Abstract
Background/Aim: The aim of this study was to evaluate the usefulness of circulating tumor cells (CTCs) after preliminary chemotherapy for prediction of response to further anticancer therapy in patients with initially unresectable metastatic colorectal cancer. Patients and Methods: CTCs from 14 consecutive patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type colorectal cancer with synchronous or metachronous unresectable metastatic lesions were measured using the CellSearch system between January 2009 and December 2011. CTCs were measured before and after chemotherapy. The regimen consisted of four courses (three months) of oxaliplatin with oral S-1 (SOX) + panitumumab. Results: Ten (71%) out of all patients had no detectable CTCs after chemotherapy. Eight out of these ten patients received further chemotherapy, and liver metastases were completely resected in the other two patients; none of these patients died of cancer within a year after starting chemotherapy. The remaining four patients with CTCs continued to have CTCs after chemotherapy, and all four of these patients died of cancer within eight months after starting chemotherapy. The prognosis of the patients who had no detectable CTCs after the chemotherapy was significantly better than that of those who had CTCs even after the chemotherapy (p<0.01). Conclusion: CTCs after preliminary chemotherapy may be useful in predicting the response to further anticancer therapy.
Patients with initially unresectable metastatic colorectal cancer may conceptually be divided into three groups. In the first group, initially unresectable metastatic lesions may shrink remarkably and can then undergo resection after chemotherapy with fair outcome (1-3). In the second group, the patients receive continuous chemotherapy without resection and with improved survival, which is called ‘palliative chemotherapy’ (4-7). The third group consists of those whose disease progresses even after chemotherapy and further chemotherapy is abandoned. When the diagnosis of initially unresectable metastatic colorectal cancer is entertained, it is actually difficult to classify patients into these three groups. The aim of this study was to evaluate the usefulness of determining circulating tumor cells (CTCs) after preliminary chemotherapy in predicting outcome in patients with unresectable metastases from colorectal cancer.
Patients and Methods
Patient eligibility. The protocol was approved by the Ethics Committee for Biomedical Research of the Jikei Institutional Review Board 21-010 (5588) for a 3-year period between January 2009 and December 2011, and all patients provided their written informed consent. This prospective study was conducted in patients whose eligibility required compliance with the following criteria: Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type colorectal adenocarcinoma with synchronous or metachronous unresectable metastatic lesions, such as liver metastases, who underwent curative resection of the primary lesion, so-called R0 operation, as defined in the Japanese Classification of Colorectal Carcinoma (8); sufficient oral intake; no prior treatment except for surgery; and age between 30 and 80 years. Patients also had to have adequate organ function (4,000≤leukocytes<12,000/mm3; thrombocytes, ≥100,000/mm3; serum total bilirubin, ≤1.5 mg/dl; aspartate aminotransferase (AST) and alanine aminotransferase (ALT), <100 IU/l; and creatinine, ≤1.5 mg/dl). Patients were expected to receive medication and to be followed-up regularly for more than 24 weeks. Patients with a history of drug hypersensitivity, serious surgical and non-surgical complications, or active secondary cancer were excluded. Pregnant or lactating women were also excluded.
Clinicopathological features of the patients included in this study.
Treatment schedule. Physical examination, routine blood analysis, serum carcinoembryogenic antigen (CEA) measurement, computed tomography (CT) and CTC measurement were counted out before and after chemotherapy. CTCs were counted by the CellSearch system (Veridex, Raritan, NJ, USA).
The chemotherapy regimen consisted of four courses (three months) of oxaliplatin with oral S-1 (tegafur, gineracil, oteracil potassium; Taiho Pharmocentical, Tokyo, Japan) plus panitumumab. The regimen of one course of chemotherapy consisted of oxaliplatin at 130 mg/m2 and panitumumab at 6 mg/kg administered on the first day respectively, followed by 14-day administration and six days withdrawal of S-1 at 80 mg or 100 mg per day according to the body surface area (BSA): 80 mg/day for BSA<1.5m2; and 100 mg/day for BSA>1.5m2. S-1 was administered orally twice daily after meals.
Isolation of CTCs. Blood samples were drawn into 10-ml evacuated tubes (CellSave; Immunicon, Huntingdon Valley, PA, USA). Samples were maintained at room temperature and processed within 72 h after collection. The determination of CTCs in blood was performed with the semi-automated CellSearch System (Veridex). CTCs were defined as epithelial cell adhesion molecule (EpCAM) isolated intact cells staining positively for cytokeratin and negatively for CD45, and we judged CTC-negative cases to be those with fewer than three CTCs per sample.
Statistical analysis. All data were analyzed using the Statistical Package for Social Sciences (SPSS 18). The statistical significance was determined by the Mann-Whitney U-test and the Chi-square test. The survival rate was calculated by the Kaplan Meier method, and the statistical significance was determined by the generalized Wilcoxon test. A p-value of less than 0.05 indicates statistical significance.
Response to chemotherapy in the patients who received chemotherapy.
Results
Characteristics of the patients (Table I). Between January 2009 and December 2011, 14 patients were enrolled into the study. Their characteristics are summarized in Table I. Nine patients (64%) received the chemotherapy as first-line therapy, and the other five patients (36%) received the regimen as the third line. Serum CEA levels of twelve patients (86%) were more than 50 ng/ml, which was ten times as high as the normal limit. Five patients (36%) had no CTCs before chemotherapy, even though they had unresectable metastatic lesions.
