Abstract
Background:
Surgical resection is not always achievable in thyroid cancer patients. Neoadjuvant therapy is rarely used, but recent trends favor multikinase inhibitors or selective tyrosine kinase inhibitors. These aim to reduce tumor volume, enabling previously unfeasible surgeries.
Patients and Methods:
Consecutive patients with locally advanced malignant thyroid tumors who received systemic therapies with a neoadjuvant intention were included in this retrospective multicenter case series conducted in five Latin American referral centers. Primary outcomes were pre- versus postneoadjuvant response evaluations using the Response Evaluation Criteria in Solid Tumors, feasibility of surgery, and completeness of resection. Secondary outcomes were mortality and status at the last visit.
Results:
Twenty-seven patients were included in this analysis. Patients with unresectable differentiated thyroid cancer (DTC) or poorly differentiated thyroid cancer (PDTC) received sorafenib (n = 6) or lenvatinib (n = 12), those with medullary thyroid cancer (MTC) were treated with vandetanib (n = 5) or selpercatinib (n = 1), and those with anaplastic thyroid cancer (ATC) harboring a BRAFV600E mutation (n = 3) received dabrafenib and trametinib. The median patient age was 66 years (range 12–82), and 52% of the patients were female. In patients with PTC and PDTC, the median reduction in the diameter of the primary tumor was 25% (range 0–100%) after a median of 6 months of treatment. Surgical intervention was performed in 10 (55%) of the patients. Among these, six patients (60%) achieved R0/R1 resection status.
Six patients with MTC had a median reduction in tumor diameter of 24.5% (range 1–49) after a median treatment time of 9.5 months. Only one patient receiving selpercatinib, with a tumoral reduction of 25% could undergo surgery, resulting in an R2 resection due to extensive mediastinal extension. Three patients with ATC showed a median tumor diameter reduction of 42% (range 6.7–50) after a median treatment time of 2 months. Two patients underwent surgical intervention and achieved R1 and R2 resection, respectively.
Conclusions:
While neoadjuvant therapy achieved tumoral responses, surgical resection was feasible in 55% of DTC, 33% of ATC, and 16% of MTC patients, with R0/R1 resection in 26% of the cohort, underscoring the need for patient selection and further research in this area.
To the Editor :
Unresectable thyroid cancer represents a rare scenario. The prevalence of locally invasive thyroid cancer ranges from less than 10% to 90%, depending on tumor histology, encompassing differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), high-grade follicular-derived tumors, medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC). 1 –3
Recent years have witnessed notable tumoral responses caused by antiangiogenic multikinase inhibitors (MKI), particularly in patients with locally advanced disease. 4 The emergence of selective tyrosine kinase inhibitors (STKI) targeting RET and NTRK alterations, as well as BRAF + MEK inhibitors, has opened new doors for reevaluating neoadjuvant therapy. 5 –9
We present a retrospective consecutive case series of locally advanced unresectable thyroid cancers receiving MKI or STKI in a real-life scenario at five different referral centers in Latin America. This study explores the feasibility of surgery and the outcomes following neoadjuvant therapies.
Materials and Methods
This multicentric case series included patients with locally advanced and unresectable thyroid cancer for whom neoadjuvant therapy was feasible (owing to availability and coverage of MKI or STKI in each country) who, after a multidisciplinary discussion, had a reasonable expectation to achieve resectability upon neoadjuvant therapy. Patients with poor performance status or large-volume distant metastases were excluded. These patients underwent neoadjuvant therapy from April 2013 until December 2023 across five referral centers spanning Argentina, Brazil, and Colombia. All patients who received MKI or STKI with a neoadjuvant proposal were included in this study.
Primary outcomes were pre- versus postneoadjuvant response evaluations using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). 10 Tumoral reduction enabling surgery was evaluated in up to 12 months. If there was no tumor shrinkage allowing surgical treatment, intervention was considered ineffective.
The efficacy of neoadjuvant therapy was determined based on the feasibility of surgery. Final pathological results dictated the extent of resection: R0 (complete resection), R1 (microscopic persistence), and R2 (macroscopic residual disease). Secondary outcomes were mortality and status at the last evaluation. The local institutional review board approved this series of cases from each participating institution.
