Preoperative thrombocytosis predicts prognosis in stage II colorectal cancer patients

Colorectal cancer (CRC) remains a leading cause of cancer related death worldwide. A consistent fraction of patients will relapse, mostly within the first 3 years. There is clear evidence that 5-fluorouracil (5-FU)-based adjuvant chemotherapy has a beneficial effect on tumor relapse and overall survival in patients with a curative resected stage III colon cancer [1]. On the contrary, the benefit of adjuvant treatment is still debatable in stage II colon cancer [2]. Prognostic markers have been investigated to establish which stage II patients will suffer from recurrences and which could benefit from adjuvant treatment. Currently, several histopathologic factors associated with poor outcomes in stage II CRC include the depth of transmural tumor invasion, tumor differentiation, the presence of lymphovascular and perineural invasion, and the pattern of growth at the edge of the tumor [3, 4, 5, 6].

Thrombocytosis has been identified as an adverse prognostic indicator in lung cancer [7], esophageal cancer [8], renal cell carcinoma [9], and gynecological malignancies [10, 11], and breast cancer [12].

In case of CRC, there are some studies showing an inverse correlation between the survival of CRC patients and preoperative platelet count levels [13, 14, 15].

In this study, we investigated the impact of preoperative thrombocytosis on prognosis for patients with stage II CRC.

The medical records of 330 consecutive patients who confirmed to be stage II after curative surgical resection for CRCs at our hospital between December 2003 and December 2009 were retrospectively reviewed. We excluded patients who received preoperative chemoradiation therapy (n = 18), or had a history of other primary cancer (n = 28). The data that were analyzed included age at diagnosis, gender, primary tumor site, tumor T stage, and histological grade and preoperative platelet count. Staging was performed according to the TNM classification of the American Joint Committee on Cancer (7th edition, 2002). The study was approved by the Institutional Review Board at Ajou University School of Medicine.

Preoperative blood samples were obtained from patients with CRC within 2 weeks prior to operation. Thrombocytosis was defined as a pretreatment platelet count > 450 × 10⁹/L without known inflammatory conditions.

Regimens of chemotherapy were capecitabine or infusional 5-FU/leucovorin (LV), UFT, Doxifluridine, and 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX). We recommended adjuvant chemotherapy with Xeloda, infusional 5-FU/LV, and FOLFOX after complete surgical resection in stage II CRC patients with poorly differentiated tumor, T4 lesion, lymphovascular invasion, and perineural invasion. Patients without these features were recommended to receive UFT or Doxifluridine. Capecitabine was scheduled to be administered orally twice daily on days 1–14 every 3 weeks to 8 cycles. Infusional 5-FU (800 mg/m²) plus bolus injection of 30 mg of LV were planned to be administered for 5 consecutive days to six cycles. FOLFOX chemotherapy was planned to be administered to 12 cycles during a 6-month period. The patients received a 2-hour infusion of oxaliplatin (85 mg/m² on day 1, in addition to the standard LV/5-FU2 regimen (FOLFOX4). The UFT or Doxifluridine was given daily and intended to continue for 1 year. Planned schedule was stopped in case of disease relapse, patient refusal, or intolerable toxicity.

Median follow-up period were 92 months (range: 3–131 months). Disease-free survival and cancer-specific survival (CSS) is calculated for all patients from the date of surgery until recurrence and death from CRC.

Pearson chi-square or Fisher exact test was used to assess differences in the clinicopathological features. Continuous data were compared by Student t-test. Kaplan-Meier survival analysis with the log-rank test was used to evaluate the prognosis for CRC. Univariate comparisons between survival curves for each variable were performed by using the log-rank test. Variables with a P-value < 0.30 were entered into a multivariate analysis. Multivariate analysis was performed using the Cox regression model with a stepwise forward method to derive a final model of the variables. Data were analyzed using SPSS ver. 13.0 (SPSS Inc., Chicago, IL, USA).

