In the present study, we performed a propensity score matching study based on population analysis to explore the survival benefit of chemotherapy on stage II CRC and described three major findings: First, the adverse histological features of colonic cancer did not influence the survival at all for patients with T3N0M0 staging. Second, adjuvant chemotherapy seemed to be invalid to improve the survival of patients of adverse histological features with T3N0M0 staging, so it may be reasonable to subtract chemotherapy due to the considerable toxicity; Third, there has been a contradictory behavior of the tumor location as left side colonic cancer appeared to be associated with a poorer survival in population with good histological features whereas it’s well accepted that right side colonic cancer represents a poorer survival, and the inflection point may lie in patients of adverse histological features with T3N0M0 staging just as illustrated in Fig. 2. Females remain at a lower risk for advanced stage CRC across all age groups, and probably benefit from protective effect against colon cancer of estrogen pathway[9] and microsatellite instability arising in females[10].
The therapy of rectal cancer is routinely referred to that of colonic cancer, however, these two diseases show their respective situation frequently, such as different lymphatic drainage pathway, molecular subtypes and application of radiotherapy, so only colonic cancer were included in the current study to minimize the bias. In this study, we also adopted the PSM to eliminate the difference of baseline between patients of adverse histological features with and without chemotherapy. PSM is a technique to improve the comparability between groups, as shown by the well-balanced demographics and clinicopathological characteristics in Table 1. Both the lymphovascular invasion and perineural invasion are recognized as adverse factors responsible for poor prognosis, so these two histological features were well balanced by PSM method to invalidate the confusion, despite of the actuality that the specific data was only on access from SEER database since year 2010.
The common adenocarcinoma (AC) accounts for the majority of colonic cancer cases, left 10–15% patients with mucinous adenocarcinoma (MC) and approximately 1% of CRC patients with SRCC[11]. Although SRCC represents a rare condition, it is associated with a poor prognosis compared with AC[11, 12]. Five-year relative survival rate of SRCC in stage II colonic cancer patients was 67.9% compared with 77.0% of AC; while in stage II rectal cancer patients five-year relative survival rate of SRCC was 27.4% compared with 67.1% of AC[11], indicating a significant influence of tumor location on survival, which was similar with our findings that the left side colonic cancer appeared to be associated with a poorer survival in population with good histological features opposite to the well accepted fact that right side colonic cancer represents a poorer survival in metastatic colorectal cancer. In concordance with SRCC, mucinous colorectal adenocarcinomas usually have poorer responses to chemotherapies[13], resulting in a poor prognosis in advanced disease[14]. Either MC or SRCC patients more often develop metastatic disease, and are more likely to develop peritoneal metastases and metastasizes via the lymphatic route, whereas AC metastasizes primarily to the liver[12], which may partially explains the poor prognosis of MC and SRCC. The standard treatments for colorectal adenocarcinoma are recommended to MC and SRCC patients since no clinical guidelines have been developed specifically for these groups of patients[13]. Due to the low frequency, SRCC and MC has not been well-studied in stage II colonic cancer patients and reports in the literature are uncommon. In the present study, poorly differentiated histology, which was routinely considered as an adverse prognostic factor, was integrated as adverse histological features with MC and SRCC together to illustrate the benefit of adjuvant chemotherapy in stage II colonic cancer excluding T4. In our study population, 22.89% of patients staging as T3N0M0 were sequential deal with adjuvant chemotherapy, which was more likely to be administrated in patients of adverse histological features histology (27.65% in adverse histological features compared to 21.97% in good histological features, P < 0.01). So, this kind of adverse histological features was accepted for clinicians to evaluate the necessity of chemotherapy. However, it is denied to administrate adjuvant chemotherapy in the current study for patients of adverse histological features, which is regarded currently as one of the high risks, implying the adverse histological features alone is not sufficient for the decision of adjuvant chemotherapy in T3N0M0.
