Rectal cancer level significantly affects rates and patterns of distant metastases among rectal cancer patients post curative-intent surgery without neoadjuvant therapy

Over the past two to three decades, total mesorectal excision [1] and neoadjuvant chemoradiation therapy have been widely adopted to reduce local recurrence [2] and improve the surgical outcome of rectal cancer. Unfortunately, most studies have not been able to show any significant improvement in survival because the frequency of distant metastases remained high [2‐5]. Moreover, patients with distal rectal cancer who underwent abdominoperineal resection (APR) had worse oncological outcomes than those who underwent anterior resection [6]. These data raised the possibilities that low-rectal cancer possesses a distinct biological behavior or that extended APR might require a more radical excision [7, 8].

Previous reports have shown that rectal cancer patients have a much higher incidence of synchronous and metachronous pulmonary metastases than those with colon cancer [9‐11]. Tan et al.[9] reported a 12% versus 6% rate of synchronous lung metastases for primary rectal cancer compared with primary colon cancer. Similarly, Mitry et al.[10] demonstrated that compared with colon cancer, rectal cancer showed a 2.8-fold increase (16.7% versus 7.5%, respectively) in the five-year cumulative rate of synchronous lung metastases and a 2.63-fold increase (9.1% versus 4.1%, respectively) in the rate of metachronous lung metastases. Some clinicopathological factors such as nodal status and tumor invasion depth were also found to significantly affect surgical outcomes in these studies [9‐12]. However, the impact of the rectal cancer level on local recurrences or distant metastases remains unknown.

Here, we retrospectively analyzed the surgical outcomes of rectal cancer patients who did not undergo neoadjuvant chemoradiation therapy to characterize the rates and patterns of recurrence in relation to locations of rectal cancer and clinicopathological factors.

Here, we have demonstrated that in addition to nodal status, tumor invasion depth, and tumor differentiation, location of the rectal cancer also significantly affects the surgical outcome (OS and DFS) of patients who did not undergo neoadjuvant chemoradiation therapy. Compared with those with upper-rectal cancer, patients with distal and mid-rectal cancers were more likely to have distant metastases, including lung, bone, and systemic lymph node metastases. A significant increase in the frequency of developing lung metastases was observed for distal and mid-rectal cancers (3.18-fold and 1.76-fold, respectively). Similarly, significant increases in the frequencies of bone metastases (4.04-fold and 2.09-fold for distal and mid-rectum, respectively) and systemic lymph node metastases (5.04-fold and 2.78-fold for distal and mid-rectum, respectively) were also observed. To our knowledge, this is the first report revealing the influence of rectal cancer location on distant metastases patterns among patients without CCRT, and the findings presented here may impact several aspects of clinical practice.

First, our data may influence the preoperative staging protocol and postoperative follow-up strategy. Some studies question the clinical value of routine preoperative chest CT’s and indicate that it does not influence therapeutic strategy in colorectal cancer patients. This is because interpretation of the nature of pulmonary lesions is not always easy and only a small proportion of these lesions are actually malignant [13]. However, other studies have shown that a chest CT should be recommended as a routine staging method at least for low- and mid-rectal cancers because of their higher rates of lung metastases [9‐11]. In addition, a preoperative chest CT is useful for the early detection of pulmonary metastases as a baseline study for abnormal lung nodules [12]. Currently, a wide variety of imaging methods are available for colorectal cancer staging, thus, selection based on the particular organs involved and high-risk sites may be important.

Second, our data might provide a baseline reference for comparisons of treatment outcomes with and without neoadjuvant chemoradiation therapy. Many previous neoadjuvant CCRT studies have shown that although reduced local recurrence could be achieved, survival was not significantly improved because the frequencies of distant metastases remained high [2‐5]. Furthermore, a recent report showed that pulmonary recurrence predominates after combined chemoradiation therapy and surgical resection for locally advanced rectal cancer patients [14]. The study demonstrated that post-resection rectal cancer without neoadjuvant chemoradiation showed a higher risk of lung metastases for lower-lying rectal cancers, similar to the findings presented here. Thus, the ratio of different levels of rectal cancer patients included in different studies may significantly affect the observed recurrence patterns and rates in the same way that T or N stages do. Based on these results, the prevention of systemic metastases should be emphasized during the introduction of more effective neoadjuvant chemotherapy. This is especially important for subgroups of patients with one or more risk factors such as low- and mid-rectal cancers, high degrees of invasion of the bowel wall, and involvement of local lymph nodes.

