Twenty Years On: RECIST as a Biomarker of Response in Solid Tumours an EORTC Imaging Group – ESOI Joint Paper

Response evaluation criteria in solid tumours (RECIST) v1.1 are currently the reference standard for evaluating efficacy of therapies in patients with solid tumours who are included in clinical trials, and they are widely used and accepted by regulatory agencies. This expert statement discusses the principles underlying RECIST, as well as their reproducibility and limitations. While the RECIST framework may not be perfect, the scientific bases for the anticancer drugs that have been approved using a RECIST-based surrogate endpoint remain valid. Importantly, changes in measurement have to meet thresholds defined by RECIST for response classification within thus partly circumventing the problems of measurement variability. The RECIST framework also applies to clinical patients in individual settings even though the relationship between tumour size changes and outcome from cohort studies is not necessarily translatable to individual cases. As reproducibility of RECIST measurements is impacted by reader experience, choice of target lesions and detection/interpretation of new lesions, it can result in patients changing response categories when measurements are near threshold values or if new lesions are missed or incorrectly interpreted. There are several situations where RECIST will fail to evaluate treatment-induced changes correctly; knowledge and understanding of these is crucial for correct interpretation. Also, some patterns of response/progression cannot be correctly documented by RECIST, particularly in relation to organ-site (e.g. bone without associated soft-tissue lesion) and treatment type (e.g. focal therapies). These require specialist reader experience and communication with oncologists to determine the actual impact of the therapy and best evaluation strategy. In such situations, alternative imaging markers for tumour response may be used but the sources of variability of individual imaging techniques need to be known and accounted for. Communication between imaging experts and oncologists regarding the level of confidence in a biomarker is essential for the correct interpretation of a biomarker and its application to clinical decision-making. Though measurement automation is desirable and potentially reduces the variability of results, associated technical difficulties must be overcome, and human adjudications may be required.

Induction Therapy Followed by Surgery for Unresectable Thymic Epithelial Tumours

Background and ObjectivesThe treatment of unresectable thymic epithelial tumours (TETs) remains controversial. Here, we present the efficacy and safety of induction therapy followed by surgery for unresectable TET.MethodsEighty-one patients with unresectable TETs treated with induction therapy followed by surgery were selected from a retrospective review of consecutive TETs from January 2005 to January 2021. Clinicopathological data were analyzed to assess tumour responses, resectability, adverse events, progression-free survival (PFS) and overall survival (OS).ResultsInduction therapy produced a major tumour response rate of 69.1%, a tumour response grade (TRG) 1-3 rate of 84.0% and an R0 resection rate of 74.1%. The most common toxic effects were all-grade neutropenia (35.8%) and anaemia (34.6%). The 10-year OS and PFS rates were 45.7% and 35.2%. Multivariate analysis showed that ypTNM stage, ypMasaoka stage, complete resection, and TRG were significant independent prognostic factors. Exploratory research revealed that different induction modalities and downstaging of T, N, M, TNM, or Masaoka classifications did not significantly alter the pooled hazard ratio for survival.ConclusionsInduction therapy followed by surgery is well tolerated in patients with unresectable TETs, with encouraging R0 resection rates. Multimodality management provides good control of tumors for unresectable TET patients.

Unusual increase in carcinoembryonic antigen despite response to selpercatinib in two patients with medullary thyroid cancer

Introduction: Serum calcitonin (CT) and carcinoembryonic antigen (CEA) are valuable tumour markers in patients with medullary thyroid carcinoma (MTC). Both markers most often evolve in parallel after treatment. Selpercatinib (LOXO-292) is a highly selective RET kinase inhibitor indicated in advanced RET-mutant MTC patients. Case presentation: We report two observations of RET-mutant progressive metastatic and symptomatic MTC patients who were treated with selpercatinib. Patient 1, a 61-year-old man, presented dyspnoea and diarrhoea at selpercatinib initiation with large neck lymph nodes and lung metastases. Patient 2, a 76-year-old man, had acute discomfort with flush and diarrhoea, with small but diffuse bone and liver disease. Both patients had an objective response with rapid clinical improvement and RECIST 1.1 response (-90%) in patient 1. A rapid dramatic decrease in CT level was observed in both patients (-99% in both patients) while CEA levels gradually and sustainably increased after selpercatinib initiation (+207% at cycle 15 in patient 1 and + 835% at cycle 14 in patient 2). In both patients, FDG PET/CT did not show any abnormal uptake that could explain the CEA increase. Colonoscopy and oesogastric fibroscopy showed colonic polyposis with mild oesophagitis and gastritis in patient 1 and were normal in patient 2. Conclusion: These observations show an unusual and lasting increase in serum CEA in two MTC patients who exhibited an objective tumour response to selpercatinib. The mechanism behind this unexpected rise in CEA level remains unknown. The frequency of this evolving profile will be determined in further phase III studies.

