Prognostic Value of Baseline Skeletal Muscle Index in Colorectal Cancer Patients Treated with Fruquintinib：A multi-center real world analysis

doi:10.21203/rs.3.rs-4969712/v1

Background

The Skeletal Muscle Index (SMI) is an objective indicator for evaluating the nutritional status in malignant tumors. The baseline nutritional status may affect the efficacy and prognosis of targeted anti-tumor therapy, and growth factor tyrosine kinase inhibitors often lead to drug-related sarcopenia. Fruquintinib has been approved for metastatic colorectal cancer. In this study, we analyzed the prognostic value of baseline SMI in metastatic colorectal cancer treated with fruquintinib, and observed the incidence of SMI reduction after fruquintinib treatment to evaluate its impact on prognosis.

Methods

A retrospective multi-center analysis of metastatic colorectal cancer patients treated with fruquintinib in eight medical centers in China was performed. The muscle area of the third lumbar spine was evaluated, the baseline SMI and post-treatment SMI were calculated separately. The correlation with survival was analyzed.

Results

The median PFS of 105 patients was 4.2 months (95% CI, 3.7 months to 4.9 months), and the median OS was 10.2 months (95% CI, 9.0 months to 12.7 months). The baseline SMI before fruquintinib therapy was significantly correlated with OS (P = 0.0077). Multivariate analysis demonstrated that the baseline SMI was an independent prognostic factor for OS (P = 0.005). Twenty-eight point eight seven percent (28.87%) patients experienced sarcopenia after oral administration of fruquintinib. However, there was no significant difference in OS between the SMI reduced group and the SMI nonreduced group after treatment with fruquintinib.

Conclusion

The baseline SMI was an independent prognostic factor for OS and it could affect the survival of patients treated with fruquintinib in metastatic colorectal cancer. Although fruquintinib can cause sarcopenia, there is no correlation between post-treatment SMI changes and survival.

Fruquintinib

metastatic colorectal cancer

sarcopenia

skeletal muscle index

Colorectal cancer is one of the most common gastrointestinal tumors. Patients with metastatic colorectal cancer eventually receive third-line treatment after front-line chemotherapy and targeted therapy. The strategy of optimizing third-line treatment for metastatic colorectal cancer is helpful for improving the quality of life, survival and prognosis. After several systemic front-line treatments, the physical state and nutritional status of patients with advanced third-line disease significantly decreased compared with those at initial diagnosis, and the incidence of malnutrition and poor performance status increased. Malnutrition is common in patients with terminal malignant tumors and ultimately leads to cachexia. Significant (>5%) involuntary weight loss may be a precursor to cachexia, especially if it is accompanied by anorexia or metabolic disorders such as decreased glucose tolerance^[1]. Cachexia is a multifactorial syndrome characterized by sarcopenia with or without loss of adipose tissue and progressive loss of skeletal muscle mass. Sarcopenia is a progressive, widespread loss of skeletal muscle mass and strength that can lead to functional impairment and impairment, longer hospital stays, increased risk of infection, and reduced survival in cancer patients^[2]. When tumors enter an advanced stage, in addition to the disease itself leading to sarcopenia, chemotherapy and other therapeutic measures may also lead to sarcopenia. Growth factor tyrosine kinase inhibitors (TKIs) have become commonly used therapeutic drugs for various advanced tumors. Small sample clinical studies have shown that sorafenib, regofenib, sunitinib, lenvatinib and other TKIs may lead to muscle loss and aggravate muscle atrophy in advanced patients^[3-8]. Even if the targeted drug is effective and the tumor shrinks, muscle loss may still occur. Tyrosine kinases are enzymes that target proteins involved in many normal cellular regulatory processes. Fruquintinib, a highly selective antiangiogenic tyrosine kinase inhibitor, can prolong the survival time of patients with advanced colorectal cancer^[9,10]. Is it true that the lower baseline SMI before treatment, the worse survival of patients treated with fruquintinib? And can fruquintinib cause sarcopenia like other TKIs? We evaluated muscle changes in 105 colorectal cancer patients receiving fruquintinib treatment in an attempt to answer this question.

Patients

This was a retrospective observational analysis of 105 patients with metastatic colorectal cancer who received fruquintinib at eight medical centers in China from January 2019 to December 2023. All patients had a histopathological diagnosis of colorectal cancer and underwent peritoneum CT scans prior to receiving fruquintinib. This study was approved by the Ethics Committee of Jinyi Medical Group.

