Colorectal cancer (CRC) is the most common type of gastrointestinal cancer worldwide and the third leading cause of cancer-related death, resulting in an estimated 1.9 million new cases and about 935,000 deaths each year [1]. The burden of CRC varies greatly by geographic region, likely due to differences in lifestyle and socio-economic status [2]. China has the largest number of cases and CRC-related deaths as a result of its large population [3]. In 2016, it was estimated that about 408,000 new CRC cases and 195,600 CRC deaths occurred in China, giving it the second highest incidence and fourth highest mortality rate of all cancers [4]. While early screening and treatment have reduced the number of deaths [5], 25% of CRC patients are diagnosed with metastases, and 50% will go on to develop metastases [6], resulting in poor prognosis and a heavy disease burden.

Chemotherapy is the primary treatment for metastatic CRC (mCRC) [7]. However, chemotherapy alone is often limited by the lack of tumor cell selectivity, insufficient drug concentration in tumor tissues, systemic toxicity, and the appearance of drug-resistant tumor cells [8, 9]. According to the Pan-Asian adapted ESMO consensus guidelines for the management of patients with mCRC, the chemotherapy should be combinations of cytotoxic agents, in singlet, doublet, or combination chemotherapy along with appropriate targeted biological agents [10]. Over more than 10 years, the remission and survival conditions of mCRC patients have been revamped mainly because of development in prescribing conventional chemotherapy in combination with targeted agents. For example, clinical data indicated that the addition of bevacizumab to chemotherapy using fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) prolonged median progression-free survival (PFS) from 9.7 to 12.1 months, and increased the overall response rate from 53% to 65% among the untreated mCRC patients [11]. A randomized controlled trial among Chinese patients with RAS wild-type mCRC found that first-line cetuximab combined with leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) improved the PFS (9.2 vs. 7.4 months), overall survival (OS) time (20.7 vs. 17.8 months) and overall response rate (61.1% vs. 39.5%) compared with FOLFOX-4 alone [12]. A meta-analysis demonstrated that aflibercept plus leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) showed better survival efficacies as a second-line treatment for mCRC compared with FOLFIRI alone [13]. In mCRC patients who had progressed following treatment with all approved standard drugs, both regorafenib and fruquintinib treatment offered substantial survival benefits. Compared with the placebo, patients treated with regorafenib or fruquintinib had prolonged OS and PFS [14–17].

Given the recognized clinical benefits of targeted cancer therapy, many countries and professional organizations have approved its use in clinical practice [18, 19]. In China, four targeted agents (bevacizumab, cetuximab, regorafenib, and fruquintinib) for mCRC were approved and listed in the medical insurance directory [19]. Bevacizumab, a recombinant humanized immunoglobulin monoclonal antibody that binds to and inhibits the activity of human vascular endothelial growth factor-A (VEGF-A), was approved for mCRC treatment in 2010 and is now used as a first- or second-line therapy in combination with chemotherapy [20, 21]. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, was approved in China in December 2005 as a second- or third-line medication for mCRC and as a first-line therapy in combination with chemotherapy in September 2019 [12, 22]. Regorafenib, an oral multi-kinase inhibitor that blocks and inhibits the activity of multiple protein kinases including vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptor (FGFR), platelet-derived growth factor (PDGF)-α and -β, epidermal growth factor (EGF), angiotensin 2, and the Rapidly Accelerated Fibrosarcoma kinase pathway, was approved as the third-line therapy for mCRC in March 2017 [19, 23]. Fruquintinib, which inhibits VEGFR signaling was approved as the third-line therapy for mCRC in September 2018 [19, 24]. However, the use of targeted agents in real-world clinical practice has never been investigated. Thus, this study sought to explore the use of targeted therapy, identify potential barriers to its utilization, and identify factors associated with treatment initiation by Chinese mCRC patients. The goal was to provide reference data for clinicians and policymakers to prolong mCRC patient survival.

This study is the first to provide real-world evidence in support of the use of targeted treatment for mCRC patients in China. The findings illustrated that 51.6% of mCRC patients had ever initiated targeted therapy, one-third of whom first initiated targeted therapy as the third-line treatment. Bevacizumab was the most commonly used medication. High medical cost, lack of belief in the efficacy of targeted therapy and a fear of side effects were the most frequently reported barriers to the initiation of targeted therapy.

While targeted agents have been approved for >10 years, and are recommended by Chinese clinical guidelines, use remains lower than in developed countries. In the United States, for example, >70% of CRC patients with stage IV disease have ever received targeted therapy [29]. The high medical cost was the predominant barrier against initiating targeted agents in this study. In China, the cost for a 1 month’s supply of bevacizumab, cetuximab, regorafenib, fruquintinib is about 9,500 CNY [30], 15,000 CNY [31], 15,000 CNY, and 5,500 CNY [32], respectively. However, more than half of mCRC patients have an annual family income of <50,000 CNY to cover their daily spending needs. While all the targeted agents were listed in the medical insurance directory, and 98.6% of the patients had insurance, the reimbursement rate was limited. In addition, particular limits were added to the cost of treatment during hospitalization. Thus, a cost-reduction strategy may be the first step to facilitate the use of targeted therapy.

