Tumor volume dynamics and tumor growth rate in ALK-rearranged advanced non-small-cell lung cancer treated with crizotinib

Abstract

The purpose of the study is to investigate volumetric tumor burden dynamics and tumor growth rates in ALK-rearranged advanced NSCLC patients during crizotinib monotherapy. Methods: The study included 44 ALK-rearranged advanced NSCLC patients treated with crizotinib monotherapy as their initial ALK-directed therapy, who had at least one measurable lung lesion and at least two follow-up CT scans, and experienced tumor volume increase while on crizotinib. The tumor volume (in mm 3 ) of the dominant lung lesion was measured on serial CT scans during therapy for analysis of tumor growth rates after the volume nadir. Results: A total of 231 volume measurements from the nadir to the end of crizotinib therapy or the last follow-up in 44 patients were analyzed in a linear mixed-effects model, fitting time (in months since baseline) as a random effect. When measured from the volume nadir, the tumor growth rate of the logarithm of tumor volume (log e V) was 0.04/month (SE = 0.012, P = 0.0011) in the unadjusted model. When adjusted for the baseline volume (log e V 0 ), the growth rate was again 0.04/month (SE = 0.011, P = 0.0004). When adjusted for clinical variables and log e V 0 , the growth rate was 0.045/month (SE = 0.012, P = 0.0002), indicating that the tumor growth rate after nadir in this cohort remains very close to 0.04/month regardless of log e V 0 or clinical factors. Conclusions: Tumor volume growth rate after nadir in ALK-rearranged NSCLC patients treated with crizotinib was obtained, providing objective reference values that can inform physicians when deciding to keep their patients on ALK directed therapy with slowly progressing lung cancer.

Tumor Growth Rate After Nadir Is Associated With Survival in Patients With EGFR-Mutant Non–Small-Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

“…After segmentation and manual correction, the software automatically calculates tumor volume (measured in mm 3 ). [5][6][7]15,18,20 The intra-and interobserver variability of the tumor volume measurements using this technique in patients with advanced NSCLC has been previously published, documenting a high reproducibility with an interobserver concordance correlation coefficient of 0.990. 15…”

“…Additionally, the approach can be applied to patients with other genomic drivers such as ALK-rearranged patients treated with ALK inhibitors who demonstrate similar pattern of tumor volume dynamics with initial response and subsequent tumor growth after nadir. 17,18 In conclusion, slower tumor growth rates after nadir in patients with EGFR-mutant advanced NSCLC treated with erlotinib were associated with longer OS, providing a rationale for using tumor growth rates to guide precision therapy for lung cancer. The findings can be further validated in prospective cohorts of patients treated with EGFR-TKIs including newer agents such as osimertinib and can be extended to other cohorts of patients with different genomic drivers treated with effective targeting agents.…”

“…All patients had at least one dominant measurable lung lesion (≥ 10 mm in the longest diameter) on baseline chest CT before initiation of therapy. 5,18 All patients also had initial tumor volume decrease after starting erlotinib and experienced subsequent tumor growth after reaching nadir (the smallest tumor volume after initiating therapy) noted on at least two postnadir CT scans while on erlotinib. 5,18 Following the institutional review board approval, chest CT scans were retrospectively reviewed and the demographics and clinical characteristics were collected from the medical records.…”

“…[5][6][7]15,17 The workflow for tumor volume measurements has been previously published in patients with advanced NSCLC treated with EGFR inhibitors and ALK inhibitors. [5][6][7]15,18,20 In brief, the axial chest CT images were displayed with a realtime interactive navigation and a reader manually selects a small region of interest within a tumor by a mouse click, determining a seed point. The software automatically segments the lesion from the surrounding lungs and adjacent structures, using a three-dimensional seed-growing algorithm.…”

“…15,16 The pattern of initial response, nadir, and subsequent regrowth is reproducibly observed in patients with EGFR mutations and in patients with anaplastic lymphoma kinase (ALK) rearrangements treated with effective targeted therapy. [5][6][7][8][16][17][18][19] As an example, our previous report has characterized the volumetric tumor growth rate after nadir in patients with EGFR-mutant advanced NSCLC treated with erlotinib or gefitinib and provided a reference value of 0.12/mo for the logarithm of the volume (log e V) as an overall tumor growth rate in these patients using a linear mixed-effects model. The overall growth rate after nadir of 0.12/mo was reproduced in the external validation cohort, demonstrating the consistency of the tumor growth rate after nadir among EGFR-mutant patients treated with EGFR-TKIs.…”