Inclusion criteria

Progression after receiving at least two prior treatment regimens containing oxaliplatin or irinotecan; fruquintinib treatment for at least 2 months; no history of serious heart, liver, kidney or other underlying diseases; no serious complications such as gastrointestinal bleeding or obstruction; no uncontrolled hypertension; and no limitations on food access or intake.

The prescription for fruquintinib was 5 mg once daily for 3 weeks in a 4-week cycle. All patients underwent peritoneum computed tomography (CT) examination within 1 week before treatment and 2 months after treatment to measure the area of skeletal muscle (SMA) at the third lumbar vertebra (L3) level. An peritoneum CT scan was performed with a thickness of 5 mm, and the CT scan was located in the plane of the lumbar 3 vertebral body. The area of all peritoneum muscles with CT Hounsfield unit (Hu) tissue thresholds ranging from − 29 Hu to 150 Hu was calculated by subtracting the area of nonskeletal muscles in the peritoneum cavity to obtain the SMAs of 7 muscle groups (psoas major, erector spine, lumbar peritoneum muscles, transverse abdominis, external oblique and rectus abdominis). The skeletal muscle index (SMI, SMI = SMA/body surface area) was calculated. The cutoff value for sarcopenia was defined as an SMI < 54.1 cm²/m², which was calculated by Xtile version 3.6 (https://x-tile.software.informer.com/).

Eastern Cooperative Oncology Group Performance Status (ECOG PS), body mass index (BMI), hemoglobin, serum albumin, lymphocyte count, Nutritional Risk Screening 2002 (NRS2002) and Patient-Generated Subjective Global Assessment (PG-SGA) nutritional scores were monitored before treatment and 2 months after treatment. The prognostic nutritional index (PNI) was calculated. PNI = serum albumin (g/L) + 5×total number of peripheral blood lymphocytes (×10⁹/L).

Resist criteria version 1.1 was used to observe and evaluate the efficacy of fruquintinib treatment. All patients were followed up, and progression-free survival (PFS) and overall survival (OS) were recorded. PFS was calculated as the time from treatment with fruquintinib to tumor progression, and OS was calculated as the time from treatment with fruquintinib to death or the last follow-up.

Statistical analysis

All the statistical analyses were performed using RStudio version 4.3.2 (http://www.r-project.org/). Survival analysis was plotted on Kaplan–Meier curves, and hazard ratios were calculated using Cox regression analysis. A P value of < 0.05 was considered to indicate a significant difference.

Patient characteristics

Between January 2019 and December 2023, a total of 105 mCRC patients received fruquintinib therapy. There were 71 males and 34 females. The age range was 43 to 79 years, with a median age of 65 years. The PG-SGA nutritional score ranges from 1 to 8 points. The PNI ranged from 23.05 to 63.35, with a median value of 44.45. Among all patients, 29 had tumors located in the ascending colon, 4 had tumors in the transverse colon, 8 had tumors in the descending colon, 15 had tumors in the sigmoid colon and 49 had tumors in the rectum. Among them, 75 patients had liver metastasis, 58 patients had lung metastasis, and 43 patients had peritoneal omental metastasis. The basic clinical features of the patients according to the baseline SMI are presented in Table 1.

Changes in skeletal muscle mass index

All patients had a baseline SMI of 41.40-88.36 cm²/m²(SMA based on CT images at the level of L3 in a colorectal cancer patient is shown in Fig. 1A), and the median SMI was 62.88 cm²/m². Among them, 26/105 (24.76%) patients had sarcopenia. The changes in the SMI of each patient after 2 cycles of fruquintinib treatment are shown in Fig. 1B. After 2 cycles of fruquintinib treatment, 69/97 (71.13%) patients experienced a decrease in SMI, with the median SMI decreasing by 2.27 cm2/m2 to 60.61 cm2/m2, and 28/97 (28.87%) patients experienced sarcopenia.

SMI and clinical features

Before receiving fruquintinib treatment, the baseline SMI of patients was positively correlated with the PNI and PG-SGA and negatively correlated with peritoneum metastasis. The baseline SMI of patients were as follows: those with PG-SGA less than 4, PNI greater than or equal to 40, and those without peritoneum metastasis had higher SMI than those with PG-SGA greater than or equal to 4, PNI less than 40, or with peritoneum metastasis (Fig. 2A, 2D, 2H). However, there were no similar correlations between baseline SMI and BMI, ALB, Hb, lung metastasis, or liver metastasis (Fig. 2B, 2C, 2E, 2F, 2G).