Results
Baseline characteristics of the 27 patients are shown in Table 1. The median age was 66 years (range 12–82), and 52% of the patients were female. The median follow-up was 18 months (range 3–124). Treatment strategies varied based on the specific thyroid cancer subtype as follows: patients with DTC or PDTC received sorafenib (n = 6) or lenvatinib (n = 12), those with MTC (n = 6) underwent neoadjuvant treatment with vandetanib (n = 5) or selpercatinib (n = 1), and patients with ATC (n = 3) received combined therapy with dabrafenib and trametinib (D-T). Surgical results according to histology and drug prescribed are shown in Figure 1.
Neoadjuvant treatment outcomes in thyroid cancer patients: systemic therapies and surgical results stratified by histology and tyrosine kinase inhibitor indication.
Baseline Characteristics of 27 Patients with Thyroid Cancer Treated with Neoadjuvant Therapy
Data are expressed as the mean and ranges or frequencies.
ECOG PS, Eastern Cooperative Oncology Group performance status; PTC, papillary thyroid carcinoma.
Differentiated thyroid cancer and poorly differentiated thyroid cancer
This separate analysis involved 17 patients diagnosed with DTC and one patient with PDTC. The median age at diagnosis was 65.5 years (range 18–80 years), with an equal distribution between males and females. Summarized information is presented in Supplementary Table S1 and Figure 1. Most patients (67%, n = 12) underwent neoadjuvant therapy with lenvatinib, while 33% (n = 6) received sorafenib.
The analysis demonstrated a median reduction in the diameter of the primary tumor of 25% (range 0–100) after a median treatment duration of six months. The reduction was greater but not statistically significant in patients receiving lenvatinib (47% vs. 23% for those on sorafenib) (p = 0.15). Similarly, ≥50% reductions in tumor diameter were more frequent in lenvatinib-treated patients (41.6%) than in those on sorafenib (16.6%) (p = 0.33). Surgical intervention was performed in 55% of the patients (10 out of 18). Among these, six patients achieved R0/R1 resection status (60% of operated patients, 33% of all 18 treated patients).
Among 10 patients who had surgery, (1) three with classical PTC underwent total thyroidectomy (TT) with R0 resection, followed by radioactive iodine treatment (RAI), two had received lenvatinib 24 mg/d and one sorafenib 800 mg/d; (2) two patients (one with PTC and one with PDTC) who were treated with lenvatinib underwent TT, then RAI with an R1 resection. One of these patients had a tall cell PTC with a BRAFV600E mutation, and the pathological report revealed a previously undiagnosed area of ATC. Lenvatinib was then replaced with D-T therapy after surgery; (3) four patients had an R2 resection, two had received lenvatinib and two sorafenib as neoadjuvant therapy; and (4) in addition, a 68-year-old with tall cell PTC on lenvatinib achieved 100% tumor reduction at 10 months, ultimately experiencing a complete response without the need for surgery (Supplementary Table S2).
Median follow-up after MKI initiation, including nonresectable patients, was 14 months (range 3–124). Best overall responses were as follows: complete response in seven (38.9%), partial response in three (16.7%), and stable disease in six (33.3%). The mortality rate was 11% (n = 2), due to progressive disease.
Medullary thyroid carcinoma
Six patients with MTC were included in this study (Fig. 1). The median age at diagnosis was 37.5 years (range 12–79), and 67% of patients were male. None of them harbored germline RET mutations; two patients underwent evaluation for somatic mutations, revealing M918T RET mutations.
Vandetanib was prescribed as first-line treatment in five patients (83%); three of them received 300 mg/day. One patient required dose reduction due to grade 2 uterine bleeding. In two patients, the initial dose of vandetanib was 100 mg/day. In one patient, the dose was increased to 200 mg/day during follow-up, whereas in the remaining patient, the dose was adjusted based on renal function and remained constant throughout the follow-up.
The median reduction in tumor diameter in the entire group was 24.5% (range 1–49) after a median treatment time of 9.5 months. The median follow-up period was 50 months (range 15–92). The best response was partial response in one patient (whose primary tumor remained unresectable) and stable disease in three patients (Supplementary Table S2).
In a patient harboring a somatic RET mutation, selpercatinib was administered as first-line treatment (dose of 320 mg/day). This patient experienced a tumor reduction of 25%, underwent surgical intervention, and achieved an R2 resection. While TT was feasible, extensive mediastinal tumor extension precluded complete resection.
