Given the large population of the U.S. and China, mortality due to LM for CRC patients constitutes a great portion of the international burden of CRC. In the past decade, fast development of medical oncology including the optimization of chemotherapy and targeted therapy regimens(14–16), novel pharmaceutical development such as immunotherapy(17–19), contributed to large improvement of survival benefit in the treatment of metastatic CRC. More importantly, progression in the surgical techniques, development of local treatment for LM and evolving concept of patient selection for HR played indispensable roles in improvement of the prognosis for CRC patients with LM(20–23). However, there is no study to illustrate the treatment strategy and prognosis in CRC patients with LM between China and the U.S. during recent decade.
In this study, we found differences of tumor characteristics and treatment strategy of LM for CRC patients between the U.S. and China. Compared with patients in the U.S., mean age of CRC patient with LM is 5.2 years lower in China, larger proportion of male patients and rectal cancer in China. For patients in China, the AJCC T stage and N stage at diagnosis were more advanced., and lower proportions of lung metastasis, bone metastasis and brain metastasis were observed compared with those in the U.S.
Surgical resection has been shown to improve prognosis from patients with LM and is the preferred treatment whenever possible(3, 24, 25). In a retrospective study, the 5-year overall survival increased from 9.1% in 1990–1997 to 19.2% in 2001–2003, and the improved outcomes were associated with increased application in HR(12). Approximately 19–40% of patients remain alive 5 years after HR with a median survival time of 28 to 46 months, but those who underwent palliative treatment only survived 7 to 8 months(26). In our study, the proportion of HR and prognosis after HR were comparable to the outcomes reported in previous studies(12, 27, 28). From 2010 to 2017, the proportions of HR was obviously increasing and significant improvement of 3-year CSS for patients with LM were also observed in two nations, which demonstrated that these rapid improvements were closely associated with increased application of HR from 2010 to 2017. As in previous studies, improved prognosis from hepatic resection have been always criticized for patient selection bias(12, 29). Here, we preformed the subgroup analyses for patients in both AJCC M1a stage and AJCC M1b stage, which was considered as a key influencing factor that contributed some of the effects of selection bias for HR. Furthermore, it is impossible to quantify the degree of benefit from HR on survival because of the absence of a randomized controlled trial in retrospective studies.
The proportions of patients who only PSR were decreasing over time in the U.S. and China, which might be associated with the increased proportion of HR and systematic chemotherapy. PSR has been performed to relieve tumor-related complications and to avoid life-threatening conditions such as intractable bleeding, intestinal obstruction, and perforation. However, it remains controversial whether only PSR improves survival in patients with LM. A recent randomized clinical trial has suggested that PSR followed by chemotherapy showed no survival benefit over chemotherapy alone(30). Previous studies have confirmed that systemic chemotherapy can improve survival in metastatic CRC(12). Systemic chemotherapy is the primary treatment for unresectable metastatic CRC. Clinical trials completed in the past 5 years have demonstrated that tailoring treatment to the molecular and pathologic features of the tumor improves overall survival(31). For 50% of patients with metastatic CRC with KRAS/NRAS/BRAF wild-type tumors, cetuximab and panitumumab, in combination with chemotherapy, can extend median survival by 2 to 4 months compared with chemotherapy alone(32). For the 5–10% with BRAF V600E sequence variations, targeted combination therapy with BRAF and EGFR inhibitors extended overall survival to 9.3 months, compared to 5.9 months for those receiving standard chemotherapy(33). For the 5% with microsatellite instability or mismatch repair deficiency, immunotherapy may be used in the first or subsequent line and has improved treatment outcomes with a median overall survival of 31.4 months in previously treated patients(34). Unresectable LM can be transformed into surgically resectable lesions after more effective chemotherapy regimen and the adoption of novel agents(18, 35, 36), which indicated that improvements of survival from HR was also attributed to recent progressions in medical oncology. Furthermore, the collaboration of multidisciplinary team including surgeons, radiologists, medical oncologists and other medical professionals to develop a more optimized treatment strategy for each of individual metastatic CRC patients played a key role to the improved long-term outcomes(37–39).
This study still has some limitations. First, it is inevitable to exclude all potential selection biases in retrospective study. Second, due to the different socioeconomic conditions, the heterogeneity of diagnosis and treatment levels may be confounding factors in the analysis of CSS between China and U.S. Third, we could not determine the effect of chemotherapy regimen on the prognosis in patients with LM because of the lack of related information in the SEER database. Fourth, the SEER registry only records the initial treatment data for patients. Whether patients received subsequent treatment is unknown, which could potentially influence the effect of HR on the prognosis of patients with LM. Nevertheless, the strengths of this study include a long observation period as well as two large scale sample size population with relatively homogenous treatment strategy identified in two national databases.
Our findings suggested that the prevalence of CRC patients with LM will continue to increase because of more long-term survivors accumulated in both the U.S. and China. According to the convincing results from our study, we boldly speculated that more patients diagnosed with metastatic CRC after 2017 will be alive for 5 years. With the advancement in surgical technique for HR and fast pharmaceutical development, these gains could be continuously extended to the improvement of outcomes for patients with LM.