was measured and modeled with Cox proportional hazard model. The weighted mean averages were considered with TSH level cutoff. The initial cut-off level of TSH was explored through a P value chain proposed by Bhattacharjee et al.[19] Later on, a total of five arbitrary cutoffs of TSH were selected. These were Category 1 (<10 uIU/ml or >10 uIU/ml), Category 2 (<20 uIU/ml or >20 uIU/ml), Category 3(<30 uIU/ml or >30 uIU/ml), Category 4 (<40 uIU/ml or >40 uIU/ml), and Category 5 (<50 uIU/ml or >50 uIU/ml). The HR's among these categories were calculated for LRF, PFS, and OS. The hazard rate associated with the lowest value of P was considered as the most appropriate TSH level for a favorable outcome. [Supplementary Appendix Figure 1] provides the flow of patients used for various analyses in this study.


  Results Top


Incidence and factors affecting hypothyroidism

Of 300 patients recruited in the study, at a median follow-up of 22 months, 84 patients had developed hypothyroidism. The cumulative incidence curve of hypothyroidism is shown in [Figure 1] and [Supplementary Appendix Table 1]. The cumulative incidence of hypothyroidism at 1 year was 30.35% (25.15%–25.55%), at 2 years was 38.73% (33.11%–44.35%), and at 3 years was 40.02% (95% CI, 34.47%–45.57%). Median time to development of hypothyroidism was not reached for the overall population. In patients who developed hypothyroidism, the median time was 6.92 months (interquartile range 4.38–9.94 months). Young patients (P = 0.007), patients with primary in larynx or hypopharynx (P = 0.004), and a lower T-stage (P = 0.004) had a higher incidence of hypothyroidism. [Supplementary Appendix Table 2] provides the details of factors impacting the development of hypothyroidism.
Figure 1: Cumulative incidence curve for development of hypothyroidism

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The hypothyroid cohort and the euthyroid cohort were not statistically well balanced. The hypopharyngeal and laryngeal primaries (10.71% vs. 3.24%, P = 0.018), ECOG PS 0 patients (22.6% vs. 12.0%, P = 0.030), and Stage III patients (15.48% vs. 6.02%, P = 0.031) had greater representation in the hypothyroid cohort. There were no statistical differences in the radiation or cisplatin dose delivery between the two cohorts. The baseline characteristics and treatment details can be seen in [Table 1].
Table 1: Baseline details between euthyroid and hypothyroid cohort

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Impact of development of hypothyroidism on outcomes

The study population selected for this analysis is shown in the [Supplementary Appendix Figure 1].

Locoregional failure rate

At a median follow-up of 22 months (range 3–51 months), the 2 years LRFR was 36.61% (95% CI: 29.08–44.14) in the euthyroid cohort, whereas it was 12.37% (95% CI: 5.33–19.41) in the hypothyroid patients cohort [Figure 2]. The unadjusted HR for 2 years LRF was 0.345 (95% CI: 0.122–0.972, P = 0.044) in favor of hypothyroid cohort. On multivariate analysis, the hypothyroid cohort had a statistically favorable HR of 0.342 (95% CI: 0.121–0.968, P = 0.043). The details of 2 years LRFR are depicted in the [Supplementary Appendix Table 3]. [Table 2] shows the details of multivariate analysis for LRFR.
Figure 2: Two-years locoregional failure rate between the euthyroid and hypothyroid cohort

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Table 2: The results of multivariate analysis for locoregional failure rate

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In the euthyroid cohort, of 157 patients, 49 patients had either local or regional relapse. The exact site of the first relapse was local in 10 patients, regional in 22 patients, and local and regional simultaneous in 17 patients. In the hypothyroid cohort, of 84 patients, 12 had relapsed. The exact site of the first relapse was local in seven patients, regional in four patients, and local and regional simultaneously in one patient.

Progression free survival

The median PFS was 28.4 months (95% CI: 11.30–45.56) in the euthyroid cohort, while it was not reached in the hypothyroid cohort (P < 0.001, log-rank test) [Supplementary Appendix Figure 2]. The unadjusted HR was 0.571 (95% CI: 0.324–1.006, P = 0.053) trending in favor of hypothyroid cohort. This trend was in favor of hypothyroid state, and this was confirmed on multivariate analysis (HR: 0.579, 95% CI: 0.329–1.022, P = 0.059). Progression, either locally or distant was observed in 66 patients (42.0%) in the euthyroid cohort as against 19 (22.6%) in the hypothyroid cohort. The [Supplementary Appendix Table 4] and [Supplementary Appendix Table 5] provide the details of PFS and its multivariate analysis.

