Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival

Gastrointestinal cancers are currently one of the most common malignancies in the world [1],and more than 70% of patients with gastrointestinal malignancies have metastases and a poor prognosis [2]. In recent years, immunotherapy has become a major breakthrough in cancer therapy [3] . For advanced or metastatic colorectal cancer (CRC),which is also developing rapidly [3, 4]. Immune checkpoint inhibitors, such as programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) antibodies, appear to be one of the most promising approaches in tumor immunotherapy [5, 6]. Compared to conventional cancer therapy, the anticancer mechanism of immune-checkpoint inhibitors is based on the blockade of immune inhibition by tumors, which leads to the simulation of host immunity against tumors, rather than direct cytotoxic or targeted effects to tumor cells [7‐9]. In-depth mechanistic studies have shown that T cells play a major role in immune-mediated processes in cancer patients. Moreover, for PD-1/PD-L1 therapy, patterns of tumor response may differ from those observed with chemotherapy or targeted therapy. Atypical tumor response patterns such as “pseudoprogression” were recognized in immune-related responses [7]. Pseudoprogression is defined as an increase in the sum of the longest diameter (SLD) of the target lesions by at least 20% from the baseline after initial immunotherapy followed by a decrease by more than 30% from the time of determination of disease progression, not from baseline [7, 10].

According to the revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1), pseudoprogression is normally categorized as progressive disease (PD) [11]; however, during subsequent follow-up imaging, the tumor burden often actually decreases. This phenomenon poses a challenge to clinicians and investigators, which may lead to misclassifying pseudoprogression as PD and terminating PD-1/PD-L1 inhibitor therapy. The mechanism of pseudoprogression is thought to be caused by the infiltration of T cells into the tumor, leading to a significant increase in the initial tumor burden, rather than the true proliferation of tumor cells [12‐14]. Therefore, updated criteria have to be used to capture these atypical response patterns in patients treated with cancer immunotherapy to distinguish them from those of traditional cytotoxic chemotherapy and molecular targeted therapy. Therefore, the most commonly used and validated treatment response criteria of conventional chemotherapies in solid tumors, RECIST 1.1 are not capable of properly assessing response after PD-1/PD-L1 inhibitor therapy [15]. To further improve imaging markers for evaluating the efficacy of PD-1/PD-L1 inhibitor therapy, the consensus guidelines for iRECIST were revised in 2017 [16]. The definition of RECIST 1.1 forms the basis of iRECIST, so the definitions of measurable and nonmeasurable lesions, as well as target and nontarget lesions, remain unchanged. Immune unconfirmed progressive disease (iUPD) has been newly added, and mainly includes the following aspects: first, the assessment of tumor response may be delayed, so two consecutives (time interval of at least 4 weeks) imaging assessments of progressive disease or tumor response evaluation are required; second, the appearance of new lesions does not necessarily indicate the progression in immunotherapy patients. To assess tumor response after PD-1/PD-L1 inhibitor therapy, follow-up imaging studies should be performed at least 4 weeks later to evaluate new lesions [16].

Previous studies lacked detailed immune-related response assessments and tumor diameter changes by iRECIST in advanced gastrointestinal malignancies during PD-1/PD-L1 inhibitor therapy. Whether the continuation of immune checkpoint inhibitor therapy is beneficial, how to evaluate the tumor response during immunotherapy and how to predict overall survival (OS) in advanced gastrointestinal malignancies are currently unclear clinically. The purpose of this study was to systematically analyze the dynamic changes in tumor diameter based on the iRECIST criteria on contrast-enhanced CT (CE-CT) images from baseline scans and follow-up scans during PD-1/PD-L1 inhibitor therapy and to identify imaging biomarkers for tumor response and OS in advanced gastrointestinal malignancies.

Gastrointestinal malignancies are one of the most common tumors, and their incidence and mortality have been increasing in recent years [19], especially colorectal cancer (CRC), which is the third most common cancer and the second in terms of mortality [19]. The treatment of CRC includes surgery, chemotherapy, radiotherapy, and molecular targeted therapy. These treatments have improved the prognosis of patients to some extent. Unlike traditional tumor therapies, tumor immunotherapy works by improving the patient’s immune system and destroying tumor cells through the immune system. Therefore, patients receiving immunotherapy respond relatively slowly. However, emerging immunotherapies, such as PD-1/PD-L1 inhibitor treatment, can show atypical response patterns such as pseudoprogression [4, 7, 20, 21]. Imaging plays an important role in evaluating and characterizing immune-related tumor responses and progression and is becoming increasingly important for clinical treatment decisions [7].

iRECIST is the latest imaging criterion for evaluating the tumor diameter after immunotherapy [16]. Using the iRECIST criteria, this study evaluated tumor diameter dynamics on serial CT scans in 75 patients with advanced gastrointestinal tumors treated with PD-1/PD-L1 inhibitors. We found that patients with a tumor diameter that maintained a < 20% increase compared to baseline measurements throughout therapy had longer OS. Notably, many patients can benefit from PD-1/PD-L1 inhibitor therapy as long as their tumor diameter maintains a < 20% increase from baseline. Therefore, we infer that the threshold of tumor diameter maintained at < 20% increase will provide a potential imaging biomarker of whether patients with advanced gastrointestinal tumors should continue treatment with PD-1/PD-L1 inhibitors, which is expected to play an important role in clinical decision-making.