SMI and therapeutic response to fruquintinib

Among all patients, the best therapeutic response of CR was achieved in 0 patients, PR was achieved in 8 patients, SD was achieved in 61 patients, and PD was achieved in 34 patients (ORR, 7.62%; DCR, 65.71%). A waterfall plot of the best therapeutic response for the target lesions is shown in Fig. 3. There was no significant correlation between the baseline SMI of patients and the therapeutic response to fruquintinib (Fig. 4A). There was also no significant correlation between the changes in the SMI and the efficacy of fruquintinib after 2 cycles of treatment (Fig. 4B).

Survival analysis

The median PFS of the 105 patients was 4.2 months (95% CI, 3.7 months to 4.9 months), and the median OS was 10.2 months (95% CI, 9.0 months to 12.7 months) (Figure 5). OS was significantly associated with age, baseline SMI, baseline PNI and peritoneum metastasis (Fig. 6A, 6B, 6C, 6D). Multivariate analysis further demonstrated that age, baseline SMI and PNI were independent prognostic factors for OS (P=0.005, P=0.003, P=0.006, respectively) (Table 2). Elderly patients, with a lower baseline PNI and lower baseline SMI had poorer survival. Considering the imbalance in PG-SGA, PNI, and peritoneum metastasis among the included patients, we conducted a propensity score matching (PSM) analysis, which showed that even after excluding the interference of these factors, there was still a significant difference in survival between patients with a low baseline SMI and those with a normal baseline SMI (P=0.0077) (Fig. 6E). However, there was no significant difference in OS between the reduced-SMI group and the nonreduced-SMI group after treatment with fruquintinib (Fig. 6F). In this study, changes in the SMI after fruquintinib therapy were not significantly correlated with OS. Additionally, no statistically significant differences were detected for OS according to sex, PG-SGA score, primary tumor location, primary colorectal cancer status, liver metastasis status, lung metastasis status, or KRAS status (P=0.3, P=0.05, P=0.19, P=0.89, P=0.05, P=0.11, P=0.28, respectively). Subgroup analysis revealed that among patients with liver and peritoneum metastases, patients with a low baseline BMI had a shorter survival time (Fig. 6G, 6H).

Research has shown that 35% of patients with metastatic colorectal cancer receive third-line treatment^[11]. Currently, the main drugs used for the third-line treatment of colorectal cancer in China are trifluuridine tetrapyrimidine (TAS-102), regofinib and fruquintinib^[12]. Antivascular therapy is a commonly used treatment strategy and a very promising treatment method for advanced tumors. Fruquintinib, an anti-vascular tyrosine kinase inhibitor that acts on vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2 and VEGFR-3, is an optional drug for the third-line treatment of metastatic colorectal cancer. Both the FRESCO and FRESCO2 studies have confirmed that compared to placebo, fruquintinib can significantly prolong the OS and PFS of metastatic colorectal cancer patients as a third-line treatment^{[9, 10]}. In our retrospective study, the median OS of 105 patients was 10.2 months, and the median PFS was 4.2 months, demonstrating similar efficacy to that of the FRESCO study. Our study validated the value of furoquinib in the third-line treatment of advanced colorectal cancer.

In recent years, the impact of skeletal muscle loss during antitumor treatment on clinical outcomes has been a focus of attention. Generally, compared to cancer patients without sarcopenia, cancer patients with sarcopenia have poorer survival. The presence of sarcopenia increases the incidence of complications and reduces survival in patients with head and neck tumors and increases radiochemotherapy complications, such as mucositis, swallowing pain, nausea, and vomiting^{[11, 12]}. Patients with upper gastrointestinal tumors and pelvic tumors also have a greater incidence of sarcopenia^[13–16]. Multiple tyrosine kinase inhibitors have been shown to prolong the survival time of advanced cancer patients. While treating tumors, studies have shown that some antivascular TKIs, such as sorafenib, regorafenib, sunitinib and lenvatinib, induce a decrease in skeletal muscle mass^[3–7]. However, not all anti-vascular TKIs lead to sarcopenia. There are very few TKIs that have not been found to cause sarcopenia, such as pezopanib. Sunitinib can cause muscle loss in renal cancer patients, while pezopanib, another commonly used TKI for advanced renal cancer, does not cause muscle loss in renal cancer patients^[17]. Therefore, what happens after treatment with a relatively new antivascular targeted drug, fruquintinib?

