Changes in CT morphology can be an independent response marker for patients receiving regorafenib for colorectal liver metastases: retrospective pilot study

Background Regorafenib is a multi-kinase inhibitor, which was shown to be effective for patients with metastatic colorectal cancer refractory to standard therapies. However, its patterns of response has not yet been fully understood. Methods Clinical records of 10 patients who received regorafenib for evaluable colorectal liver metastases were reviewed. Response to chemotherapy was evaluated with the RECIST and morphologic response criteria, and its clinical relevance was analyzed. Results All patients received multiple lines of fluorouracil-based chemotherapy before regorafenib. The median follow-up duration after introduction of regorafenib was 4.9 months (range, 2 to 12.5 months). Median number of chemotherapy cycles was 2 (range, 1 to 15). In size-based response evaluation, 4 patients presented SD and 6 patients showed PD according to the RECIST. In non-size-based response evaluation, 3 patients were classified as optimal morphologic response and 7 patients were categorized as suboptimal morphologic response. Patients who presented optimal morphologic response showed significantly longer progression-free survival compared with those presented suboptimal response (median, 4.9 months vs. 0.7 months; P = 0.028), while size-based response evaluation could not well stratify patient prognosis. Conclusion Non-size-based CT morphologic response could be a potential alternative response marker for patients treated with regorafenib. Electronic supplementary material The online version of this article (10.1186/s12885-018-4067-5) contains supplementary material, which is available to authorized users.


Background
Regorafenib is a small-molecule multikinase inhibitor that has been proven to be effective for prolonging the survival of patients with treatment-refractory metastatic colorectal cancer. [1,2] However, the reported outcomes in former randomized studies were not clinically sufficient, with a median progression-free survival (PFS) period of 2.0 to 3.2 months and a median overall survival (OS) period of 6.4 to 8.8 months. Although approximately 40% to 50% of patients achieved disease control for at least 6 weeks, the objective response rates were only 1% to 4%, and most of the cases were categorized as stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Nevertheless, in actual clinical settings, several cases exhibiting a relatively long response to regorafenib (in terms of tumor markers) without any size response or even with an increase in the size of the tumor have been encountered. Therefore, response evaluations might require a multifaceted approach to evaluate the effects of this biologic agent accurately.
Although a size-based response evaluation according to the RECIST is the gold standard, [3] some reports suggested the morphologic change should be taken into account especially in patients treated with a regimen that includes bevacizumab. [4][5][6][7][8][9][10] The computed tomographic (CT) morphologic response criteria [4,6] were proposed to assess the non-size-based response to chemotherapy (e.g., the pathologic response to chemotherapy), and the efficacy of these criteria has been validated in medical [11] and surgical [8] populations. Because regorafenib has an inhibitory effect on the same signal pathways that other anti-vascular endothelial growth factor (VEGF) antibodies block, its effect might need to be evaluated using non-size-based criteria similar to those required for bevacizumab.
The objective of this study was to clarify the presence of non-size-based responses in patients treated with regorafenib and to investigate the potential clinical impact of a morphologic response in patients treated with salvage-line therapy.

Study population
By searching a database of medical records at Toranomon Hospital, we identified 29 patients who had received regorafenib for metastatic colorectal cancer after standard chemotherapy including fluorouracil, oxaliplatin and irinotecan with or without molecularly targeted drugs between the period of January 2013 and April 2016. Among these, 10 patients who had liver metastases evaluable with pre-and post-chemotherapy contrast enhanced computed tomography (CECT) were retrospectively reviewed. All the analyses in the current study were performed in accordance with the ethical guidelines for clinical studies at Toranomon Hospital and were approved by the Institutional Review Board.

Imaging analysis
The imaging analysis was performed using CECT scans, and the images were reviewed by a radiologist (WG) who was blinded to the clinical data. The response to chemotherapy was determined according to RECIST ver.1.1 [12] and the morphologic response criteria. [4] The morphologic criteria were defined as follows: group 1, homogeneous low attenuation with a thin, sharply defined tumor-liver interface; group 3, heterogeneous attenuation with a thick, poorly defined tumor-liver interface; and group 2, intermediate morphology that could not be rated as group 1 or 3 (Additional file 1: Figure S1). An optimal morphologic response was defined as a change in morphology from group 3 or 2 to group 1, and a suboptimal morphologic response was defined as a change in morphology from group 3 to group 2 or the absence of remarkable changes in morphology, as previously described. [4,6] In patients with multiple tumors, the morphologic response was assigned based on the response seen in the majority of tumors.

Statistical analysis
Continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using the chi-squared test or the Fisher exact test, where appropriate. Interobserver agreements in image reading were evaluated using the kappa value. The OS period and the PFS period were determined from the date of initial treatment with regorafenib until the date of death or the initial tumor progression, respectively. All the cases without specific prognostic events were censored at the date of the last follow-up examination. The survival curves were generated using the Kaplan-Meier method and were compared using a log-rank test. Data on serum tumor markers were collected for an exploratory analysis. The statistical analyses were performed using JMP (version 11.0; SAS Institute Inc., USA). All the statistical tests were two-sided, and significance was set at P < 0.05.

