Systemic inflammation adversely affects response to anamorelin in patients with pancreatic cancer

doi:10.21203/rs.3.rs-3094499/v1

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Systemic inflammation adversely affects response to anamorelin in patients with pancreatic cancer

https://doi.org/10.21203/rs.3.rs-3094499/v1

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Purpose

Anamorelin, a selective ghrelin receptor agonist, has been approved for pancreatic cancer treatment in Japan. We aimed to investigate whether systemic inflammation, represented by the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP)-albumin ratio (CAR), could predict the effect of anamorelin in patients with advanced pancreatic cancer.

Methods

This study included 31 patients who had received anamorelin for advanced pancreatic cancer between 2021 and 2023. Patients’ NLR, PLR, LMR, and CAR were evaluated before anamorelin administration. The patients were classified as responders and non-responders based on whether they gained body weight after 3 months of anamorelin administration. We investigated the association between systemic inflammation and anamorelin efficacy using a univariate analysis.

Results

Twelve (39%) patients were non-responders. A high serum CRP level (p = 0.007) and high CAR (p = 0.013) was associated with non-response to anamorelin. According to the receiver operating characteristics analysis, the CAR cutoff value was 0.06, and CAR ≥ 0.06 was a risk factor (odds ratio, 5.6 [95% confidence interval 1.2–27.1], p = 0.032) for non-response to anamorelin.

Conclusion

CAR can be a predictor of non-response to anamorelin in patients with advanced pancreatic cancer, suggesting the importance of a comprehensive assessment of the inflammatory status.

Anamorelin

cachexia

pancreatic cancer

systemic inflammation

Anamorelin is an orally active and selective ghrelin receptor agonist. When administered to patients with advanced non-small cell lung cancer for 12 weeks, it increases body weight and substantially improves the symptoms of anorexia [1, 2]. Its effect on patients with gastrointestinal cancers has been validated, and the drug has been approved in Japan for patients with gastric, colorectal, and pancreatic cancers, in addition to non-small cell lung cancer [3, 4]. However, few studies have examined the efficacy of anamorelin in patients with pancreatic cancer in a clinical setting [5]. Furthermore, the predictors of the response to anamorelin remain unelucidated.

A growing body of evidence suggests that the host inflammatory response plays an important role in the initiation, promotion, and metastasis of cancer and the progression of cachexia, which is characterized by a decrease in skeletal muscle mass and body weight [6]. The systemic inflammatory response, which involves intricate interactions between tumour and host immunity, can be assessed using inflammation-based biomarkers. Various preoperative inflammation-based prognostic markers, such as the neutrophil-lymphocyte ratio (NLR) [7], platelet-lymphocyte ratio (PLR) [8], lymphocyte-monocyte ratio (LMR) [9], and C-reactive protein (CRP)-albumin ratio (CAR) [10], are associated with survival in patients with cancer. Therefore, we hypothesized that systemic inflammation could affect the efficacy of anamorelin.

Thus, in the present study, we retrospectively investigated systemic inflammation as a predictor of the efficacy of anamorelin in patients with advanced pancreatic cancer.

Patient selection

Between June 2021 and February 2023, 33 patients with advanced or recurrent pancreatic cancer were administered anamorelin for cachexia at Jikei University Hospital, Tokyo, Japan. Of these, two were excluded because of discontinuation of anamorelin within 1 month, and the data for the remaining 31 patients were studied.

We retrospectively reviewed data from a prospectively maintained patient database. This study was approved by the institutional Ethics Committee of The Jikei University School of Medicine [27–177(8062)] and conforms to the provisions of the Declaration of Helsinki, as revised in Fortaleza, Brazil in October 2013.

Anamorelin administration and follow-up

The patients were administered 100 mg of anamorelin once daily for 12 weeks.

Body weight measurements, blood chemical tests, and interviews regarding patients’ symptoms were performed at 1, 2, and 3 months during the administration period. Patients’ appetites were assessed using a quality of life questionnaire for cancer patients treated with anticancer drugs (QOL-ACD) (appetite-related question 8: “Did you have a good appetite?”) [11].

To assess the predictors of response to anamorelin, patients were classified into the responder and non-responder groups. Those who maintained or gained body weight, compared to their baseline weight, at 3 months of anamorelin administration were considered responders. Non-responders were those who failed to maintain or gain at body weight at 3 months of anamorelin administration, compared to their baseline data.

