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. 2022 Apr 8:46:101381.
doi: 10.1016/j.eclinm.2022.101381. eCollection 2022 Apr.

Elevated tumor markers for monitoring tumor response to immunotherapy

Yi Yang  1 , Xiaolin Jiang  1 , Yun Liu  1 , Huan Huang  1 , Yanli Xiong  1 , He Xiao  1 , Kan Gong  1 , Xuemei Li  1 , Xunjie Kuang  1 , Xueqin Yang  1
Affiliations

Elevated tumor markers for monitoring tumor response to immunotherapy

Yi Yang et al. EClinicalMedicine. .

Abstract

Background: As the immune-related response evaluation criteria in solid tumors (irRECIST) by imaging greatly underestimated the objective response to immunotherapy, we established the response evaluation criteria in solid tumors based on tumor markers (RecistTM) to explore whether RecistTM can compensate for the deficiencies of the irRECIST criteria.

Methods: This was an observational study, which consisted of two parts. The first part (Group A) was a retrospective study including the patients with malignant solid tumors. The second part (Group B) was a prospective study, which were EGFR-negative and ALK-negative patients with stage IIIB-IV non-small cell lung cancer receiving first-line treatment. From January 2017 to September 2020, one hundred and ten patients with a three-time increase in tumor markers receiving immunotherapy were recruited. The treatment response to immunotherapy was evaluated by irRECIST and RecistTM. Efficacy, overall survival (OS), first evaluation time and earliest response time under the different evaluation criteria were compared by statistics.

Findings: The treatment response evaluated by the RecistTM criteria was not consistent with that evaluated by the irRECIST criteria (Kappa = 0.386, p < 0.001). RecistTM had a higher completed response (CR) rate compared to irRECIST criteria (20.9% vs 1.8%, p < 0.001). The earliest response time under the RecistTM criteria was 3.42 weeks earlier than that under the irRECIST criteria (u = -5.233, p < 0.001). There were significant differences in median OS between tumor marker-related complete response (tmCR) and tumor marker-related partial response (tmPR), as well as between tmPR and tumor marker-related stable disease (tmSD) (χ2 = 15.572, p < 0.001; χ2 = 7.720, p = 0.005), but not between tmSD and tumor marker-related progressive disease (tmPD) (χ2 = 1.596, p = 0.206). When applying both criteria together, for patients with immune-related CR / immune-related PR (irCR/irPR) (n = 54) under irRECIST criteria, there was a significant difference in median OS between achieving tmCR (n = 22) and tmPR (n = 32) (χ2 = 14.011, p < 0.001). RecistTM criteria can predict 1-year and 2-year OS more accurately than irRECIST criteria (AUCs:0.862 vs 0.552, 0.649 vs 0.521, respectively;both p < 0.001). In RecistTM, 4 patients had been observed with pseudoprogression in tumor markers.

Interpretation: The RecistTM criteria could effectively distinguish CR, PR, and SD, which may help resolve the shortcomings of the RECIST criteria in evaluating the treatment response to immunotherapy, especially in assessing whether patients can achieve deep or even complete response as soon as possible.

Funding: This work was supported by the Key projects of Chongqing Health and Family Planning Commission (to Xueqin Yang, 2019ZDXM011).

Keywords: CR, Complete response; Efficacy evaluation; ICIs, Immune checkpoint inhibitors; Immunotherapy; NE, Not estimated; NSCLC, Non-small cell lung cancer; ORR, Objective response rate; OS, Overall survival; PD, Progressive disease; PR, Partial response; RECIST; RECIST, Response Evaluation Criteria in Solid Tumors; RecistTM, Response evaluation criteria in solid tumors based on tumor markers; SD, Stable disease; Tumor markers; irCR, Immune-related complete response; irPD, Immune-related progression disease; irPR, Immune-related partial response; irRECIST, Immune-related Response Evaluation Criteria in Solid Tumors; irSD, Immune-related stable disease; tmCR, Tumor marker-related complete response; tmPD, Tumor marker-related progression disease; tmPR, Tumor marker-related partial response; tmSD, Tumor marker-related stable disease.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig 1
Figure 1
STROBE flow diagram.
Fig 2
Figure 2
Consistency between RecistTM and irRECIST in all patients (n = 110). The treatment response to immunotherapy was evaluated by the irRECIST and RecistTM criteria. The consistency between these two criteria was 57.3% in the total population. A kappa test showed a poor consistency of assessment between the two methods. RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors; irCR, immune-related complete response; irPR, immune-related partial response; irSD, immune-related stable disease; irPD, immune-related progressive disease; tmCR, tumor marker-related complete response; tmPR, tumor marker-related partial response; tmSD, tumor marker-related stable disease; tmPD, tumor marker-related progressive disease.
Fig 3
Figure 3
The first evaluation time and the earliest response time of the patients with objective response under both criteria (n = 54). Arrow: The cases that were assessed as pseudoprogression by RecistTM or irRECIST. RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 4
Figure 4
Median overall survival (OS) of different efficacy evaluations by RecistTM (A) or irRECIST (B) in group A (n = 77). RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 5
Figure 5
Time-dependent receiver operating characteristic (ROC) analysis for predicting overall survival (OS) by RecistTM or irRECIST in group A (n = 77). A: ROC curves of 1-year OS; B: ROC curves of 2-year OS. RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 6
Figure 6
Median overall survival (OS) of different efficacy evaluations by RecistTM or irRECIST in all patients (n = 110). RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 7
Figure 7
Time-dependent receiver operating characteristic (ROC) analysis for predicting overall survival (OS) by RecistTM or irRECIST in all patients (n = 110). A: ROC curves of 1-year OS; B: ROC curves of 2-year OS. RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 8
Figure 8
Median overall survival (OS) of combined efficacy evaluations by RecistTM and irRECIST. RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 9
Figure 9
Median overall survival (OS) of different efficacy evaluations by RecistTM with carcinoembryonic antigen (CEA) or irRECIST in non-small cell lung cancer (NSCLC) patients (n = 40). RecistTM, response evaluation criteria in solid tumors based on tumor markers; irRECIST, immune-related Response Evaluation Criteria in Solid Tumors.
Fig 10
Figure 10
Tumor marker pseudoprogression in four patients. Cases 1–3 showed a short-term increase in tumor markers within 3 weeks after treatment, followed by a rapid decrease, accompanied by pseudoprogression in radiology. In Case 4, CEA and CA199 showed different responses; CEA decreased rapidly after treatment while CA199 showed pseudoprogression after treatment. PR, partial response; SD, stable disease; PD, progressive disease. CT, computed tomography; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 19–9; CA125, carbohydrate antigen 125.
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