Patient characteristics
The baseline demographics and clinical characteristics of the 10 patients who had evaluable liver metastases are listed in Table 1. The median age was 63 years (range, 39-83 years), and 8 patients were male (80%) and 2 patients were female (20%). The primary tumor site was the colon in 2 patients (20%) and the rectum in 8 patients (80%). Extrahepatic disease was observed in all the patients. All the patients received fluorouracil-based chemotherapy before regorafenib, and the number of prior chemotherapy regimens was 1 in 1 patient (10%), 2 in 3 patients (30%), 3 in 3 patients (30%), and 4 in 3 patients (30%). These prior chemotherapy regimens included oxaliplatin, irinotecan, bevacizumab, cetuximab, panitumumab and TAS-102. Bevacizumab was used in all the patients, and oxaliplatin was used in nine patients (90%). Eight patients (80%) were treated with irinotecan regimens. Cetuximab was used in 1 patient (10%), and panitumumab was used in 4 patients (40%). All the patients whose RAS status was wild-type received either cetuximab or panitumumab as a prior chemotherapy regimen. Three patients received TAS-102 before regorafenib. The median follow-up duration was 4.9 months from the initiation of regorafenib treatment (range, 2 to 12.5 months). The median number of treatment cycles was 2 (range, 1-15). The reasons for discontinuation were progressive disease (PD) in 3 patients and adverse events in 4 patients; 1 patient was continuing to receive treatment at the time of the analysis.

Response to chemotherapy
Among the 10 patients, optimal morphologic responses were observed in 3 patients, and 7 patients did not show any changes in CT morphology during the treatment. According to the RECIST, the response rate was 0%: 4 patients had SD, and 6 patients had PD. In all 3 patients who achieved an optimal morphologic responses, the size of the tumor nodule had increased at the time of the initial diagnosis of an optimal morphologic response (+ 6.0% [SD], + 16.0% [SD], and + 31.5% [PD], respectively) (Figs. 1, 2). Although these patients had histories of bevacizumab as a first-or second-line treatment, no morphologic changes were seen at the time of the former treatment with bevacizumab.
Serum tumor markers, such as carcinoembryonic antigen (CEA), were analyzed in all the patients at the time of radiographic evaluation during regorafenib treatment. The median rate of CEA increase was 2.02 (range, 0.75-32.3) in 7 patients with a suboptimal morphologic response, whereas it was 0.95 (range, 0.72-1.59) in 3 patients with an optimal morphologic response. The median duration of the morphologic response was 3.4 months, and there were no significant increases in the CEA levels during the period of the morphologic responses in all 3 patients.

Prognostic outcomes
In the entire cohort, the median PFS was estimated as 1.6 months and the median OS was 4.9 months after the initiation of regorafenib. When stratified according to Difference in background characteristics between the optimal response group and the suboptimal response group Table 2 compares the background characteristics between the patients with an optimal response and those with a suboptimal response. Although a statistical comparison is difficult because of the limited number of cases, the group with an optimal morphologic response tended to be younger and had completed a larger number of treatment cycles without discontinuation because of toxicity before disease progression.

Discussion
In this study, we examined the existence of a non-sizebased morphologic response in patients receiving regorafenib for colorectal liver metastases that were refractory to standard chemotherapies. An optimal morphologic Progression-free survival stratified by the CT morphologic response response was correlated with a significantly longer PFS, and patients who exhibited an optimal morphologic response seemed to achieve better disease control. The CT morphologic response to chemotherapy has been reported to be a good prognostic indicator in both medical [4,11] and surgical [4,6,8] populations with colorectal liver metastases, especially in patients treated with bevacizumab. The reported strength of a CT morphologic response is that it may predict differences in pathological response "quality," [7,13,14] and a strong correlation between CT morphology and the pathological viability of tumors has been confirmed in previous studies. [4,6,8] The potential utility of the CT morphologic response for medical populations with unresectable tumors is that it could be used in decisionmaking processes to reduce the intensity of treatment during the maintenance phase of intensive chemotherapy. However, its usefulness in salvage-line treatment has never been reported.
The current study was conducted to clarify the existence of a non-size-based response among patients receiving regorafenib and to investigate its clinical relevance. Three out of 10 patients showed evident changes in CT texture in liver metastases presenting with relatively stable serum CEA levels (Fig. 1). Interestingly, a significantly longer PFS was observed in patients with optimal morphologic responses, though all 3 patients exhibited an increase in tumor size at the time of the diagnosis of the morphologic response. Although previous studies have confirmed that the morphologic response occurs independently of the size response, [4,6,8] given that 40%-60% of patients with the optimal responses also exhibited size-based responses, [6,8] the patterns of response observed in the present study seem to differ from those reported for first-line chemotherapy.
The actual clinical impact of a CT morphologic response in salvage-line therapy remains uncertain. However, the current results are potentially encouraging in terms of a multifaceted approach for evaluating whether regorafenib is actually effective. Given that most patients showed disease progression and suffered from toxicity as early as the initial evaluation, the early stratification of patients who might truly benefit from regorafenib therapy could contribute to the improved supportive management of patients with advanced-stage colorectal cancer.
The limitations of the current study include its retrospective nature, the strictly selected population, and the limited number of cases. However, this is the first report to describe the presence of a non-size-based response to regorafenib, and to suggest the prognostic advantage of an optimal morphologic response. A validation study using a large number of patients is strongly recommended to confirm the present results and to improve the management of patients receiving salvage-line chemotherapy with regorafenib.

Conclusions
In conclusion, a non-size-based CT morphologic response could be a potential prognostic marker for patients receiving regorafenib for unresectable colorectal liver metastases. A multifaceted evaluation might be required to evaluate the response to regorafenib accurately. Abbreviations. SD stable disease, PD progressive disease