Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab

doi:10.21203/rs.3.rs-4958109/v1

In later-line treatment of metastatic colorectal cancer (mCRC), there may be large differences in treatment efficacy depending on cancer cachexia. Recently, the cachexia index (CXI), which was calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio, was developed to evaluate cancer cachexia. We retrospectively examined the CXI of 80 patients who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) + bevacizumab (Bmab) therapy as a later-line treatment for mCRC and assessed the impact of cancer cachexia on chemotherapeutic efficacy using the CXI. Progression-free and overall survival rates were significantly worse in the low CXI group than in the high CXI group. As the cross-sectional area of the iliopsoas muscle was significantly associated with that of the skeletal muscle, the accuracy of the CXI based on the psoas mass index (P-CXI), which is easier to calculate than the SMI, in predicting treatment outcomes was equivalent to that of the CXI based on the SMI (S-CXI). Cancer cachexia is an important factor related to treatment efficacy in later-line treatments, such as FTD/TPI + Bmab therapy.

Health sciences/Gastroenterology

Health sciences/Oncology

colorectal cancer

cachexia

FTD/TPI

Trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) is effective even in patients with metastatic colorectal cancer (mCRC) who are refractory to standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and is expected to further extend survival times in later-line therapy¹. In addition, the survival benefit of adding bevacizumab (Bmab) to FTD/TPI has been reported^2–4.

The therapeutic effects of FTD/TPI + B therapy vary depending on the patient. It is possible that the cause is related to the host. Cancer cachexia is a multifactorial syndrome defined by the persistent loss of skeletal muscle mass that cannot be completely reversed by conventional nutrition support⁵. As cancer cachexia has been reported to be associated with reduced efficacy of chemotherapy⁶, in later-line treatments, where many patients with cancer cachexia or pre-cancer cachexia are included, there may be large differences in treatment efficacy depending on cancer cachexia. However, the diagnostic criteria for cancer cachexia are vague, making objective evaluation difficult.

Recently, the cachexia Index (CXI), an index for evaluating cachexia, was developed by Jafri et al. ⁷. The CXI calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio (NLR), can comprehensively evaluate sarcopenia, malnutrition, and systemic inflammation.

This study aimed to assess the impact of cancer cachexia on chemotherapeutic efficacy using the CXI in patients treated with FTD/TPI + Bmab therapy for mCRC.

Patients

This retrospective study included 80 patients who were treated with FTD/TPI + Bmab therapy for mCRC at the Osaka Metropolitan University Hospital between January 2016 and December 2023. All the patients enrolled in this study were refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Osaka City University (approval number: 2020-026). Written informed consent was obtained from all patients. All patients were given the opportunity to opt out of the study.

Treatment

Patients were treated with FTD/TPI 35 mg/m² orally twice a day on days 1–5 and 8–12 in a 28-day cycle, with Bmab 5 mg/kg administered intravenously every 2 weeks. Treatment was discontinued because of disease progression or unacceptable toxicity. Response evaluations using computed tomography (CT) were performed every 8–10 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1⁸.

Data collection

We retrospectively collected clinical and laboratory data, including computed tomography (CT) findings, from the institution’s electronic medical records. Blood samples were obtained within 1 week before the initiation of FTD/TPI + Bmab therapy, and abdominal CT scans were performed within 1 month before the initiation of FTD/TPI + Bmab therapy.

Calculation of the CXI

The CXI based on the SMI (S-CXI) was calculated as follows: SMI (cm² /m²) x serum albumin concentration (g/dL) / NLR. The CXI based on the psoas muscle index (P-CXI) was calculated as follows: The psoas muscle index (PMI [cm² /m²]) x serum albumin concentration (g/dL) / NLR. Abdominal CT images taken within 1 month before the initiation of FTD/TPI + Bmab therapy were used to measure the skeletal muscle area (cm²) and psoas muscle area (cm²). The cross-sectional areas of the skeletal mass and psoas mass were measured at the level of the umbilicus using a 3-dimensional medical image analysis system SYNAPSE VINCENT® (Fuji-Film Corporation, Tokyo, Japan) (Fig. 1a). The total volume of the psoas muscle was also measured semi-automatically using SYNAPSE VINCENT (Fig. 1b). SMI (cm² /m²) was calculated as the skeletal muscle area divided by the square of height (m²). The PMI (cm² /m²) was calculated as the psoas muscle area divided by the square of the height (m²). The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. A receiver operating characteristic curve analysis was performed using the median progression-free survival status to determine the cutoff values of S-CXI and P-CXI separately in male and female patients, considering that muscle mass differs depending on sex.