[18F]FDG-PET accurately identifies pathological response early upon neoadjuvant immune checkpoint blockade in head and neck squamous cell carcinoma

Purpose To investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery. Methods In the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11–50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder. Results Median ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least − 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of − 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median − 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen. Conclusions Primary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. Trial registration https://www.clinicaltrials.gov/, NCT03003637, December 28, 2016.

Hepatic GIST metastases: An illustrative case series

Gastrointestinal Stromal Tumours (GISTs) are uncommon mesenchymal tumours affecting the gastrointestinal tract. The liver is one of the most common sites for metastatic disease from GISTs and may exhibit a variety of CT and MR imaging appearances. These imaging features can vary prior to and following treatment with tyrosine kinase inhibitors. We report on the spectrum of imaging appearances of hepatic GIST metastases on multiphase contrast CT imaging and hepatocyte-specific contrast enhanced MR To our knowledge, there are no published series specifically focusing on the appearances of liver metastases from GISTs. An awareness of the protean appearances and pitfalls on CT and MRI of hepatic GIST metastases, prior to and at different times along the treatment pathway, will assist in early diagnosis of liver metastases, accurate assessment of tumour response and detection of recurrent metastatic disease.

Neoadjuvant therapy bridging patients with hepatocellular cancer waiting for liver transplant

Introduction. Liver transplant (LT) is a widely accepted treatment for hepatocellular carcinoma (HCC). The role of neoadjuvant (NAT) is still under debate.The aim of the work is to assess the effect of NAT on relapse-free survival (RFS) and overall survival (OS) in patients with HCC who underwent LT.Methods and materials. 63 patients diagnosed with HCC were observed at Blokhin National Medical Research Center of Oncology from October 2010 to January 2020. Of these, 28 patients did not receive any type of treatment before transplantation, 35 patients received various types of NAT. Two groups had similar patient and tumour characteristics at baseline. A significant number of patients with decompensated cirrhosis were observed in the non-NAT group (n = 14; 50%), while no patients with CP-C liver cirrhosis were observed in the NAT group (n = 0; 0%; p = 0.000). The average wait for a liver transplant was 10.3 months in the NAT group and 6.8 months in the NAT-free group (p = 0.561).Results. In the bridging subgroup, the tumour progression was detected in 29% of patients, stable disease in 47% of patients, partial response was achieved in 14% of patients, complete tumour response was observed in 5%. For 5% of patients, it was not possible to estimate the effect of the therapy due to the lack of appropriate data archives. In the subgroup of downstaging therapy, the tumour progression was detected in 23% of patients, stable disease in 41% of patients, a partial response was achieved in 12% of patients, a complete tumour response was observed in 6%. The treatment allowed the Milan criteria to be fulfilled in 18% of patients.Conclusion. There was no difference in overall survival (OS) or disease-free survival (DFS) between the NAT and control groups.