Overall survival

The median OS was 36.07 months (95% CI, 25.43–46.71) in the euthyroid cohort, whereas it was not reached in the hypothyroid cohort (P < 0.001, log-rank test) [Figure 3]. The unadjusted HR for death was 0.321 (95% CI, 0.167–0.614, P-0.001) in favor of the hypothyroid cohort. On multivariate analysis too, the hypothyroid cohort had a statistically favorable HR of 0.336 (95% CI: 0.175–0.643, P = 0.001). [Table 3] provides the details of multivariate analysis for OS.
Figure 3: The overall survival between the euthyroid and hypothyroid cohort

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Table 3: Multivariate analysis for overall survival

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Impact of duration of hypothyroidism on outcomes

The impact of duration of hypothyroidism was tested in the cohort of hypothyroid patients (n = 84). The higher duration of time spent in hypothyroid state had a favorable impact on PFS (HR: 0.996, 95% CI: 0.994–0.999, P = 0.007), and OS (HR: 0.995, 95% CI: 0.991–0.999, P = 0.016). This favorable impact on LRF (HR: 0.963, 95% CI 0.929–0.997, P = 0.034), PFS (HR: 0.996, 95% CI: 0.993–0.999, P = 0.005), and OS (HR: 0.993, 95% CI: 0.987–0.999, P = 0.022) was confirmed on multivariate analysis too. [Supplementary Appendix Table 6], [Supplementary Appendix Table 7], [Supplementary Appendix Table 8] provide the detailed results of multivariate analysis.

Impact of level of thyroid-stimulating hormone on outcomes

Category 4 (<40 uIU/ml or >40 uIU/ml peak TSH value) provided the maxmum benefit for LRF with HR of 4.76 (SE of HR as 0.627, P = 0.01) [Supplementary Appendix Table 9] and [Supplementary Appendix Figure 3]. Similarly, Category 4 (<40 uIU/ml or >40 uIU/ml peak TSH value) provided the maximum benefits on both PFS (HR: of 2.67, SE of HR: 0.57 with P = 0.085) and OS (HR 13.42, SE of HR 1.16 and P-0.025) [Supplementary Appendix Table 9].


  Discussion Top


The reporting of an improvement in outcomes with the development of treatment-induced hypothyroidism in patients treated with curative intent therapy in the current study is probably the first of its kind. We came across only a single retrospective study reported by Nelson et al. in head-and-neck cancers treated with chemoradiation, where the development of hypothyroidism was associated with a statistically insignificant trend toward improvement in recurrence-free survival and OS.[20] The authors had concluded that development of hypothyroidism may be associated with improvement in outcomes and had suggested the need for larger studies to confirm their results. Our data prove that the suggestions provided by Nelson et al.[20] are valid and development of hypothyroidism is in fact associated with improvement in locoregional failure rate, PFS, and OS in head-and-neck cancer patients treated with chemoradiation.

Whether hypothyroidism leads to or is merely associated with an improvement in outcomes is a question which needs to be answered. It may be a surrogate marker for the adequate delivery of the therapeutic agent and thereby related side-effects, as seen with sunitinib-induced hypothyroidism.[11],[12] Hence, the development of hypothyroidism in head-and-neck cancer may be a marker of adequate and accurate delivery of radiation. This explanation, however, would fail to explain why hypothyroidism would improve outcomes in glioma or other solid tumor patients. Hypothyroidism post-radiation is a function of dose as well as the volume of the thyroid gland, receiving that dose. Data from our institute suggest that, if the dose received by 100% of thyroid is >40.27 Gy, it is associated with the development of hypothyroidism in two-thirds of patients.[2] However, the relationship between hypothyroidism and dose received by thyroid is not an all-or-none phenomenon. Therefore, the development of hypothyroidism is not an absolute quality index of delivery of radiation. Further, the fact that a higher TSH level and longer duration of hypothyroidism were associated with improvement in outcomes suggests that hypothyroidism per hypothyroidism per se may have an impact on tumor regrowth. In cancer cell lines, thyroid hormone T3 leads to an increased expression of epidermal growth factor receptor, a receptor associated with cell proliferation.[21],[22],[23] In breast cancer and pituitary tumor cell line studies, addition of T3 hormone was associated with increased proliferation.[24],[25] Thyroid hormones led to decreased apoptosis and help in neoangiogenesis.[23] Such changes at a cellular level may be the cause for the correlation of hypothyroidism with improved cancer-related outcomes.

