Abstract

Background: This study aims to evaluate prognostic factors on survival in pulmonary metastases of colorectal cancers.

Methods: In this single-center study, 33 patients (17 males, 16 females; mean age 55.6 years) who underwent metastasectomy due to lung metastases of colorectal cancer in our clinic between March 1998 and June 2011 were retrospectively analyzed. The prognostic factors associated with survival were investigated.

Results: The median survival of the patients was 74 months (range 6 to 99 months) and five-year survival rate was 62%. The median, one, three, and five-year survival rates were 49 months, 94%, 70%, and 33% in males respectively, while the corresponding figures for female patients were 92 months, 100%, 89%, and 89%, respectively (p=0.001). In patients with a pre-thoracotomy carcinoembryonic antigen (CEA) level below 5 ng/mL, one, three and five-year survival rates were 100%, 89%, and 75% respectively, while the corresponding figures for those patients with a CEA level above 5 ng/mL were 83%, 42%, and 0%, respectively (p=0.001).

Conclusion: Although metastasectomy is associated with improved survival in lung metastases of colorectal cancer, prognostic factors have not been fully elucidated. Our findings suggest that female gender and a preoperative CEA level below 5 ng/mL are more eligible candidates for metastasectomy.

The lung is a common site of metastasis from various cancers, and patients with lung metastases have an unfavorable prognosis. Lung and liver metastases occur in more than half of the patients who undergo resection for colorectal cancer. Left untreated, these metastases are known to be associated with an average survival rate of approximately 10 months and a fiveyear survival rate of less than 5%.[1-3]

Many studies have shown that metastasectomies in appropriately selected cases may improve the chance of survival for patients with different primary tumors. In addition, there has been limited data suggesting that metastasectomies may improve the five-year survival rate to between 21 and 61.4% in patients with colorectal tumors, provided there is no metastasis in other organs and the patients’ health status allows for this kind of surgery.[4-6] The wide variation in reported survival rates reflects not only the absence of clearly defined prognostic criteria but a consensus regarding the appropriate cases that would benefit from a metastasectomy as well. The prognostic factors included in our patient group were age, gender, the localization of the metastatic node, the stage and localization of the primary tumor, the size of the metastatic nodes, lymph node metastases, recurrent metastases, the carcinoembryonic antigen (CEA) levels, and the disease-free survival rate.[7,8]

In this study, the results of a pulmonary metastasectomy and the prognostic factors in a group of patients with colorectal cancer were evaluated.

Methods

Of the 3,700 patients that underwent surgery between March 1998 and June 2011 in our unit, 440 (11.8%) underwent a thoracotomy for a metastasectomy. However, only 33 (7.5%) patients (17 males and 16 females; median age 55.6 years; range 31-88 years) who underwent a complete pulmonary metastasectomy for the metastasis of colorectal cancer were included in this retrospective study. Those who underwent an incomplete metastasectomy or a metastasectomy for other tumor types were excluded.

Preoperatively, thoracic computed tomography (CT), abdominal CT to assess the primary tumor, and positron emission tomography (PET)-CT to evaluate other possible metastases were performed on all of the patients. In addition, the CEA levels were measured in all of the subjects before the surgery.

In order for a metastasectomy to be performed, all of the patients needed to have the following: a complete resection of the primary tumor with no local recurrence or extra pulmonary metastasis, the presence of appropriate lesions for a complete resection in terms of number and localization, an adequate respiratory reserve, and no comorbidities preventing thoracic surgery. Those who were unable to meet these criteria underwent chemotherapy and radiotherapy and were not included in the study.

The patients were followed up by having a chest X-ray one month after the surgery and undergoing thoracic and abdominal CT every six months as well as a yearly PET-CT examination.

Due to the high proportion of smokers in our study group, the threshold for CEA was set at 5 ng/mL. Disease-free survival was defined as the length of time from the surgery for the primary tumor to the detection of lung metastases, and survival was defined as the period between the diagnosis of lung metastasis and death. We also explored the effects of age, gender, primary tumor localization, CEA levels, recurrence, and disease-free survival with respect to the overall survival and mortality rates of the patients.

Statistical analysis was performed using the PASW Statistics for Windows version 18.0 (SPSS Inc., Chicago, IL, USA) software program. Continuous data was expressed as mean ± standard deviation (SD) when there was normal distribution, and medians were used when the data was not normally distributed. Survival curves were obtained using the Kaplan-Meier product limit estimation method, and the survival curves of different groups were compared using a log-rank test. A p value of below 0.05 was considered to be significant.