Thrombocytosis has been reported to be associated with poor prognosis in a variety of solid tumours, including gynaecological [16], lung [7], renal [9], esophageal [8], and breast malignancies [12]. Association between thrombocytosis and CRC was also investigated by several studies. The majority of the studies demonstrate that thrombocytosis is a prognostic indicator for outcome [13, 14, 15], while one study suggests that it has no prognostic value [17]. However, the prognostic role of thrombocytosis in CRC remains determined because the inclusion criteria are different and definition of thrombocytosis differs.

We found that patients with thrombocytosis show decreased disease free survival in stage II CRC. In multivariate analysis, thrombocytosis is associated with poor prognosis in stage II rectal cancer. Stage II CRC was classified into T3 and T4 cancer according to the depth of invasion. This study suggests thrombocytosis may be a more powerful prognostic factor in stage II CRC although the definition of thrombocytosis is various between studies.

The definition of thrombocytosis in patients with CRC was used differently by previous studies. We analyzed survival analysis using different definition to get a significant difference in stage II CRC. According to the results of the analysis, thrombocytosis was defined as higher than 450 × 10⁹/L in this study. As a result, the incidence of thrombocytosis was lower in our studies compared to previous studies, although the sample size is much larger than previous studies.

There are several reports that demonstrated the association of thrombocytosis with survival in CRC [13, 14, 15, 18]. On the contrary, Nyasavajjala et al. [17] asserted that preoperative thrombocytosis is not a prognostic factor for CRC. They asserted the previous result to the small number of cases.

Sasaki et al. [15] investigated association of thrombocytosis with survival of 636 patients with CRC. They reported that the preoperative thrombocytosis is a potential predictive factor of poor survival and high recurrence rate in patients with CRC. They explained the difference from the previous study was due to the different definition of thrombocytosis and the length of the follow-up period.

Many abnormalities of the coagulation system have been reported to be associated with cancer progression and prognosis. Among them, the in vivo depletion of platelets markedly reduced experimental metastasis, and the formation of platelet aggregates around tumor cells has been shown to inhibit the in vitro tumor lysing activity of natural killer cells.

We hypothesized that the prognostic significance may be different according to the stage. Kandemir et al. [18] suggested that thrombocytosis is strongly associated with poor survival in patients with node-negative colon cancer, which indicate that abnormal thrombocytosis strongly correlates with local cancer progression of the primary tumor, but not with distant metastasis.

Sasaki et al. [15] analyzed the association between preoperative thrombocytosis and survival according to the stage. They reported that preoperative thrombocytosis was a prognostic factor in CSS in patients at stage II and in disease-free survival in patients at stages II and III. They showed that the most evident prognostic significance of thrombocytosis for both CSS and DFS could be observed in stage III cases.

Our study showed that the preoperative thrombocytosis was a significant prognostic factor for survival in patients with stage II CRC.

Adjuvant chemotherapy is the standard of treatment for stage III colon cancer. Regarding stage II disease, it is recommended for patients with high-risk factors, including T4 tumor, lymphovascular invasion, and poorly differentiated tumor. In this study, adjuvant chemotherapy was performed in patients with high-risk factors. This is why these factors were not prognostic factors in this study. However, preoperative thrombocytosis was a prognostic factor in stage II CRC in multivariate analysis. Preoperative thrombocytosis should be considered in the decision of adjuvant chemotherapy in stage II CRC. All patients with thrombocytosis underwent chemotherapy, but most of them received oral chemotherapy and did not complete the intended schedule. In this study, it is difficult to evaluate the impact of chemotherapy because the chemotherapy regimens are various, most of them are oral regimens, and chemotherapy is incomplete.

Our study has a few limitations. First, the number of patients is small to provide enough power to draw any definitive conclusions regarding oncologic outcomes. Second, a single-institution retrospective analysis has inherent selection bias. Third, the definition of thrombocytosis should be discussed in the future.

In conclusion, this study showed that thrombocytosis is a prognostic factor predicting DFS in stage II CRC patients, although the cutoff of thrombocytosis needs to be discussed. And further studies using a larger sample size are warranted to establish the role of thrombocytosis in stage II CRC more precisely.