Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy

Abstract

The 'Design, Setting and Participants' section of the abstract has been split to incorporate the interventions sections and now reads (lines 45-47): 'Design, Setting, and Participants: A retrospective analysis was conducted of a second-line phase II study in metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. Intervention: The phase II trial assessed VEGF-targeted therapy ± Src inhibition.' The words 'to validate these findings' have been removed from the abstract conclusion (line 61) to keep the word count below 300. 2) The authors used definitions of radiological heterogeneity which were developed in patients with CRC liver mets and which were modified accordingly by the authors. Are the cutoffs used for 'homogeneous', 'low heterogeneous' and 'high heterogeneous' response arbitrary or is there evidence why these were chosen by the authors. Please briefly clarify to make it more understandable for our readers. The following has been added to the Patients and Methods section (lines 152-155): 'The cutoffs were determined using an optimal response model by van Kessel and colleagues. This involved modelling different cutoff values to identify which provided the highest discriminative capacity. Further details are provided in [6]. No further modelling was undertaken for the analysis presented in this paper.' 3) Please add the number of patients at risk at each time point with KM-curves. Please also use 12-mo intervals to make it easier to see yearly changes. 'Uni-and multivariate analyses were undertaken using Cox regression to calculate Hazard Ratios (HR). The univariate parameters were chosen on the basis of being known prognostic variables from previous studies (gender, Eastern Cooperative Oncology Group [ECOG] performance status, Memorial Sloan Kettering Cancer Center [MSKCC] risk group, nephrectomy status) or because they may be confounding factors to radiological heterogeneity (number of target lesions, sum of lesion diameters) [2, 7, 8]. All univariate parameters were included in the multivariate analysis.' Reviewer 1: We thank the reviewer for their kind comments. Reviewer 2: We thank the reviewer for their kind comments.

Heterogeneous radiological response to chemotherapy is associated with poor prognosis in advanced non‐small‐cell lung cancer

“…In this study, 11.5% of patients in the PR group and 44.7% of patients in the SD group showed radiological heterogeneity. This incidence is comparable to those of radiological heterogeneity in other kinds of cancer in previous studies 12,13 . We defined radiological heterogeneity as more than 20% increase in the size of particular lesion in patients with PR or SD, considering the criteria in RECIST.…”

“…Therefore, it is important to identify heterogeneous radiological responses because they reflect tumor heterogeneity 7,9,10 . Although a few studies have investigated the association of radiological heterogeneity and prognosis in colorectal cancer and renal cell carcinoma, the prognostic impact on aggressive malignancies, such as lung cancer, have not yet been investigated 7,11–13 . Positron emission tomography (PET) is expected to provide additional information on metabolic responses for the evaluation of tumor responses, based on anatomic changes evaluated with RECIST 14 .…”

Comprehensive Systematic Review of Biomarkers in Metastatic Renal Cell Carcinoma: Predictors, Prognostics, and Therapeutic Monitoring

“…The findings revealed that higher radiological response heterogeneity was associated with poorer outcomes and shorter survival in mRCC patients. These results highlight the importance of considering the heterogeneity of radiological response as a prognostic factor when evaluating treatment response and predicting patient outcomes in mRCC patients undergoing VEGF-targeted therapy [106].…”

Response to Immune Checkpoint Inhibitors in Recurrent or Metastatic Esophageal Squamous Cell Carcinoma May Be Affected by Tumor Sites

“…Mixed or heterogeneous tumor response to systemic chemotherapy or targeted therapy occurring in different tumors of individual patients has been previously described in patients with colorectal cancer, breast cancer, non-small cell lung cancer (NSCLC), and renal cell carcinoma [7][8][9][10][11][12][13][14][15][16]. As ICIs have been increasingly used in the treatment of multiple cancer types, this heterogeneous tumor response has been reported in patients with advanced melanoma, NSCLC, and hepatocellular carcinoma (HCC) [17][18][19][20][21].…”