We retrospectively investigated the SMI of patients with metastatic colorectal cancer who received treatment with fruquintinib from multiple medical centers. CT images were used to obtain the SMA at the L3 level, the SMI was calculated, and the relationships between the SMI and clinical factors were analyzed. After treatment with fruquintinib, 71.13% of colorectal cancer patients experienced a decrease in SMI, and the proportion of patients with sarcopenia increased from 24.76–28.87%. The baseline SMI before treatment with fruquintinib was lower, and patients often had a lower PNI and poorer PG-SGA. Patients with peritoneum metastasis may have poorer gastrointestinal function and nutritional status and a lower SMI than those without peritoneum metastasis. Univariate analysis revealed that age, baseline SMI, baseline PNI, and peritoneum metastasis were significantly associated with OS. Further multivariate analysis suggested that age, baseline SMI, and baseline PNI were independent prognostic factors. The value of skeletal muscle loss in the survival of patients with advanced colorectal cancer has been evaluated and analyzed^[18–23]. Research has shown that those with lower SMI in the diagnosis of colorectal cancer have a higher risk of death compared to those without sarcopenia^[18–21]. Sarcopenia was significantly associated with a poorer prognosis for patients with colorectal cancer. At this point, our research findings are consistent. However, there was no difference in survival according to whether the SMI decreased after treatment with fruquintinib in this study. Therefore, although fruquintinib leads to a decrease in the SMI, it does not affect patient survival. This is the difference between fruquintinib and other antivascular TKIs. This indicates that baseline muscle loss itself leads to poorer survival rather than being a result of the muscle loss caused by fruquintinib. Multiple studies have reported a correlation between a low PNI and OS in patients with colorectal cancer^[24–25], which was also validated by our study.

Why do TKIs cause muscle loss? What is the underlying mechanism? There is little exploration on this issue, and in-depth research is necessary. A study showed that imatinib, sunitinib and sorafenib inhibited the activity of mitochondrial complexes and glucose and nucleoside uptake, leading to decreased energy production and mitochondrial function in a skeletal muscle cell model^[26]. Sorafenib might decrease serum carnitine levels by inhibiting the absorption of carnitine, thereby inducing presarcopenia^[27]. In many cancers, the PI3K/AKT/mTOR pathway is overactive, reducing cell apoptosis and allowing cell proliferation. TKI drugs ultimately block the activation of the AKT/mTOR signaling pathway by targeting different factors, thereby achieving the therapeutic effect of inhibiting tumor cell proliferation. The maintenance of skeletal muscle mass depends on a close balance between protein synthesis and protein degradation. In healthy individuals, activation of the AKT/mTOR pathway promotes muscle hypertrophy, regulates the size of skeletal muscle fibers and prevents muscle atrophy^[28]. However, TKIs also inhibit muscle hypertrophy, promote atrophy, and inhibit protein synthesis, leading to sarcopenia^[29]. mTOR inhibition is mediated via the activation of AMP-activated protein kinase (AMPK) by IL-6 in C2C12 myoblasts, which suggests that a reduction in anabolic mTOR complex 1 (mTORC1) in skeletal muscle contributes to a loss of muscle mass^[30].

In our retrospective analysis, we observed that a low baseline SMI before fruquintinib treatment was associated with poor survival. After treatment with fruquintinib, the patient's SMI decreased. Generally, a decrease in muscle mass is significantly associated with low tolerance to antitumor therapy and a low survival rate in cancer patients. In this study, although fruquintinib increased the incidence of sarcopenia, it did not have a significant impact on survival. Perhaps the muscle loss caused by fruquintinib was not severe enough to affect patient survival.

Of course, as this was a retrospective study and the number of patients was relatively small, it may not fully reflect the true situation. We need to include larger sample sizes in the future and design rigorous studies to validate our conclusions.

Patients treated with fruquintinib in metastatic colorectal cancer may experience muscle loss. The baseline SMI before treatment affect the survival of patient. However, although fruquintinib may lead to muscle loss, it does not yet affect the survival of patients. Fruquintinib-induced sarcopenia cannot predict the prognosis of patients. We should pay more attention to the nutritional status of patients before they receive fruquintinib treatment in clinical practice.

Conflict of Interest

There was no conflict of interest.

Funding

This study was supported by grants from Science and Technology Bureau of Jinhua City (grant number 2021-3-080, 2020-3-028).

This study was supported by grants from Department of Health of Zhejiang Province (grant number 2022KY1330).

This study was supported by grants from Affiliated Jinhua Hospital, Zhejiang University School of Medicine (grant number JY2020-2-04).