Calculation of systemic inflammatory markers

The NLR was calculated as the ratio of the peripheral neutrophil to peripheral lymphocyte counts [7]; PLR, ratio of peripheral platelet to peripheral lymphocyte counts [8]; LMR, ratio of peripheral lymphocyte to peripheral monocyte counts [9]; and CAR, ratio of the serum CRP to serum albumin levels [10].

Statistical analysis

Statistical analyses were performed using the STATA/SE (version 14.2; Stata Corp., College Station, TX, USA) software. A two-sided α level of 0.05 was used. Continuous variables are expressed as median values and interquartile ranges, while categorical variables are expressed as absolute numbers. Clinical datasets were compared using the Mann–Whitney U test or chi-square test, as appropriate.

First, we assessed the association between clinical variables and the response to anamorelin using univariate analysis. Subsequently, we compared the predictive ability of each systemic inflammation marker for the response to anamorelin. The cutoff value for each marker was determined using receiver operating characteristic (ROC) analysis based on whether patients maintained or gained body weight after 3 months on anamorelin.

Patients’ (n = 31) clinical characteristics are presented in Table I. The median age of the patients was 72 (interquartile range, 62–78) years, and 17 (55%) patients were men. Seven (23%) patients had locally advanced pancreatic cancer, 10 (32%) had metastatic pancreatic cancer, and 14 (45%) had recurrent pancreatic cancer. Of the 14 patients with recurrent disease, eight (26%) underwent pancreaticoduodenectomy, five (16%) underwent distal pancreatectomy, and one (3%) underwent total pancreatectomy. Regarding concomitant treatment, 28 (90%) patients underwent chemotherapy, two (6%) underwent chemoradiotherapy, and one (3%) received best supportive care.

Table I and Fig. 1 present the clinicopathological variables according to response to anamorelin. Twelve (39%) and 19 (61%) patients were classified as non-responders and responders, respectively. Non-response was associated with a high serum CRP level (p = 0.007) and high CAR (p = 0.013). Further, 75% of non-responders experienced an improvement in appetite during the administration period.

Figure 2 shows the association between body weight and the CAR. Among non-responders, CAR progressively worsened, and body weight tended to increase for a month but then decreased. According to the ROC curve, the CAR cutoff value was 0.06 (sensitivity, 75%; specificity, 74%). In the univariate analysis, CAR ≥ 0.06 was a risk factor (odds ratio, 5.6 [95% confidence interval, 1.2–27.1], p = 0.032) for non-response to anamorelin.

In the present study, we found that inflammatory status, represented by CRP and CAR, was higher in non-responders than in responders to anamorelin. In the univariate analysis, CAR ≥ 0.06 was a risk factor for non-response to anamorelin. Our findings suggest that systemic inflammation plays an important role in cancer cachexia progression.

Cancer cachexia is a multifactorial syndrome characterized by persistent weight loss with concomitant loss of skeletal muscle mass (with or without loss of fat mass), which leads to progressive functional impairment and reduced physical performance [6]. Inflammatory cytokines produced by tumours and hosts are proposed to affect different cells, including muscle cells, hepatocytes, and adipocytes, causing metabolic abnormalities that lead to cachexia [12]. For instance, inflammatory cytokines produced by tumour cells, such as tumour necrosis factor-α, interleukin (IL)-6, and IL-8, may contribute to muscle wasting and atrophy by inducing oxidative stress in the skeletal muscles and activating muscle degradation pathways [13]. A composite index combining systemic inflammation and skeletal muscle mass was developed to measure ongoing cachexia, but this is not widely used in clinical practice. As there are no effective treatment methods for cancer cachexia, anamorelin may be promising for preventing weight loss and ameliorating anorexia. Therefore, identifying the predictors of drug response is of clinical significance.

Interestingly, in this study, CAR was identified as the only inflammation-based biomarker associated with the response to anamorelin. This result is consistent with that of a previous report [5]. Other biomarkers of systemic inflammation, including the NLR, PLR, and LMR, were not associated with the response to anamorelin in this study. The NLR, PLR, and LMR are white blood cell-based biomarkers involving peripheral blood cell counts, whereas CAR is a CRP-based biomarker. One possible reason is that CAR may reflect sustained and chronic systemic inflammation more sensitively than do white blood cell-based biomarkers [14]. CAR reportedly reflects systemic inflammation in the cancer microenvironment and parallel tumour progression. While administration of anamorelin did not improve the CAR, even among the non-responders, 75% experienced an enhanced appetite. Moreover, non-responders tended to gain body weight one month after treatment initiation. However, the efficacy of anamorelin was not sustained and non-responders’ body weight eventually decreased.