In this study, 75 patients with gastrointestinal malignancies received PD-1/PD-L1 treatment, and the tumor response rate was 32.0%. The definition of durable disease control is a tumor diameter with a less than 20% increase compared to baseline, which lasts for at least 6 months. In this study, durable disease control was noted in 23 patients (23/75,30.7%). Figure 3 provides the dynamic changes in the tumor burden of the patients in this study during the follow-up, reflecting the information about the immune-related response patterns in the cohort. Using univariate analysis, the < 20% group had a longer OS than the ≥20% group, and this finding is similar to that of previous studies of immunotherapy for melanoma and lung cancer [18, 22].

Next, 48 patients with tumor diameter that maintained a < 20% increase from baseline had significantly reduced hazards of death (HR = 0.15, P = 0.01) after adjusting for age, combined surgery, KRAS status, cancer type, MMR, treatment course and cancer differentiation using multivariable analysis. According to previous research [23‐25], deficient mismatch repair (dMMR) is a good predictor of the clinical benefit of PD-1/PD-L1 inhibitor therapy in many cancers, especially CRC. Based on MMR status, CRC patients can be divided into two subgroups based on the clinical benefit of immunotherapy: dMMR colorectal cancer (dominant population) and pMMR colorectal cancer (ineffective population). Based on the dynamic changes in the tumor diameter of 75 patients with advanced gastrointestinal tumors, iBOR was obtained for each patient. According to iRECIST, the responses were divided into typical response, typical progression, immune disease progression (iUPD), stable disease and pseudoprogression. The difference in MMR between the above two groups was statistically significant (P = 0.04). Moreover, for the cohort of 65 CRC patients, 41 patients who had tumor diameters with less than a 20% increase had a longer OS and a reduced risk of death.

In previous studies [18, 22], immune-related response patterns of tumor burden dynamics have been described for the treatment monitoring of patients with advanced non-small cell lung cancer (NSCLC) and advanced melanoma. However, studies have reported limited data on advanced gastrointestinal tumors [26].

The iRECIST criteria include immune-related response patterns such as the response after initial increase and the appearance of new lesions [16]. These phenomena are often defined as pseudoprogression. Recognizing pseudoprogression is an important challenge when deciding whether to continue treatment after immunotherapy [7]. Previous studies have reported pseudoprogression in patients with advanced melanoma, NSCLC and metastatic gastrointestinal stromal tumors [10, 18, 22, 26]. This study identified two patients with pseudoprogression. One patient had gastric cancer, and the other had colorectal cancer. Studies have shown that the incidence of pseudoprogression is low, in most cases not exceeding 10% [10, 27‐29]. In this study, of the 75 patients with advanced gastrointestinal malignancies with measurable lesions, 2(2.7%) patients showed pseudoprogression, and the tumor diameter increased by more than 40% at the first follow-up (8.9 weeks and 1.1 weeks) after immunotherapy. A second follow-up was performed in the fourth month and it was found that the tumor diameter gradually decreased, reaching a more than 30% decrease at 10 months and 4 months after immunotherapy. The results of this study are basically consistent with the conclusions of previous studies; pseudoprogression occurred in most patients within 12 weeks after immunotherapy [30].

This study has the following limitations. First, one of the limitations of this study is that the patients in this study had already received other treatments and the time of hospital admission was different from the time of receiving commercial PD-1/PD-L1 treatment, which will lead to data heterogeneity. Secondly, according to the iRECIST criteria, lesions from the primary site in gastrointestinal cancer patients are not counted in the target or measurable lesions for evaluation. Third, this study reports on a retrospective design from a single institution, most of the patients’ information such as PD1/PD-L1 expression, BRAF status, and KRAS status, was not tested, and that information could not be analyzed well. Thus, future prospective multicenter studies are warranted.

In summary, our study demonstrated that patients with a tumor diameter that maintained a < 20% increase from baseline during PD-1/PD-L1 inhibitor therapy had a therapeutic benefit and longer OS. This factor might be a practical imaging biomarker for treatment response and clinical outcome, and has the potential to play an important role in treatment decisions. The phenomenon of pseudoprogression was uncommon and was observed in only 2 patients (2.7%). The immune-related response of patients with only primary tumors and nonmeasurable lesions requires further study.