Anaplastic thyroid carcinoma
We included three patients with ATC harboring BRAFV600E mutations (Fig. 1). The median age was 65 years (range 62–77), and all patients were female. Dabrafenib (300 mg/day) and trametinib (2 mg/day) were prescribed as first-line treatment. The median reduction in tumor diameter after neoadjuvant therapy was 42% (range 6.7–50) after a median of treatment of two months.
Two patients underwent surgical intervention and achieved R1 and R2 resection, respectively. The patient who achieved an R1 resection received external beam radiotherapy (EBRT) and sequentially underwent D-T after surgery. However, this patient developed a progressive disease due to discontinuation of systemic therapy. The other patient developed a generalized infection in the postoperative period, preventing the resumption of D-T therapy, and presented progressive disease. The best overall response was stable disease in one patient (33%). The median follow-up was nine months (range 6–25 months). The mortality rate was 67% (n = 2), related to progressive disease.
In total, only the following two patients experienced local adverse events related to neoadjuvant therapy: one patient receiving lenvatinib had mild local necrosis, and one patient treated with D-T had mild and intermittent bleeding from tracheostomy.
Discussion
Neoadjuvant therapy is a novel approach for thyroid cancer, with results typically presented in isolated case reports or series, particularly for DTC. 4 In this real-life study, we aimed to assess the effectiveness and feasibility of surgical treatment following neoadjuvant therapy in patients with various types of malignant thyroid tumors from five referral centers in Latin America. Surgical resection feasibility varied across histologies, with rates of 55% for DTC, 33% for ATC, and only 16% for MTC. In our observation, despite not reaching statistical difference, DTC patients treated with lenvatinib achieved greater tumor reductions with more frequent R0/R1 resections.
Data on MKI as neoadjuvant therapy in MTC are even more limited. Although variable reductions in tumor size were observed in MTC patients, none of the subjects treated with vandetanib was amenable to surgical treatment due to the persistence of invasion of adjacent vital structures resulting in unacceptable surgical morbidity. Selpercatinib shows promise, yet our single patient achieved only a 25% reduction, resulting in an R2 resection due to extensive mediastinal involvement. 7
Neoadjuvant D-T therapy has shown feasibility, with improved survival in BRAFV600E -mutated ATC; 7,8 however, our series underscores the difficulties reproducing these results in Latin America.
Although our study benefits from consecutive cases at reputable centers, it has limitations. These include its retrospective nature, which may introduce selection bias, the indeterminate total number of locally advanced cases evaluated, and challenges related to regional disparities in access to genomic testing and medication availability.
In conclusion, neoadjuvant therapy shows promise in improving overall survival in ATC patients, yet in our experience, significant and consistent tumor reductions and satisfactory resections remain challenging across the spectrum of pathology and neoadjuvant therapy.
Footnotes
Author Disclosure Statement
F.P.: Conceptualization (lead), writing—original draft (lead), formal result analysis (lead), and writing—review and editing (lead); E.A.: writing—original draft (equal), formal result analysis (equal), writing (equal), construction of table (lead), and review and editing (equal). A.R.G.: conceptualization (equal), writing (equal), and review and editing (equal). D.D.: formal result analysis (equal), writing (equal), and review and editing (equal). R.S.: writing (equal) and review and editing (equal). A.L.M.: conceptualization (equal), writing (equal), and review and editing (equal). Ana Hoff: writing (equal) and review and editing (equal). I.C.: writing—original draft (equal), formal result analysis (equal), construction of table (equal), construction of figure (lead), and review and editing (equal). All authors approved the final version.
Author Disclosure Statement
F.P.: Clinical Investigation (Bayer, Novartis, Exelixis). Advisory Board (Bayer, Raffo). Speaker (Bayer); A.R.G.: Speaker (Bayer, Knight, Ipsen); R.S.S.: Clinical Investigation (Sanofi, Exelixis, Lilly). ALM: Clinical Investigation (Exelixis, Lilly, Sanofi); A.H.: Advisory board: Knight, Bayer, Eli Lilly; I.C.: Clinical Investigation (Bayer, Novartis), speaker (Bayer, Knight). The remaining authors have no conflict of interest to declare relevant to this article’s content.
Funding Information
We acknowledge funding for fees publication from the Asociación Colombiana de Endocrinología, Diabetes y Metabolismo. No other funds, grants, or support were received.
Supplementary Material
Supplementary Table S1
Supplementary Table S2