The present study has several limitations. First, this was a retrospective study with a limited sample size from a single institution, and the potential for bias cannot be excluded. Second, we did not examine the changes in patients’ dietary intake, including caloric intake. Third, we did not evaluate the efficacy of concomitant treatment or the overall survival of patients who were administered anamorelin. Therefore, the predictive ability of the CAR for response to anamorelin should be validated in large-scale studies.

In conclusion, the CAR, which is calculated based on serum CRP and albumin levels, may be a predictor of non-response to anamorelin in patients with advanced pancreatic cancer. Our findings suggest that the CAR is a promising stratification tool for patients with pancreatic cancer and cachexia. Patients with pancreatic cancer who have cachexia and high systemic inflammation may benefit from limitation of anamorelin administration to a short period.

Acknowledgements

None

Authors’ contributions

Masashi Tsunematsu: Study design, data collection and analysis, and manuscript drafting. Tadashi Uwagawa: Data collection and manuscript revision. Shinji Onda: Data collection. Yoshihiro Shirai: Data collection. Norimitsu Okui: Data collection. Michinori Matsumoto: Data collection. Kenei Furukawa: Data collection. Koichiro Haruki: Data collection. Shunta Ishizaki: Data collection. Toru Ikegami: Manuscript revision and final approval.

Funding

This work was supported by JSPS KAKENHI grant numbers JP22K16453 (to M.T.), 21K08806 (to T. U.), JP21K08718 (to T. I.), and JP21K08805 (to K. H.), and by a research grant from the Princess Takamatsu Cancer Research Fund (to T.I.).

Data availability

The data in this article is available from the corresponding author upon reasonable request.

Conflicts of interest

The authors declare no conflicts of interest in association with the present study.

Ethics approval

This study was approved by the institutional Ethics Committee of The Jikei University School of Medicine [27-177(8062)] and conforms to the provisions of the Declaration of Helsinki, as revised in Fortaleza, Brazil in October 2013.

Consent to participate

Informed consent was obtained from all patients by the opt-out method.

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Table 1. Comparison of the clinicopathological variables between the two groups classified by response to the anamorelin in patients with advanced pancreatic cancer (n=31)

Variables	Overall (n=31)	Non-responder (n=12)	Responder (n=19)	p-value
Sex, male	17 (55%)	9 (75%)	3 (25%)	0.073
Age, years	72 (62–78)	70 (61–76)	72 (64–79)	0.440
Body mass index, kg/m²	22 (20–25)	19.2 (16.5–20.6)	16.4 (15.6–19.7)	0.311
CA19-9, U/ml	74 (34-430)	106 (45-734)	69 (30-209)	0.556
Disease status				0.550
Locally advanced cancer	7 (23%)	3 (25%)	4 (21%)
Metastatic disease	10 (32%)	5 (42%)	5 (26%)
Recurrent disease	14 (45%)	4 (33%)	10 (53%)
Past history of surgery				0.600
Pancreaticoduodenectomy	8 (26%)	3 (25%)	5 (26%)
Distal pancreatectomy	5 (16%)	1 (8%)	4 (21%)
Total pancreatectomy	1 (3%)	0 (0%)	1 (5%)
None	17 (55%)	8 (67%)	9 (47%)
Concomitant treatment				0.690
Chemotherapy	28 (90%)	11 (92%)	17 (89%)
Chemoradiotherapy	2 (6%)	1 (8%)	1 (5%)
Best supportive care	1 (3%)	0 (0%)	1 (5%)
Number of treatment regimens				0.320
1^st	27 (87%)	10 (83%)	17 (94%)
2^nd	3 (10%)	2 (17%)	1 (6%)
Improvement of appetite	27 (87%)	9 (75%)	17 (89%)	0.286
Adverse effects	2 (6%)	0 (0%)	2 (11%)	0.245
Body weight, kg
Pre	44.9 (37.9-54)	53 (38-58)	44 (37.9-52.5)	0.231
Post	47.1 (39-55.2)	47.6 (37.7-54.6)	46.2 (39-55.2)	0.903

Abbreviations: CA19-9, carbohydrate antigen 19-9.

No competing interests reported.

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You are reading this latest preprint version

Systemic inflammation adversely affects response to anamorelin in patients with pancreatic cancer

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Patients and Methods

Patient selection

Anamorelin administration and follow-up

Calculation of systemic inflammatory markers

Statistical analysis

Results

Discussion

Declarations

References

Table

Additional Declarations

Status:

Version 1