Results

The colon was the primary tumor site of in 13 (39%) of the patients while for 20 patients (61%), it was in the rectum. In addition, the CEA concentration was above 5 ng/mL in six patients but was below that level in the other 27. Furthermore, a right-sided thoracotomy was performed on 18 (55%) of the patients, whereas it was left-sided in 14 (42%) others, and bilateral in one (3%). Moreover, the resection was non-anatomic (wedge/ precision cautery excision) in 27 (82%) of the patients while six (18%) had a lobectomy due to a centrally localized metastatic lesion (Table 1). No mortality occurred in our study.

Table 1: Patient characteristics

A total of 52 metastatic nodules were excised from the 33 patients. Table 2 shows the site of the primary tumor and the number and location of the metastatic nodules as well as the disease-free survival and overall survival rates.

Table 2: Carcinoembryonic antigen levels and the follow-up data of the patients who underwent a metastasectomy

Thirteen of our patients (39%) had recurrent disease, and in five of these (15%) it was confined to the lungs. These five subsequently underwent a re-thoracotomy for the metastasectomy. In the other eight patients, chemoradiotherapy was administered due to widespread metastases (Table 2).

The median survival rate for the 33 patients was 74 months (6-99) while the one-, three-, and five-year survival rates were 97%, 79%, and 62%, respectively (Figure 1).

Figure 1: Overall survival rate.

When we divided the patients into two subgroups on the basis of age (≥70 years and <70 years), they did not differ significantly in terms of survival rate 50% and 66% (p=0.952) (Table 3). In addition, the median survival rate for the male patients was 49 months (95% CI 26-72), and the one-, three-, and five-year survival rates were 94%, 70%, and 33%, respectively. For the female subgroup, the median survival rate was 92 months (95% CI, 80-105), and the one-, three-, and five-year survival rates were 100%, 89%, and 89%, respectively. The difference in the overall survival between the genders was statistically significant (p=0.001) (Figure 2).

Table 3: Correlation between age, gender, primary tumor localization, disease-free intervals, prethoracotomy carcinoembryonic antigen levels, and recurrence and the patient survival rates

Figure 2: Survival curve by gender. Solid line: Males; Dotted line: Females.

We also evaluated the patients by dividing them into two subgroups by whether their primary tumor location was the colon or the rectum and found that for 13 (39%), it tumor was in the colon while for the other 20 (61%), it was in the rectum. The median survival rate for the patients with a primary tumor in the colon was 89 months, whereas it was 71 months for those with a rectal tumor. Furthermore, the five-year survival rates in the colon subgroup was 86%, and in the rectum subgroup, it was 51%, (p=0.057) (Table 3).

A pre-thoracotomy CEA level of below 5 ng/mL was associated with the 100%, 89%, and 75% survival rates at one-, three-, and five-years, respectively, whereas the corresponding figures for those with a CEA level above 5 ng/mL were 83%, 42%, and 0% (p=0.001) (Figure 3).

Figure 3: Survival curve by CEA level. Solid line, CEA >5 ng/mL; Dotted line, CEA <5 ng/mL. CEA: Carcinoembryonic antigen.

The patients with a disease-free interval (DFI) of less than 12 months had a median survival rate of 71 months while those with a DFI of over 12 months had a slightly higher median survival rate of 74 months. However, this difference was not statistically significant (p=0.346). When we divided the patients into subgroups according to whether their DFI was ≤36 months or >36 months [a risk factor in the International Registry of Lung Metastases (IRLM) criteria], no significant differences were noted with regard to the survival rates (p=0.414) (Table 3).

Additionally, we found that the patients with recurrent disease following the pulmonary metastasectomy had a five-year survival rate of 71 months (range 54-86), whereas the corresponding figure for those without a recurrence was 74 months (range 37-110) (p=0.734) (Table 3).