Statistical analysis

All statistical analyses were performed using SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of differences in CXI, clinicopathological factors, and treatment outcomes were analyzed using the chi-squared test, Fisher’s exact test, and Mann-Whitney U-test. The correlation between the cross-sectional area of the iliopsoas muscle at the umbilicus level and other indicators of muscle mass, such as the total volume of the psoas muscle calculated by a 3-dimensional analysis and the cross-sectional area of the skeletal muscle at the umbilicus level, was evaluated using Spearman’s rank correlation coefficient. The overall survival was defined as the interval between the date of initiation of FTD/TPI + Bmab and the date of death from any cause or the last follow-up. Progression-free survival was defined as the interval between the date of initiation of FTD/TPI + Bmab and the date of disease progression, death from any cause, or the last follow-up examination. An objective response was defined as a complete or partial response. Disease control was defined as a complete or partial response or stable disease. Survival curves were estimated using the Kaplan–Meier method, and differences in survival curves were assessed using a log-rank test. Two-sided P values of < 0.05 were considered to indicate statistical significance.

The study population included 41 men and 39 women, and the median age of the overall population was 70 years (range: 36–88 years). The median follow-up period was 227 days. Seventy-three patients (91.3%) discontinued treatment due to progressive disease, and 3 patients (3.8%) discontinued treatment due to unacceptable adverse events.

The median S-CXI in men and women was 69.76 (range: 5.22–285.63) and 49.62 (range: 17.36–209.61), respectively. The median P-CXI in men and women was 9.87 (range: 0.73–44.70) and 6.69 (range: 0.32–28.18), respectively.

The median progression-free survival from the initiation of FTD/TPI + Bmab therapy was 108 days. ROC curve analyses revealed that the cutoff values of S-CXI for men and women were 72.8 and 33.6, respectively, while those of P-CXI for men and women were 9.97 and 5.57 (Fig. 2).

Associations between S-CXI/P-CXI and clinicopathological factors

The correlations between CXI and clinicopathological factors are shown in Table I. No correlation was observed between S-CXI/P-CXI and clinicopathological factors, except that low P-CXI tended to be more common in left-sided colorectal cancer.

Results of a survival analysis according to the S-CXI/P-CXI

The progression-free and overall survival rates were significantly worse in the low S-CXI group than in the high S-CXI group (p = 0.012 and p = 0.015, respectively) (Fig. 3). The progression-free and overall survival rates were significantly worse in the low P-CXI group than in the high P-CXI group (p = 0.022 and p = 0.006, respectively) (Fig. 4).

Correlation between the cross-sectional area of the iliopsoas muscle at the umbilicus level and other indicator of muscle mass

The cross-sectional area of the iliopsoas muscle at the umbilicus level was significantly associated with the total volume of the psoas muscle calculated by a 3-dimensional analysis (r = 0.887, p < 0.001) (Fig. 5a). The cross-sectional area of the iliopsoas muscle at the umbilical level was also significantly associated with that of the skeletal muscle at the umbilical level (r = 0.700, p < 0.001) (Fig. 5b).

This study demonstrated that both S-CXI and P-CXI were significantly associated with progression-free and overall survival in patients with mCRC who were treated with FTD/TPI + Bmab therapy.

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle with or without a decrease in fat mass that cannot be fully reversed by conventional nutritional support⁵. Cancer cachexia is caused by anorexia, muscle atrophy, and increased energy consumption due to tumor necrosis factor-α and interleukin-6⁹. Evaluation of the muscle mass, body weight, physical function, and nutritional and inflammatory state are important for the assessment of cancer cachexia. Cancer cachexia reportedly accounts for > 30% of the direct causes of death in cancer patients¹⁰ and requires careful attention in patients with advanced cancer.

