As we all know, thyroid cancer is a kind of "lazy cancer". For example, the most common type of thyroid cancer, differentiated thyroid cancer (DTC), usually has a good prognosis.
However, there are also hard bones in "lazy cancer". Patients with refractory LATC (RAI-RDTC) have a 10-year survival rate of approximately 10 percent[1] and a worse prognosis for metastatic RAI-RDTC, with a median survival of only 3 to 5 years [2].
The results of the Phase 3 study of SELECT, which is an oral polykinase inhibitor, show that renvatinib versus placebo significantly prolongs progression-free survival (PFS) (18.3 vs 3.6 months) in patients with RAI-RDTC [3]. As a result, lenvatinib is approved by the FDA for the treatment of patients with locally advanced or metastatic, invasive RAI-RDTC.
In 2016, post-mortem analysis of the SELECT study showed low baseline tumor burden ([4]. In addition, patients with a lower tumor load at baseline had a longer median remission duration than those with a higher tumor burden [5].
Nonetheless, the relationship between baseline tumor burden and overall survival (OS) after renvatinib treatment remains unclear.
Recently, Professor Naomi Kiyota of kobe University Hospital Cancer Center conducted a post-event analysis of the SELECT trial and evaluated the effect of patient responses and baseline tumor burden on the OS of patients receiving RAI-RDTC treatment with renvatinib, and the results were published in Cancer.
They found that patients who responded to lenvatinib had a significantly longer median OS (52.2 months vs. 19.0 months; HR, 0.32) and a 68 percent reduction in the risk of death in patients who responded to the non-response. In addition, patients treated with renvatinib with a lower tumor burden also had significantly longer OS (median OS, not reached and 29.1 months, respectively; HR, 0.42), with a 58 percent lower risk of death [6].
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This analysis comes from SELECT updated OS data (deadline: September 1, 2016). To explore the association between OS and response, patients in the renvatinib group were divided into response groups (those with complete or partial remission) and no response groups (those with stable or progressive disease).
Of the 261 patients randomly assigned to the renvatinib group, 247 (14 unassessable or unknown) were included in the POST-OS analysis.
The results of the survival analysis showed that the median OS of the renvatinib response group was 52.2 months, while the median OS of the non-response group was 19.0 months (HR, 0.32).
Total survival curves for the lenvatinib and non-response groups
To elucidate the relationship between baseline tumor burden and OS, the researchers defined tumor burden as the sum of the diameters of each target lesion. Patients in the Lenvatinib group were subdivided according to the sum of the diameters of the baseline target lesions.
Finally, based on the quartile of the diameter of the baseline target lesion in all patients (n=392) in SELECT, the baseline tumor burden was divided into four subgroups: ≤35 mm, 35-60 mm, 60-92 mm, and > 92 mm.
261 patients randomly assigned to the lenvatinib group were included in the OS analysis by baseline tumor burden. Based on the results of the analysis of tumor burden in the four different subgroups defined, the subgroup with the smallest total diameter of the target lesion had a longer median OS than the 3 subgroups with the larger total diameter of the target lesion.
The lenvatinib group was divided into 4 different tumor burden subgroup survival curves
In order to determine the optimal truncation value of the sum of the diameter of the target lesion, the investigators performed two patient operation characteristic analysis, determined that the optimal cut-off value of baseline tumor burden was about 40 mm, and accordingly divided the patients in the rumpatinib group and the placebo group into low and high baseline tumor burden subgroups (rumpartinib group: ≤40 mm, n=79; >40 mm, n=182, respectively. Placebo group: ≤40 mm, n=36; >40 mm, n=95).
The results show that the baseline characteristics of the Lenvatinib group are basically similar between the two subgroups. However, the low tumor burden subgroup had a higher proportion of patients with an ECOG PS score of 0 and fewer sites of metastasis (0 or 1). In the placebo group, patients in the low tumor burden subgroup ≤ 65 years, an ECOG PS score of 0, no VEGF targeted therapy, and only 1 metastatic site.
In addition, in both the renvatinib group and the placebo group, the high tumor burden subgroup had a greater proportion of patients with metastasis at other sites than in the low tumor burden subgroup.
When comparing OS between patients with a total target lesion diameter ≤ 40 mm and > 40 mm in the renvatinib group, the meta-OS in the ≤ 40 mm subgroup was not reached, and the meta-OS in the > 40 mm subgroup was 29.1 months (HR, 0.42).
Baseline tumor burden (≤40 and >40 mm) overall survival curves for patients in the renvatinib group in both subgroups
Soshin Kiyota's team further conducted a multivariate analysis of the Lenvatinib group OS, and the results showed that the sum of the diameters of the baseline target lesions (≤40 vs >40 mm) was significantly correlated with the OS (HR, 0.56; P=0.0138), body weight (
As in the SELECT trial, patients in the placebo group can cross over to the renvatinib group if the disease progresses. The researchers' results from analyzing these patients found that the median time between randomization and crossover was 170 days for patients with low baseline tumor burden and 132 days for patients with high baseline tumor burden.
Based on a survival analysis of the lenvatinib group and the placebo group OS, respectively, based on baseline tumor burden, they found that in the ≤ 40 mm subgroup, the lenvatinib group had not achieved the upper OS and the placebo group had a moderate OS of 41.0 months (HR, 0.39). This means that with treatment with rumpatinib, the risk of death for patients decreased by 61%.
However, in the subgroup with a baseline tumor burden > 40 mm, the median OS in the renvatinib group was 29.1 months and the placebo group had a median OS and 31.6 months (HR, 1.07). The researchers believe that the reason for this result may be that patients with a high baseline tumor burden in the placebo group crossed over to the lenvatinib group after early disease progression.
The Lenvatinib and placebo groups were grouped according to baseline tumor burden (≤40 and >40 mm) after overall survival curves
Overall, from the results of this study, it can be seen that in the treatment of RAI-RDTC with lenvatinib, patients with lower tumor load had significantly longer OS than patients with higher tumor burden. In addition, the answer group OS is also significantly longer than the answer group.
This suggests that for patients with confirmed RAI-RDTC, rumpatinib can be used at low early tumor burden. In addition, the sum of the diameters of the tumor target lesion at baseline may be a prognostic indicator of the overall survival of these patients.
Bibliography:
[1] Schmidt A, Iglesias L, Klain M, Pitoia F, Schlumberger MJ. Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Arch Endocrinol Metab. 2017;61(1):81-89. doi:10.1590/2359-3997000000245
[2] 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(8):2892-2899. doi:10.1210/jc.2005-2838
[3] Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470
[4] Robinson B, Schlumberger M, Wirth LJ, et al. Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. J Clin Endocrinol Metab. 2016;101(11):4103-4109. doi:10.1210/jc.2015-3989
[5] Gianoukakis AG, Dutcus CE, Batty N, Guo M, Baig M. Prolonged duration of response in lenvatinib responders with thyroid cancer. Endocr Relat Cancer. 2018;25(6):699-704. doi:10.1530/ERC-18-0049
[6] Kiyota N, Tahara M, Robinson B, et al. Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial. Cancer. 2022;10.1002/cncr.34181. doi:10.1002/cncr.34181
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