Concern about the efficacy and safety of targeted therapy was also a common barrier to treatment initiation. More than one-third of mCRC patients delayed targeted treatment until it became the third-line option, despite studies illustrating that bevacizumab and cetuximab are effective as first- or second-line treatments at improving survival and quality of life [10, 11]. In addition, while regorafenib and fruquintinib have been recommended as the standard third-line mCRC drugs in China since 2017 [19], most patients in the current study still used bevacizumab or cetuximab, suggesting that the misuse of targeted agents is common. Thus, there is a need to improve public awareness of targeted treatments and to strengthen prescriber knowledge of clinical guidelines to promote the timely and correct application of targeted drugs.

Bevacizumab was most frequently used as a first- or second-line drug. In addition to drug cost, the affordability and availability of genetic biomarker testing may also influence the choice of targeted therapy. More than half of advanced CRC patients in the current study had never received biomarker testing due to its high price [33]. Bevacizumab may be an appealing drug choice because it targets VEGF and does not require genetic biomarker testing [21]. However, precision medicine dictates that target drugs are most effective if a predictive biomarker is available and agents that are exempt from biomarker testing should not be selected for use. Biomarkers are also recognized as predictors of targeted drugs and drug reactions and are thus recommended for the selection of personalized therapies by some leading guidelines [6, 34, 35]. For example, cetuximab is associated with a longer OS, a higher objective response rate, a higher complete response, and a greater median depth of response than bevacizumab for the treatment of RAS and BRAF wild-type mCRC [36]. Therefore, policymakers should implement specific strategies, including reducing the cost of testing for key biomarkers and ensuring that they are covered by insurance, to facilitate the use of biomarker tests.

Consistent with patient self-reported barriers to initiating targeted therapy, patients with less education, low annual family income, and no medical insurance were less likely to start targeted treatment. Education level was positively associated with CRC awareness and knowledge [37], thus, less educated patients may not be convinced that targeted therapy is effective. Patients with a low annual family income or no medical insurance may also refuse targeted therapy due to its high expense. Previous studies indicate that elderly patients have limited heath care utilization because they are likely to have less education, lower income, and receive less family support [38, 39]. The current study also found that older patients had a lower probability of using targeted therapy, suggesting that more attention should be paid to this subgroup to ensure equitable cancer care utilization. Slight differences in the use of targeted therapy were also shown by geographic region. Patients who lived in North China had the highest likelihood of initiating targeted therapy, while those living in Southwest or Northwest China had the lowest. North China has a stronger economy, culture, and healthcare system than Southwest and Northwest China, indicating that these factors may be positively associated with the use of targeted therapy. Beijing, which was randomly selected for this survey, is the city with the highest economy, culture, and healthcare services in North China. Thus, this may also have contributed to the high number of patients initiating targeted therapy in this region. These findings highlight that less developed regions should be prioritized for interventions and health education to improve access to targeted treatment.

Patient clinical characteristics were also associated with the likelihood that they would initiate targeted therapy. Those with a shorter duration of mCRC were less likely to initiate targeted therapy. This may be because symptoms were often relatively mild in these patients, suggesting that they may have a higher level of medication hesitation. Thus, more attention and care should be paid to this population. Importantly, patients with more severe disease, including those with low HRQOL scores prior to treatment and those with metastases outside the liver/lung or systemic metastasis, were also less likely to initiate targeted therapy. It is possible that supportive care, including pain management, nutritional support, and psychological intervention may be a better choice for these patients [40, 41]. These findings highlight the need to address targeted treatment hesitation to prevent mCRC from developing to a point at which targeted therapy is no longer an effective option.

Interestingly, patients who were treated in a general hospital were less likely to initiate targeted therapy than those who received treatment in an oncology hospital. This may be because more patients with underlying diseases (such as diabetes, hypertension, and renal insufficiency) or poor organ function that contribute to a poor HRQOL prefer to be treated in a general hospital. Indeed, this study found that patients treated in general hospitals had a lower HRQOL score than those treated in oncology hospitals (94.4 ± 23.12 vs. 104.8 ± 17.42; p < 0.001). Additional data is needed to further assess this hypothesis.

The strengths of this study included its large sample size, multi-center survey nature and hospital-based representative sampling. To our knowledge, this is the first geographically representative study that includes a large number (>1,600) of mCRC patients in China, allowing for a reliable and robust analysis. This study provides real-world evidence for clinicians and policymakers to design interventions that promote the use of targeted therapy and reduce CRC-related mortality.

This study also had several limitations. First, because it is a cross-sectional survey study, causal relationships between patient characteristics and the initiation of targeted treatment cannot be firmly established. Second, the self-reported data may be subject to recall and social desirability biases. Third, since the patients volunteered to enroll, their characteristics may differ from those who did not chose to participate in the study. Finally, only those patients who finished at least the first cycle of chemotherapy were included. The short treatment interval might underestimate the rate of initiating targeted therapy since some patients may delay the use of targeted agents.