The incidence of hypothyroidism post-irradiation of the head-and-neck region is variably reported in the literature.[5] This is due to a variety of factors impacting the development of hypothyroidism. The factors affecting the development of hypothyroidism in the current study were young age, site of primary in larynx or hypopharynx, and a lower T-stage. These factors are well known in the literature as factors impacting the development of hypothyroidism.[2], 3, [6],[7],[8],[9] The current study had a relatively homogenous cohort of predominantly locally advanced oral cancer primary patients, being treated with adjuvant intent chemoradiation. The cumulative incidence of hypothyroidism of 38.73% at 2 years, reported in the current study is mostly applicable to this cohort of patients.

Our institute has not formulated a uniform policy regarding treatment of secondary hypothyroidism in these patients. Hence, the TSH level considered for starting thyroxine and for modification of dose of therapeutic thyroxine varied between physicians. Even in the literature, there is no consensus regarding the level of TSH at which thyroxine needs to be started. Multiple publications have suggested that a TSH level above the upper limit of institutional normal as an indication for starting thyroxine.[3],[4],[5] However, the American Thyroid Association suggests that thyroid replacement should be considered in either symptomatic patients or in those with TSH ≥10 uIU/ml in patients with primary hypothyroidism.[26] The current study suggests that an overzealous practice of thyroxine replacement should be avoided or undertaken only after careful consideration in patients being treated with concurrent chemoradiation. The exploratory analysis in our study suggests that maintaining the TSH level between 30 to 40 mIU/ml may be beneficial for oncologic outcomes, however, this is merely hypothesis-generating and has to be weighed against the potential complications of inadequately treated hypothyroidism.

The current analysis has its own strengths and limitations. The data regarding TSH levels and outcomes were obtained from a randomized study and hence were prospectively collected. The TSH evaluation at regular time intervals was a protocol defined preplanned activity and hence we had limited missing TSH values. The analysis, however, is post hoc but had adequate power and has highlighted compelling hypothesis-generating questions. Whether medically induced hypothyroidism in euthyroid patients would improve outcomes is an important question which needs to be addressed.


  Conclusion Top


Longer duration and higher state of hypothyroidism (TSH 30–40 mIU/ml) provided the maximum improvement in outcomes; this is an interesting hypothesis which needs to be confirmed with more studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Research in this Context Top


Evidence before this study

We conducted a PubMed search with the terms,” Hypothyroidism head-and-neck cancer outcomes” and “Hypothyroidism head-and neck-cancer survival.” All articles published till August 2016 were included with no additional filters applied. The evidence suggested that the development of tyrosine kinase-induced hypothyroidism was associated with improvement in cancer-related survival outcomes in metastatic RCC. A study reported by Hercbergs et al. in recurrent glioblastoma, suggested that improvement in overall survival could be achieved by medically induced hypothyroidism. In head-and-neck cancers, a single small retrospective analysis performed by Nelson et al. observed a nonstatistically significant trend towards improvement in survival of patients developing hypothyroidism post-neck irradiation.

When we undertook the study, there was no conclusive evidence of whether treatment-induced hypothyroidism impacted outcomes in head-and-neck cancer patients. It was also unknown whether the development of hypothyroidism was a prognostic factor or a surrogate marker for effective treatment.

Added value of this study

The results of the current study suggest that development of treatment-induced hypothyroidism leads to a decrease in the locoregional failure rate, improvement in progression-free survival, and improvement in overall survival. Among the hypothyroid patients, those with higher duration of untreated hypothyroidism had further decrease in the locoregional failure rate and improved PFS and OS. Patients with peak TSH values between 30 and 40 uIU/ml had maximum benefit in outcomes.

Implications of all the available evidence

Our study suggests that the development of hypothyroidism, post-chemoradiation, leads to an improvement in outcomes. A longer duration of hypothyroidism and TSH level between 30 and 40 uIU/ml yielded maximum benefit. Physicians should be prudent regarding over-aggressive management of hypothyroidism. Further research will be required to investigate whether induction of hypothyroidism medically might improve outcomes of patients with head-and-neck cancer.



























 
  References Top

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Ashur-Fabian O, Blumenthal DT, Bakon M, Nass D, Davis PJ, Hercbergs A. Long-term response in high-grade optic glioma treated with medically induced hypothyroidism and carboplatin: A case report and review of the literature. Anticancer Drugs 2013;24:315-23.  Back to cited text no. 15
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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