Response to chemotherapy in the patients who received chemotherapy (Table II). Nine patients had received no previous chemotherapy and were able to tolerate four course of chemotherapy according to the regimen. Of these, two patients underwent hepatic resection as a conversion therapy. Two out of the other five patients who had undergone previous chemotherapy were unable to tolerate four courses of chemotherapy because of the deterioration of their general condition due to the chemotherapy.
Only two out of the nine patients who received no previous chemotherapy had serum CEA levels of less than 50 ng/ml before chemotherapy. After chemotherapy, serum CEA levels of another five out of the nine decreased to less than 50 ng/ml. On the other hand, none of the five patients, who received previous chemotherapy had a serum CEA level of less than 50 ng/ml before the chemotherapy, while only in one patient did the serum CEA level decrease to less than 50 ng/ml after the chemotherapy.
Clinicopathological features of the patients with and without circulating tumor cells (CTCs) after chemotherapy.
Five out of the nine patients who received no previous chemotherapy had no detectable CTCs before chemotherapy, while none of the nine patients had detectable CTCs after the chemotherapy. On the other hand, CTCs were detectable in all five patients who received previous chemotherapy before the chemotherapy, while only one out of the five had no detectable CTCs after the chemotherapy.
Comparison between CTC-negative and -positive patients after the chemotherapy (Table III). Ten patients who had no CTCs after chemotherapy had a significantly lower serum CEA level than the other four patients with CTCs both before and after chemotherapy. Furthermore, all ten patients without CTCs after chemotherapy were alive over a year after starting chemotherapy. On the other hand, all four patients with CTCs even after the chemotherapy died of cancer within eight months after starting chemotherapy. In particular, three patients increase in CTCs after chemotherapy died of cancer within six months after starting chemotherapy.
The survival period of the patients who had no detectable CTCs after the chemotherapy was significantly better than that of the patients who had CTCs even after the chemotherapy (p<0.01) (Figure 1).
Discussion
CTCs can be released from the primary tumor and metastatic lesions into the bloodstream. In early stages, the immune surveillance system eliminates such cells from the circulation, but CTCs may persist longer and be detected later. Recent studies have highlighted the prognostic significance of the presence and number of CTCs (9-12). CTCs in the peripheral blood have been reported as a prognostic factor in colorectal cancer (9-12). A decrease in CTCs after anticancer treatment may be associated with disease remission (11). CTCs and response to chemotherapy in patients with unresectable metastases from colorectal cancer may have a strong relationship (13). Thus, we tried to evaluate the usefulness of the CTC count after preliminary chemotherapy for initially unresectable metastatic colorectal cancer to predict the response to further anticancer therapy.
Comparison of survival between patients with and without circulating tumor cells (CTCs) after preliminary chemotherapy. The survival of the patients without detectable CTCs after chemotherapy was significantly better than that of those with CTCs even after chemotherapy (p<0.01).
Ten out of all patients had no detectable CTCs after the chemotherapy, and eight of these received further chemotherapy while liver metastases were completely resected in the other two patients. On the contrary, the other four patients continued to have CTCs after the chemotherapy and died of cancer within eight months after starting chemotherapy. The prognosis of the patients who had no detectable CTCs after the chemotherapy was significantly better than that of the patients who had CTCs even after the chemotherapy. Although the combined use of 5-FU/leucovorin, as well as the addition of irinotecan or oxaliplatin (FOLFIRI, FOLFOX) (4, 5) to therapy, has increased the median survival time to over 20 months for patients with unresectable metastases from colorectal cancer, the effect of such chemotherapy was not found for cases with advanced metastases.
A method by which patients with unresectable metastases are distinguished into responders and non-responders to chemotherapy is necessary. Our preliminary chemotherapy including the molecular targeted drug panitumumab may be useful in predicting the response to further chemotherapy in patients with unresectable metastatic colorectal cancer. The patients who had CTCs even after preliminary chemotherapy may benefit from best supportive care rather than further chemotherapy. Avoidance of unnecessary chemotherapy is important both for patients indicated best supportive care and in terms of medical economy.
In the present study, two out of ten patients having no detectable CTCs after the chemotherapy underwent hepatectomy for initially unresectable liver metastases. When marked tumor shrinkage is obtained by systemic chemotherapy, initially unresectable metastatic lesions may become resectable. This is called ‘conversion therapy’. Adam et al. (1) reported that 13% of unresectable liver metastases became resectable following chemotherapy and that the 5-year survival rate after resection in these cases was 33%. A favorable long-term prognosis can thus be expected by conversion therapy.
In conclusion, CTCs after preliminary chemotherapy may be useful in predicting response to further chemotherapy and surgical treatment in patients with unresectable metastases from colorectal cancer.
Footnotes
-
Conflicts of Interest
We declare that we have no conflict of interests.
- Received February 18, 2013.
- Revision received March 18, 2013.
- Accepted March 19, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
In this issue
Jump to section
Related Articles
Cited By...
- CA19-9 Concentration After First-line Chemotherapy Is Prognostic Predictor of Metastatic Colon Cancer
- Serum Carcinoembryonic Antigen Levels Before the First Curative Hepatectomy for Metastatic Colorectal Cancer Is a Predictor of Recurrence
- Impact of Chemotherapy with S-1 and Oxaliplatin (SOX) in Combination with Molecular-targeting Agents on Colorectal Liver Metastases