The significant increase of distant metastases for distal and mid-rectal cancers may be multifactorial rather than related to an increase in local recurrence, as only 17.7% (32 of 181 patients) of lung metastases were followed by local recurrence with a mean time of 271 days (Table 6). These increased lung and other distant metastases may be explained by existing anatomic reasons. Anatomically, the rectum is approximately 15 cm in length commencing from the sacral promontory to the anorectal ring. The rectum is usually described as having three segments: an upper, a middle, and a lower. Lymphatic drainage accompanied with blood supplies to these three segments are from the superior, middle, and inferior rectal artery and vein. The superior rectal vein is drained into the inferior mesenteric vein and then to the portal system, while the inferior rectal vein drains into the common iliac vein and to the inferior vena cava, and middle rectum drainage may be both cephalad to the inferior vein and lateral to the internal iliac vein. Therefore a distal rectal tumor may easily metastasize initially to the lungs because the inferior rectal vein drains into the inferior vena cava, bypassing the portal venous system. Basically, distant metastasis of cancer is presumed to occur via lymphatic or vascular drainage routes, and the liver is the first organ of the reticuloendothelial system that would allow for the initial dissemination of colon and upper-rectal cancers entering through the portal vein. Thus, the liver is clinically reported to be the most common site of distant metastases. However, if the drainage of distal or mid-rectal cancer cells were via the inferior and middle rectal vein into the inferior vena cava (systemic circulation) rather than drainage into the portal system (such as the colon and upper rectum via the inferior mesenteric vein), then the metastasis patterns might differ based on the location of the rectal cancer. Unfortunately, very few papers have described the existing anatomic factors that significantly affect metastasis variances; for example, for lower rectal cancer, systemic venous circulation plays a more important role in the metastatic process.

Distant metastases basically follow mechanical vascular spreading, a ‘cascade’ process of metastasis of metastases described by Viadana et al.[15]. This process might be also affected by a process described by the ‘seed and soil’ theory [16], which indicates that delivery of cancer cells to different organs varies in efficiency [16, 17]. However, the seed and soil theory is not mutually exclusive with hemodynamic theories [17]. In this study, our data highlights the importance of vascular parameters related to the metastatic pattern. Most cases (156 of 176, 88.6%) followed the theory of mechanical vascular spreading (Table 6). However, the findings that 11.4% (20 of 176 cases; 6 lung metastases followed by local recurrence, 8 lung metastases followed by liver metastases, and 6 liver metastases followed by local recurrence; Table 6) may indicate variable efficiencies in cancer cell delivery to different organs. This result may point to the fact that site and growth rate in different organs may be two independent processes for metastases. In summary, our study emphasizes that mechanical vascular-spreading theories predominantly determine the disseminating site of metastases, whereas the rate of metastasis growth may also be controlled by other factors such as the seed and soil theory.

This study provides important insight into the effects of rectal cancer location on recurrence patterns; however, this study had some limitations. First, we did not have data on the distance of the circumferential resection margin in our database for this study period (2002 to 2006). Our data registry was revised in 2009 to include circumferential resection margin status. This is recorded in the histology report of the tumor specimen, which is prepared by a pathologist. However, the high local recurrence rate for low-lying tumors may be related to the high rates of a positive circumferential resection margin. Second, during the study period, we did not adopt the cylindrical excision technique by Holm [18]. We may well consider that this technique will improve surgical outcomes for low-lying rectal cancer in terms of local recurrence. However, to what extent this technique contributes to distant metastases rates, such as the high rate of lung metastases, remains unclear. Third, although T3/T4 rectal cancer patients with or without lymph node involvement were included in this retrospective study, preoperative neoadjuvant chemoradiation therapy was not routinely applied, as this was not adopted as a guideline in our hospital until 2007. During the years 2002 to 2006, 119 patients who accepted preoperative neoadjuvant radiation therapy or CCRT based on the individual surgeon’s preference were excluded from this study. Fourth, not all diagnosed distant metastases in this series were diagnosed through confirmed histological or cytological examination results, thus some patients may not have been differentially evaluated from those who had other secondary primaries or just post-infective scarring.

In summary, the level of the rectal cancer significantly affected surgical outcomes, including rates and patterns of distant metastases for the patients who underwent surgical resection. Lung, bone, and systemic lymph node metastases significantly increased as the level of the rectal cancer decreased.