Metabolic changes associated with cancer cachexia may downregulate antitumor immunity¹¹. In addition, cancer cachexia increases the adverse events associated with chemotherapy, leading to insufficient doses of chemotherapy^6,12. Furthermore, myokines released from skeletal muscle and exerting antitumor effects may be reduced in patients with cancer cachexia, because patients with cancer cachexia often have a reduced skeletal muscle mass^13,14. Therefore, the efficacy of chemotherapy may be lower in patients with cancer cachexia.

The original method for calculating CXI is based on SMI⁷, but some follow-up reports have calculated CXI based on PMI^9,15,16. In this study, both CXI based on SMI and CXI based on PMI were associated with the prognosis. The SMI calculation is complicated because there are many measurement points. On the other hand, PMI is relatively easy to calculate because it only requires measurement of the psoas muscle mass. Furthermore, a strong correlation was observed between SMI and PMI, which is consistent with a previous report by Abbas et al. ¹⁷, and PMI is an important indicator of sarcopenia. Therefore, CXI based on PMI is a useful index for clinical application.

In this study, a semi-automatic image analyzer was used to calculate muscle mass, whereas some previous reports have used manually measured long axis × short axis to calculate the psoas muscle mass¹⁶. Therefore, the results for the cross-sectional area of the muscle obtained in this study were extremely accurate. In previous reports, the skeletal muscle area and psoas muscle area at the third lumbar vertebra, which has been reported to reflect the muscle mass of the whole body¹⁸, were often used to evaluate the muscle area^19–21. In contrast, we measured the muscle area at the level of the umbilicus in this study because the image analyzer that we used automatically analyzes muscle mass at the level of the umbilicus. However, because a correlation was observed between the total volume of the psoas muscle calculated by the 3-dimensional analysis and the cross-sectional area of the iliopsoas muscle at the umbilicus level, the cross-sectional area of the iliopsoas muscle at the umbilicus level used in this study may be a valid method for evaluating muscle mass.

The present study was associated with several limitations. This study was principally limited by its small sample size and single-center, retrospective design. In addition, the cutoff value used in this study was a provisional value calculated from the data of the patients who were enrolled in this study. Therefore, large prospective studies should be conducted to confirm our findings and to determine a more accurate cutoff value for CXI as a prognostic marker.

Cancer cachexia is an important factor related to treatment efficacy in later-line treatment of mCRC, and CXI is a useful marker for evaluating cachexia.

Competing interests

The authors declare that they have no competing interests.

Author Contribution

MS designed the study, performed the statistical analysis, and drafted the manuscript. HT, YS, SK, TN, YF, DI, HK, TF, and KM collected clinical data and critically reviewed the manuscript.

Acknowledgement

We thank Dr. Brian Quinn, who provided medical writing services on behalf of JMC Ltd.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Table I. Associations between S-CXI/P-CXI and clinicopathological factors.

	S-CXI			P-CXI
Factors	Low (n=36)	High (n=44)	p-Value	Low (n=31)	High (n=49)	p-Value
Age (years)
Median (range)	69 (44-83)	72 (36-88)	0.249	53 (44-88)	72 (36-85)	0.288
Performance status, n
0, 1	33	39		26	46
2	3	5	0.724	5	3	0.250
Location of primary tumor, n
Right side	7	16		5	18
Left side	29	28	0.137	26	31	0.075
RAS status, n
Wild type	19	18		14	23
Mutant type	13	26	0.163	15	24	>0.999
Unknown	4	0		2	2
Number of metastatic organs, n
1	14	21		14	21
≥2	22	23	0.500	17	28	>0.999

S-CXI, cachexia index based on the skeletal muscle mass index; P-CXI, cachexia index based on the psoas muscle index

No competing interests reported.

Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Patients and Methods

Patients

Treatment

Data collection

Calculation of the CXI

Statistical analysis

Results

Associations between S-CXI/P-CXI and clinicopathological factors

Results of a survival analysis according to the S-CXI/P-CXI

Discussion

Conclusion

Declarations