Comparison of computed tomography imaging analyses for evaluation after chemotherapy in patients with colorectal cancer: a retrospective pooled analysis of six phase II clinical trials.

BACKGROUND: There are several methods for analyzing computed tomography (CT) images to evaluate chemotherapy efficacy in clinical studies. However, the optimal analysis method for each drug is still under debate. We conducted a pooled analysis using data from six phase II studies to evaluate four analysis methods in colorectal cancers (CRCs): morphological responses (MRs), early tumor shrinkage (ETS), depth of response (DpR), and response evaluation criteria in solid tumors (RECIST) ver.1.1. METHODS: We included 249 patients in this analysis. Pretreatments and findings of subsequent CT imaging were analyzed based on the MR, ETS, DpR, and RECIST ver.1.1. Differences in overall survival (OS) between the responders and non-responders according to each method were evaluated using survival analysis. RESULTS: The responders had significantly better hazard ratios (HRs) for OS, in terms of DpR (≥ median), ETS, objective response rate (ORR) [complete response (CR) + partial response (PR)], and disease control rate [CR + PR + stable disease (SD)]. Patients with right-sided colon cancers showed better HRs for DpR, but not for ETS and ORR. Contrastingly, patients with left-sided CRCs had better HRs for ETS, DpR, and ORR. MR was not associated with outcomes in this study, even in cases where bevacizumab was used. In patients with liver metastasis, ETS, DpR, and ORR showed better HRs, but not in those with lung metastasis. CONCLUSION: Early tumor shrinkage and DpR might be predictive markers only in left-sided CRCs with liver metastasis. Each imaging analysis has a different value based on the primary and metastatic sites.

Translational analysis and final efficacy of the AVETUX trial - Avelumab, cetuximab and FOLFOX in metastatic colorectal cancer.

Introduction: In metastatic colorectal cancer (mCRC), the efficacy of immune checkpoint blockade (ICB) has so far been limited to patients with microsatellite instability high tumors (MSI-H). Unfortunately, most mCRC patients suffer from non-immunogenic microsatellite stable (MSS) tumors. Therefore, new combinatorial strategies are urgently needed to enhance the immunogenicity of MSS tumors to finally increase the number of patients benefiting from ICB. Methods: The AVETUX trial aimed to combine the PD-L1 antibody avelumab with the standard of care chemotherapy combination FOLFOX and the anti-EGFR antibody cetuximab. Furthermore, we performed a central radiological review of the pre- and on-treatment computed tomography scans to better define the individual response to treatment. Results and Discussion: In total, 43 patients were treated of which 39 patients were confirmed as RAS/BRAF wildtype in central tissue review and finally response evaluated. A final progression-free survival (PFS) of 11.1 (range: 0.8 to 22.3 months) and a herein updated final overall survival (OS) of 32.9 months (range: 0.8 to 47.1 months) was reached. We observed a strong median depth of response of 67.5% tumor shrinkage and deepness of response correlated significantly with survival. On the other hand, early tumor shrinkage was not an indicator of better outcome at a cut-off of 20% (median values). In a next step, we correlated the individual best radiological response with potential ICB response biomarkers and found that the clonality and diversity, but not frequency of tumor infiltrating lymphocytes (TiLs) and peripheral blood mononuclear cells (PBMCs), strongly correlated with response. In summary, we report the final overall survival of the AVETUX trial and propose T cell clonality and diversity as a potential marker to predict response to chemo-immunotherapy combinations in MSS mCRC by performing a central radiological review. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT03174405).

Associations between deepness of response and clinical outcomes among Japanese patients with metastatic colorectal cancer treated with second-line FOLFIRI plus cetuximab.

BACKGROUND: In the FIRE-3 trial, overall survival (OS) was significantly longer in patients treated with FOLFIRI plus cetuximab (C-mab) than in those treated with FOLFIRI plus bevacizumab (Bev), but progression-free survival (PFS) was not significantly different. This may be associated with the deepness of response (DpR) in patients treated with FOLFIRI plus C-mab. We aimed to evaluate the relationship between clinical outcome and DpR in metastatic colorectal cancer (mCRC) patients treated with second-line FOLFIRI plus C-mab. METHODS: A total of 112 patients with histopathologically confirmed mCRC treated with second-line FOLFIRI in combination with C-mab (N=42) or Bev (N=70) were retrospectively enrolled between October 2008 and June 2013. The relationship between DpR and clinical outcome in patients treated with FOLFIRI plus C-mab or Bev was determined. RESULTS: Forty-two patients treated with FOLFIRI plus C-mab had a mean DpR of 6.1% (inter-quartile range: -13.7%, 20.8%) and a minimum DpR of -62.7%. On the other hand, 70 patients treated with FOLFIRI plus Bev had a mean DpR of 0% (interquartile range: -16%, 10%) and a minimum DpR of -111%. DpR ≥30% was associated with significantly longer OS and PFS when compared with DpR ≤30% in patients given FOLFIRI plus C-mab. DpR (≥30%) was independently associated with prolongation of OS and PFS. In patients treated with FOLFIRI plus C-mab, there was a moderate positive correlation between DpR and clinical outcomes (OS: r=0.51, P<0.001; PFS: r=0.54, P<0.001). CONCLUSION: FOLFIRI plus C-mab yielded a stronger correlation between DpR and clinical outcomes. These results indicate the potential of DpR as a new measure of efficacy in mCRC patients treated with second-line chemotherapy plus C-mab.

Timing and extent of response in colorectal cancer: critical review of current data and implication for future trials.

The identification of new surrogate endpoints for advanced colorectal cancer is becoming crucial and, along with drug development, it represents a research field increasingly studied. Although overall survival (OS) remains the strongest trial endpoint available, it requires larger sample size and longer periods of time for an event to happen. Surrogate endpoints such as progression free survival (PFS) or response rate (RR) may overcome these issues but, as such, they need to be prospectively validated before replacing the real endpoints; moreover, they often bear many other limitations. In this narrative review we initially discuss the role of time-to-event endpoints, objective response and response rate as surrogates of OS in the advanced colorectal cancer setting, discussing also how such measures are influenced by the tumor assessment criteria currently employed. We then report recent data published about early tumor shrinkage and deepness of response, which have recently emerged as novel potential endpoint surrogates, discussing their strengths and weaknesses and providing a critical comment. Despite being very compelling, the role of such novel response measures is yet to be confirmed and their surrogacy with OS still needs to be further investigated within larger and well-designed trials.