Despite of the fact that inspiring therapeutic improvements have improved the survival rate in the last decade by an average of 3% every year[15, 16], CC serves as the 3rd cause of cancer deaths both in the world, no matter men or women[9], with almost 25% of patients with stage II disease suffering recurrence after radical surgery[17, 18]. Surgery is the main therapeutic modality for CRC and adjuvant chemotherapy is the widely accepted pattern of administration with promising efficacy for stage III CC, on the consensus that the pathologic stage is the most helpful prognostic factor for the colorectal cancer[3, 4]. Regardless of the recommendation of the NCCN guideline, the adjuvant chemotherapy benefit for stage II CRC is still controversial[19], and it’s believed that only a few CRC patients with stage II would benefit from adjuvant therapy[17, 20]. Several stage-specific factors in stage II CRCs, including T4 lesions, positive margins, poorly differentiated histology, inadequately sampled lymph nodes and et. al[21], which are considered as high-risk stage II CRCs, provide certain prognostic value[22]. The 5-year disease-free survival could be more than 90% in patients without any risk factor, compared to 84.8% in patients with one or more risk factors[23]. So far, adjuvant chemotherapy is administrated for high-risk stage II CRC or later stage CRC since 2004[6], but there are insufficient data based on scientific evidence to confirm the efficacy of the biomarkers to select the appropriate candidate patients[3, 5] except that pathologic T4 stage was a significant factor predicting poor DFS[24], and only a trend for benefit from chemotherapy in the stage II was seen, failing to reach a significance[17]. Neither in the IMPACT trial nor the NSABP trial, improvement from adjuvant chemotherapy in survival of stage II CRC was seen[1], so the precise decision of whether a CC patient with Stage II disease should receive adjuvant chemotherapy is essential to improve the prognosis for every individual[19]. We came to the conclusion that adjuvant chemotherapy may be invalid to improve the survival even in patients of adverse histological features with T3N0M0 staging, so it may be reasonable to subtract chemotherapy for patients of this situation in case of the presence of adverse histological features alone, and more precise indicators are essential for the selection of advantage cohort.
Nowadays, several researches have been carried out to identify the sensitive CRC patients with AJCC stage II for chemotherapy. Tumoral heterogeneity including KRAS[17, 25], BRAF, PTEN or microsatellite instability status[26], as well as tumor metabolism, such as NKX6.1 methylation[20], MMP7[27] and AQP1[28], has been established on cancer response to targeted therapy or chemotherapy in metastatic CRCs[9], while it is of no uncertain use for stage II CRCs. Her-2 status should be a predictive factor, especially for patients with pMMR status, because Her-2 positive patients can benefit from 5-fluorouracial based adjuvant[29], while low expression of the PD-L1 gene was associated with benefit from adjuvant chemotherapy[30]. Despite of the efforts, there are now insufficient or reliable indicators to identify the proper patients suitable for adjuvant chemotherapy in stage II colonic cancer unfortunately, and the personalized intertumoral and genomic biomarkers would be promising in the future instead of clinicopathological indicators.
The current study had some limitations: First, as a retrospective analysis, it always carried the risk of various biases. Second, due to the carefully chosen criteria, only 887 colonic cancer patients of adverse histological features with T3N0M0 staging who were administrated with adjuvant chemotherapy were enrolled in this study, which would influence the degree of power more or less. Third, the current SEER database is deficient in providing the entire picture of the registered patients such as genetic markers and disease-free survival (DFS), making it impossible to survey the influence of adverse histological features and other genomic biomarkers on DFS or CSS. So, more chemotherapeutic regimens are necessary to increase survival in this stage II CRC subset of patients and more valid genomic biomarkers are essential to come up with appropriate selection criteria.
The strengths of our study include: The current study minimized potential biases and had a higher degree of power with the use of a large-scale sample and PSM method. The segmentation of the high risks of the stage II CRCs, and then the only concern on adverse histological features was another merit. The SEER database allows researchers to accurately identify patients with good or adverse histological features based on histology and grade clearly, thus avoiding confusion of differentiation, and we colligate histology and grade of tumors in a new way intend to make the results more convincing. Still, the potential biases of surgery were avoided by super-selective cohort with the limit of radical resection.