Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies

Background For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively. Methods For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs). Results Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1–9.7), and the median PFS was 3.2 months (95% CI 1.9–6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%–27%) and 64% (95% CI 55%–72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%–86%). Conclusion Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.


Introduction
Anaplastic thyroid cancer (ATC) is recognized for its rare incidence, high aggressiveness, and poor prognosis.For patients without mutational driver genes (e.g., BRAF V600E, NTRK, and RET), the recommended systemic therapeutic option in the National Comprehensive Cancer Network (NCCN) guideline was chemotherapy, including paclitaxel, doxorubicin, carboplatin, and cisplatin (1).
Retrospectively, doxorubicin plus cisplatin chemotherapy has been applied in ATC since 1985.The median overall survival (OS) was approximately 6 months, with an objective response rate (ORR) of up to 26% (2).In terms of taxane-based treatments, clinicians have begun to use these strategies since 2000.In Kenneth B. Ain's study, the median OS was also nearly 6 months, but the ORR was over 50% (3).
Nevertheless, the efficacy of cytotoxic drugs is limited.The total lifetime of patients with ATC is hard to exceed half a year.In the "Systemic therapy: cytotoxic chemotherapy" section of the American Thyroid Association Guidelines for Management of Patients with ATC (2021), the cited latest record studying cytotoxic drugs in ATC was published in 2010 (4).We are eager to find out whether novel cytotoxic drugs have been explored to treat ATC after 2010.
Therefore, we conducted this updated analysis to collect and synthesize the efficacy and safety data of emerging chemotherapybased treatments reported in prospective studies from January 2010 to February 2024.Through this analysis, we intend to provide more insights into future studies.

Literature search
For this analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases to identify prospective studies from 1 January 2010 to 7 February 2024.The search terms included "chemotherapy or taxane or paclitaxel or docetaxel or taxel or doxorubicin or cisplatin or carboplatin or mitoxantrone or cyclophosphamide or fluorouracil" and "anaplastic thyroid cancer".The study type was defined as "clinical trial" or "randomized clinical trial".This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guideline (5).

Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) patients were pathologically diagnosed as ATC; (2) patients were treated with cytotoxic chemotherapy-based treatments; (3) data of survival outcomes, response rates, and incidences of treatment-related adverse events (TRAEs) were available; and (4) enrolled studies were prospective clinical trials published in English.Meeting abstracts were excluded.

Statistical analysis and risk of bias assessment
Reconstructed OS and progression-free survival (PFS) curves were pooled and analyzed using the metaSurvival package of the R software.The detailed protocol has been described in Christophe Combescure's study (6).
Pooled ORRs, disease control rates (DCRs), and incidences of TRAEs with 95% CIs were conducted using the meta package of the R software (version 4.2.2).Heterogeneity was quantified using I 2 statistic percentages (low: I 2 < 50%, p < 0.05).Single-arm analyses were done with the random-effects model.
Funnel plots and Egger's test (p < 0.01) were used to assess publication bias.
Table 1 summarizes the characteristics of the trials.Median age ranged from 56 to 71.Cytotoxic drugs included paclitaxel, docetaxel, doxorubicin, and carboplatin.The combination of chemotherapy with targeted therapy (pazopanib, fosbretabulin, and efatutazone) was applied in three trials.Although radiotherapy was pre-designed in three of the six trials (7)(8)(9), patients in the other three trials received radiotherapy either (10-12).
Survival outcomes reported in the trials are summarized in Table 2.The median OS ranged from 2.8 months (docetaxel + doxorubicin plus pembrolizumab and radiotherapy) to 7.3 months (paclitaxel plus placebo and radiotherapy), the median PFS ranged from 1.4 months (docetaxel) to 3.3 months (paclitaxel + carboplatin plus fosbretabulin), and the 1-year survival rates ranged from 8.7% (paclitaxel + carboplatin) to 37.1% (paclitaxel plus pazopanib and radiotherapy).

Risk of bias
Funnel plots and Egger's tests failed to find any publication bias during the analyses of ORR (Figures 4A, B), DCR (Figures 4C, D), and TRAE (Figures 4E, F

Discussion
In this updated analysis of emerging chemotherapy-based treatment for patients with ATC, the total lifetime remains within 6 months even if targeted therapy, immunotherapy, or radiotherapy were added, and DCR was over 60%.To overcome the issues, basic researchers and physicians still need to do numerous explorations.
Among the eligible trials, cytotoxic drugs included only paclitaxel, docetaxel, doxorubicin, and carboplatin.Such selections indicate that clinicians or the drug industry may be more confident in these drugs.According to the search strategy described in the Methods section, mitoxantrone, cyclophosphamide, and fluorouracil have also been administered in patients with ATC (13-15).However, substantial improvements in survival outcomes were not identified when patients with ATC were treated with these drugs.Since novel-designed cytotoxic drugs have been approved to treat both solid and hematological tumors, like antibody-drug conjugates brentuximab vedotin (16) and sacituzumab govitecan (17), whether antibody-drug conjugates can help to enhance the responses and prolong survival outcome in ATC deserves further investigations.
In the trials enrolled in this analysis, we found that nearly all participants have received radiotherapy.Indirectly, radiotherapy is critically essential for patients with ATC to achieve local disease control since a rapidly growing neck mass can cause asphyxiation.In other solid tumors, radiotherapy has been certified to benefit patients with a tolerable safety profile.In patients with renal cell carcinoma who decline surgery, stereotactic body radiotherapy can be suggested as a safe and effective standard treatment option (18).In advanced lung cancer, the addition of radiotherapy significantly improved response rates compared with immunotherapy alone (19).Therefore, we believe that reasonable palliative radiotherapy may bring unexpected benefits for patients with advanced ATC.
Although immunotherapy has significantly impacted previous therapeutic strategies for patients with cancer, the efficacy of immune checkpoint inhibitors on ATC was limited.In the subset of patients with PD-L1 < 1%, the median OS was 1.6 months (95% CI 1.0-19.6),while for the subset of patients with PD-L1 > 1%, the data were not reached (32364844).Clinicians have started investigating the combination of immunotherapy and radiotherapy (20,21).In head and neck cancer, a synergistic effect has been found as both irradiated sites and metastatic lesions achieved responses (21).Accordingly, digging for effective combination therapies for patients with ATC is also crucial.
Regarding the grade 3 or worse TRAEs, the incidence (68%) deserves our attention.Increased alanine aminotransferase, dermatitis radiation, dysphagia, and neutropenia were the most common grade 3 or worse TRAEs recorded in the enrolled trials.

Conclusion
In this updated analysis, the emerging chemotherapy-based treatments did not substantially prolong the survival time of patients with ATC.Novel cytotoxic or targeted drugs or creative combination therapies are warranted in future studies.The author(s) declare financial support was received for the research, authorship, and/or publication of this article.This study was supported by the National Natural Science Foundation of China (No. 82302956 to B-CW).

Acknowledgments
We truly thank Wang's group for providing the statistical support.

TABLE 1
Characteristics of enrolled studies of chemotherapy in anaplastic thyroid cancer.

TABLE 2
Survival outcomes of anaplastic thyroid cancer patients treated with chemotherapy-based treatments.