Harnessing iNKT cells to improve in situ vaccination for cancer therapy

<p>Toll-like receptor (TLR) agonism in combination with the activation of type I NKT (iNKT) cells through systemic administration of their respective agonists has been shown to have a cooperative effect on activating antigen-presenting cells, stimulating cytokine production, and inducing adaptive immune responses to co-administered antigens. Here, it was hypothesised that it might be possible to harness these activities to treat solid tumours locally via intratumoural treatment to combat tumour growth while reducing toxicity to other organs. An intratumoural treatment model combining the stimulatory activity of unmethylated DNA oligonucleotides consisting of synthetic cytosine-guanine motifs (CpG), a TLR9 agonist, with activation of iNKT cells through administration of the CD1d-binding iNKT agonist α-galactosylceramide (α-GalCer) intratumourally was shown to have significant anti-tumour activity. The treatment regimen showed superior efficacy to that achieved with either agent alone in several in vivo models representing different types of cancer. In some models, the combination of α-GalCer and CpG was effective at inducing the complete rejection of both treated and untreated tumours through the induction of a systemic adaptive immune response. Post tumour rejection, a memory response protected against rechallenge with the same, or similar, tumours. Intratumoural administration of the agents was associated with increases in IFN-α in the tumour (rather than the serum), and blockade or removal of the IFN-α receptor abrogated the anti-tumour response. The importance of the draining lymph node and spleen in anti-tumour activity (as shown by the excision of these organs), and liver enzyme responses, suggested that some of the agonists/antigens may have dispersed into the lymphoid organs and liver to support the response. Nonetheless, the anti-tumour effect was dependent on local effects of the intratumoural administration on the tumour microenvironment, as subcutaneous and peritumoural routes of administration only minimally affected tumour growth despite the reagents potentially having greater exposure to lymphoid organs. Through the use of various techniques including knockout mice, neutralising monoclonal antibodies, confocal microscopy and flow cytometry, it was shown that the combination of α-GalCer and CpG was dependent on the effector activity of CD8+ cells. However, optimal activity was associated with changes in other immune cell types, notably recruitment of iNKT cells into the tumour bed, and was also associated with induction of serum antibodies that could transfer some protection to naïve hosts. Induction of a successful response was dependent on conventional dendritic cells (DCs) of the “cDC1” phenotype, which are known to be effective at antigen cross-presentation to CD8+ T cells, while full tumour rejection also required the activity of plasmacytoid DCs, which are significant producers of IFN-α. In less immunogenic tumour models, the addition of relevant tumour associated antigens (TAAs) improved the anti-tumour response. The TAAs could be added as part of an admix, but improved responses were obtained when TAAs were chemically conjugated to α-GalCer via an enzymatically cleavable linker. Alternatively, intratumoural administration of α-GalCer and CpG as free agents could be combined effectively with low dose systemic chemotherapy to induce curative responses, potentially through a mechanism involving immunogenic cell death to improve the immunogenicity of TAAs in situ.</p>

Harnessing iNKT cells to improve in situ vaccination for cancer therapy

<p>Toll-like receptor (TLR) agonism in combination with the activation of type I NKT (iNKT) cells through systemic administration of their respective agonists has been shown to have a cooperative effect on activating antigen-presenting cells, stimulating cytokine production, and inducing adaptive immune responses to co-administered antigens. Here, it was hypothesised that it might be possible to harness these activities to treat solid tumours locally via intratumoural treatment to combat tumour growth while reducing toxicity to other organs. An intratumoural treatment model combining the stimulatory activity of unmethylated DNA oligonucleotides consisting of synthetic cytosine-guanine motifs (CpG), a TLR9 agonist, with activation of iNKT cells through administration of the CD1d-binding iNKT agonist α-galactosylceramide (α-GalCer) intratumourally was shown to have significant anti-tumour activity. The treatment regimen showed superior efficacy to that achieved with either agent alone in several in vivo models representing different types of cancer. In some models, the combination of α-GalCer and CpG was effective at inducing the complete rejection of both treated and untreated tumours through the induction of a systemic adaptive immune response. Post tumour rejection, a memory response protected against rechallenge with the same, or similar, tumours. Intratumoural administration of the agents was associated with increases in IFN-α in the tumour (rather than the serum), and blockade or removal of the IFN-α receptor abrogated the anti-tumour response. The importance of the draining lymph node and spleen in anti-tumour activity (as shown by the excision of these organs), and liver enzyme responses, suggested that some of the agonists/antigens may have dispersed into the lymphoid organs and liver to support the response. Nonetheless, the anti-tumour effect was dependent on local effects of the intratumoural administration on the tumour microenvironment, as subcutaneous and peritumoural routes of administration only minimally affected tumour growth despite the reagents potentially having greater exposure to lymphoid organs. Through the use of various techniques including knockout mice, neutralising monoclonal antibodies, confocal microscopy and flow cytometry, it was shown that the combination of α-GalCer and CpG was dependent on the effector activity of CD8+ cells. However, optimal activity was associated with changes in other immune cell types, notably recruitment of iNKT cells into the tumour bed, and was also associated with induction of serum antibodies that could transfer some protection to naïve hosts. Induction of a successful response was dependent on conventional dendritic cells (DCs) of the “cDC1” phenotype, which are known to be effective at antigen cross-presentation to CD8+ T cells, while full tumour rejection also required the activity of plasmacytoid DCs, which are significant producers of IFN-α. In less immunogenic tumour models, the addition of relevant tumour associated antigens (TAAs) improved the anti-tumour response. The TAAs could be added as part of an admix, but improved responses were obtained when TAAs were chemically conjugated to α-GalCer via an enzymatically cleavable linker. Alternatively, intratumoural administration of α-GalCer and CpG as free agents could be combined effectively with low dose systemic chemotherapy to induce curative responses, potentially through a mechanism involving immunogenic cell death to improve the immunogenicity of TAAs in situ.</p>