Discussion

Colorectal cancers represent the second most common cause of cancer-associated deaths. Of these patients, 10-20% have lung metastasis, and 2-4% of all lung metastases originate from the colon or rectum. Even with chemotherapy, five-year survival rates in cases involving lung metastasis of colorectal cancer are very low (<5%), with complete resection being regarded as a potential curative treatment for these patients.[9-11] As previously mentioned, there have been wide variations in the reported survival rates, and this has led to a continuing debate concerning the prognostic factors responsible for these differences. Some of the potential prognostic factors cited in earlier studies included age, gender, the number of metastatic nodules, the extent of metastases, disease-free survival, the CEA levels, mediastinal lymph node involvement, the presence of extrathoracic metastases, and recurrence,[8,13] and of these, CEA is generally considered to be an important prognostic marker in primary colorectal cancer, with elevated follow-up levels being suggestive of metastasis. On the other hand, the prognostic significance of CEA in candidates for thoracotomies due to lung metastases of colorectal cancer has not been clearly defined. In a multicenter study conducted between 1972 and 2002 that involved 128 cases in which CEA levels of between 2.5 and 7 ng/mL were accepted as normal, Inoue et al.[2] determined t hat t he patients with normal CEA levels had a significantly higher five-year survival rate (51.9%) than those with higher CEA levels (38.3%) (p=0.0184). Similarly, in a study by Rena et al.[10] analyzing 80 patients, the fiveyear survival rate was also higher in the patients with normal CEA levels (58.2% vs. 0%) (p=0.0001).

In addition, Rama et al.[12] reported a five-year survival rate of 61% following resection in patients with normal CEA levels, whereas the corresponding five-year survival and median survival rates for those with elevated CEA levels were 19% and 21 months, respectively. Moreover, in a 10-year study by Lee et al.,[14] CEA levels of more than 5 ng/mL were associated with poorer survival (p=0.001).

Furthermore, in a review by Warwick ad Page[15] entitled, a pre-thoracotomy CEA level of higher than 5 ng/mL was associated with a five-year survival rate of 22.7%, whereas it was 48.3% for those with normal CEA levels.

Our findings were at odds with the reports that have hypothesized that preoperative CEA levels have no prognostic significance, but they support those authors who attributed some prognostic significance to these levels.[16-21]

The majority of the studies conducted on this patient population have reported that gender had no effect on the prognosis. In the study by Riquet et al.,[22] the median survival rates for female and male patients were 38 and 48 months, respectively (p=0.17), and Pfannschmidt et al.[23] reported a rate of 40 months in female patients and 39.6 months in the males. In addition, they determined that the fiveyear survival rates for the female and male patients were 32.3% and 32.6%, respectively (p=0.98). Similar observations have also been published by Inoue et al.[24] and Chung et al.[25] In contrast, Onaitis et al.[26] observed a higher recurrence risk following pulmonary metastasectomies in male patients but found no significant differences with regard to survival.

If contrast to these studies, we identified a remarkably better median survival rate in our female subjects of 92 months and a five-year survival rate of 89% compared with a median survival rate of 49 months and a five-year survival rate of 33% for our male patients (p=0.001).

Although the 1997 IRLM report determined that a disease-free survival rate of more than 36 months can have a favorable effect on a patient’s prognosis, Pfannschmidt et al.[6] reviewed 20 series on this topic and found only two that reported that disease-free survival had an independent effect on prognosis. Furthermore, in the single-center retrospective study by Onaitis et al.[26] that was comprised of 378 cases, they observed that a disease-free survival rate of less than 12 months had a significant effect on their patients’ prognoses.

In our study, the patients with a disease-free survival rate of less than 12 months had a survival for 71 months on average, whereas those with a disease-free interval of more than 12 months survived for 74 months (p=0.346). Similarly, our patients, with an median disease-free survival rate of <36 months had an overall survival rate of 74 months, whereas the overall survival rate was 76 months for those with a median disease-free interval of ≥36 months (p=0.414).

Studies that have examined the effect of the primary tumor site with regard to survival after a pulmonary metastasectomy have generally reported no differences between colon and rectal tumors, and they found fiveyear survival rate in patients who undergo a pulmonary metastasectomy due to colon or rectal cancer of 86% and 51%, respectively (p=0.057).[2,6,14,27]

Local recurrence or new metastases following metastasectomies can conceivably affect the prognosis adversely, at least in an indirect manner through the increased morbidity and/or mortality associated with re-thoracotomies. However, contrary to what one might expect and similar to our results, many studies have found no association between recurrences and significant differences in survival rates.[14,16-17,22,28-30] The various views expressed by different authors and the study center comparisons are shown in Table 4.

Table 4: Summary of related publications

Conclusion

Although our study provides evidence to support other authors who have suggested that CEA levels significantly affect lung metastasis of colorectal cancer, our findings with respect to the effect that gender has on the prognosis is at odds with many previous reports. Therefore, multicenter studies involving larger sample sizes are needed to better define the prognostic role that gender plays in this patient group and to more clearly delineate the CEA threshold levels associated with poor survival.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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