Author Contribution

Wanfen Tang: Practical performance, Investigation, Data analysis, Formal analysis , Preparation manuscript, Funding acquisitionFakai Li: Practical performance, InvestigationHongjuan Zheng: Data analysis, InvestigationJinglei Zhao: Practical performance, InvestigationHangping Wei: Practical performance, InvestigationXuerong Xiong: Practical performance, InvestigationHailang Chen: Practical performance, InvestigationCui Zhang: Practical performance, InvestigationWeili Xie: Practical performance, InvestigationPenghai Zhang: Practical performance, InvestigationGuangrong Gong: Image analysisMingliang Ying: Image analysis, Funding acquisitionQiusheng Guo: Data curationQinghua Wang: SupervisionJianfei Fu: Design study, Conceptualization, Project administration, Funding acquisition

Data Availability

The original data can be provided with supplementary information files

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Table 1. Basic clinical features of the patients according to the baseline SMI

Clinical features

SMI high

n(%)

SMI low

n(%)

P-value

Age (years)

<65

≥65

Gender

Male

Female

PG-SGA

<4

≥4

PNI*

≥40

<40

Primary tumor location

Rectum

Sigmoid colon

Descending colon

Transverse colon

Ascending colon

Primary tumor resection

No

Yes

Liver metastasis

No

Yes

Lung metastasis

No

Yes

Peritoneum metastasis

No

Yes

KRAS

Wild

Mutation

37(46.8)

42(53.2)

57 (72.2)

22(27.8)

53(67.1)

26(32.9)

66(83.5)

13(16.5)

32(40.5)

13(16.5)

6(7.6)

4(5.1)

24(30.3)

8(10.1)

71(89.9)

22(27.8)

57 (72.2)

34(43.0)

45(57.0)

54(68.4)

25(31.6)

40(50.6)

39(49.4)

13(50.0)

14(53.8)

12(46.2)

7(26.9)

19(73.1)

16(61.5)

10(38.5)

17(65.4)

2(7.7)

0(0)

5(19.2)

21(80.8)

8(30.8)

18(69.2)

13(50.0)

8(30.8)

18(69.2)

10(38.5)

16(61.5)

0.957

0.137

0.001

0.038

0.211

0.379

0.971

0.695

0.002

0.394

*PNI: Prognostic nutritional index

Table 2. Univariate and multivariate analysis for OS

Variable

median

OS(m)(95%CI)

Univariate

Multivariate

HR(95%CI)

P-value

HR(95%CI)

P-value

Age (years)

<65

≥65

Gender

Male

Female

PG-SGA

<4

≥4

PNI

≥40

<40

SMI

≥54.1

<54.1

Tumor location

Left colon

Right colon

Proctocolectomy

No

Yes

Liver metastasis

No

Yes

Lung metastasis

No

Yes

Peritoneum metastasis

No

Yes

KRAS

Wild

Mutation

15.6(10.3-16.6)

9.5(6.5-11.6)

9.6(8.1-12.2)

12.7(6.6-NA)

10.8(9.5-16.0)

9.1(5.0-12.7)

11.8(9.7-15.6)

6.2(4.6-10.2)

11.6(9.6-15.6)

5.3(4.0-12.7)

9.3(6.6-12.7)

12.7(9.6-NA)

11.6(9.5-NA)

9.7(8.1-12.7)

12.7(9.1-NA)

9.7(8.1-12.2)

9.5(6.2-12.7)

11.8(9.3-16.0)

11.8(9.6-16.0)

6.6(5.0-12.7)

9.1(6.6-11.6)

12.7(9.6-16.3)

1

1.87(1.14-3.06)

1

0.75(0.44-1.28)

1

1.61(1.00-2.60)

1

2.74 (1.57-4.77)

1

2.37 (1.42-3.95)

1

0.70 (0.41-1.19)

1

0.96(0.47-1.94)

1

1.73(0.99-3.02)

1

0.68(0.42-1.09)

1

1.72 (1.05-2.81)

1

0.77(0.47-1.24)

0.013

0.292

0.051

＜0.001

0.001

0.184

0.905

0.053

0.108

0.031

0.279

-

2.05(1.24-3.41)

-

1

1.01(0.60-1.71)

1

2.52(1.38-4.58)

1

2.26(1.26-4.05)

-

1

1.22(0.69-2.15)

-

0.005

-

0.975

0.003

0.006

-

0.488

-

No competing interests reported.

Prognostic Value of Baseline Skeletal Muscle Index in Colorectal Cancer Patients Treated with Fruquintinib：A multi-center real world analysis

Status:

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Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Patients

Inclusion criteria

Methods

Statistical analysis

Results

Discussion

Conclusion

Declarations

Conflict of Interest

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Data Availability

References

Tables

Additional Declarations

Status:

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