Abstract
Background: 5-Fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) therapy and 5-FU, leucovorin, and irinotecan (FOLFIRI) therapy are standard chemotherapies to treat advanced/recurrent colorectal cancer. However, these chemotherapies require continuous infusion of 5-FU for a prolonged time of 40 h or more, every two weeks. Accordingly, these chemotherapies require hospitalization and placement of a central venous catheter. Because of frequent catheterization, long-term use of these therapies potentially risks complications such as infection and thrombosis. In contrast, S-1 (tegaful, gimeracil, oteracil) combined with irinotecan (IRIS) therapy involves giving one drug orally and infusing the other for about two hours every two weeks, so placement of a central venous catheter is not necessary. The current study examined the efficacy and safety of IRIS therapy in 90 patients at this Hospital who underwent such therapy to treat advanced/recurrent colorectal cancer. Patients and Methods: The study comprised 90 patients who underwent IRIS therapy to treat advanced/recurrent colorectal cancer from December 2004 to December 2011. Results: The ratio of male-to-female patients was 64:26. The mean age at the start of IRIS therapy was 64.5 years, and patients underwent an average of 11 courses of therapy. The response rate to IRIS therapy was 14.8%, the disease control rate was 60.5%, and the overall survival time was 26.7 months. The incidence of adverse events was 70.0%, and the incidence of grade 3 or more severe adverse reactions was 17.8%. Conclusion: In comparison to the standard therapies of FOLFOX and FOLFIRI, IRIS therapy had a lower response rate but led to an equivalent overall survival time. IRIS therapy had a low incidence of serious adverse events and allowed patients to continue therapy on an out-patient basis. These findings indicate that IRIS therapy may be a useful form of chemotherapy to treat advanced/recurrent colorectal cancer.
Five-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) therapy and 5-FU, leucovorin, and irinotecan (FOLFIRI) therapy have been established as chemotherapies to treat advanced/recurrent colorectal cancer as a result of several large-scale clinical trials. However, these therapies require continuous infusion of 5-FU over a prolonged time. Accordingly, these therapies require placement of a central venous catheter and hospitalization. There are several problems with these therapies, e.g. complications such as infection and thrombosis as a result of placement of a catheter and prolonged restraint of the patient. In contrast, therapy combining oral S-1 (tegaful, gimeracil, oteracil) and irinotecan (IRIS therapy) is simple and easy to continue. Multi-center studies have reported satisfactory outcomes with IRIS therapy. The current study examined the effectiveness and safety of IRIS therapy in patients undergoing that therapy at this Hospital.
Patients and Methods
Ninety patients who underwent IRIS therapy from December 2004 to December 2011 were retrospectively studied. The dose of S-1 ranged from 80-120 mg in accordance with the patient's body surface area, and S-1 was administered orally on days 1-14 of a 28-day cycle. Irinotecan (80 mg/m2) was infused intravenously over a period of two hours on day 1 and day 15. Judgment of response effect was according to the definition of the Response Evaluation Criteria In Solid Tumors (RECIST) (1) as follows: Complete response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (note: the appearance of one or more new lesions is also considered progression); stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The Response rate (RR) was defined as the sum of CR and PR and the disease control rate (DCR) as the sum of CR, PR and SD.
Results
In total, 90 patients underwent IRIS therapy. Out of these, 35 patients had advanced cancer in which metastases were noted in multiple organs at around the same time as surgery, 46 were found to have recurrence after surgery, and nine received the therapy as adjuvant therapy. The ratio of male to female patients was 64:26. The mean age at the start of IRIS therapy was 64.5 years (range: 26-82 years), and patients underwent an average of 11 courses of therapy (range=1-60 courses). The primary tumor was located in the colon in 44 patients (the cecum in six patients, the ascending colon in eight, the transverse colon in six, the descending colon in three, and the sigmoid colon in 21) and in the rectum or anus in 46 patients (the rectosigmoid in 17 patients, the upper rectum in 16, the lower rectum in 12, and the anal canal in one). All of the patients had undergone surgery. Resection was performed in 81 patients and not performed in nine.
Nine out of 90 patients had received IRIS as adjuvant chemotherapy, so the efficacy of IRIS therapy was examined in 81 patients. IRIS therapy was begun as first-line therapy in 47 patients, as second-line therapy in 27, and as third-line therapy in seven. The RR for patients who began IRIS therapy as first-line therapy was 25.5%. None of the patients who began IRIS therapy as second-line or third-line therapy had a CR or PR. The RR for patients overall was 14.8%. The DCR for patients who received IRIS therapy as first-line therapy was 66%, the DCR for those who received it as second-line therapy was 59.2%, and the DCR for those who received it as third-line therapy was 28.6%. The DCR for patients overall was 60.5% (Table I). The largest metastatic lesions served as target lesions and the effectiveness of IRIS therapy was examined in different organs that cancer had reached. In terms of the RR, IRIS therapy had a maximum effectiveness of 33.3% in treating the primary tumor but was unsuccessful in treating peritoneal metastasis. The RR for treatment of lung, liver, or lymph node metastasis was 11.1-18.2%, and major differences in the RR were not noted. The DCR for treatment of the primary tumor was 33.3% although the DCR for treatment of metastatic in the liver was 57.5%, the DCR for treatment of metastatic in the lungs was 66.7%, the DCR for treatment of metastatic in the lymph nodes, was 72.7%, and the DCR for treatment of peritoneal metastatic was 66.7%. The DCR for treatment of lymph node metastasis, lung metastasis and peritoneal metastasis was over 60%. (Table II). In terms of prognosis, 34 patients survived while 47 died. Out of the patients who survived, 30 were found to have further recurrence after the start of therapy while four were found to have no further recurrence (Table III). In terms of the overall survival time, patients who began IRIS therapy as first-line therapy survived 28.8 months, those who began IRIS therapy as second-line therapy survived 23 months, and those who began IRIS therapy as third-line therapy survived 17.4 months. The overall survival time for patients overall was 26.7 months (Table IV). The overall survival rate was 88.0% at one year and 72.4% at two years (Figure 1). The prognosis of the nine patients who received IRIS therapy as adjuvant chemotherapy is shown in Table V. Metastasis was noted in four patients, two of whom died (Table V).
Effect in timing of IRIS therapy.
Therapeutic effect in different organs.
In this study, some adverse events occurred in 63 out of 90 cases (70.0%) (Table VI). Grade 3 or more serious adverse events in accordance with the CTCAE (common terminology criteria for adverse events) (2) occurred in 16 patients at a frequency of 17.8%. None of the patients had to discontinue therapy due to adverse events. Of the 63 patients who experienced adverse events, 33 had their dose of S-1 reduced and 20 had their dose of irinotecan reduced so that they could continue therapy.
Prognosis of IRIS therapy.
Overall survival.
Discussion
Studies have reported that IRIS therapy is not inferior to FOLFIRI therapy as a second-line chemotherapy to treat metastatic colorectal cancer, and have also reported that IRIS therapy is effective as a first-line therapy and that it is effective in patients with advanced/recurrent colorectal cancer that is resistant to oxaliplatin (3-5). These studies were all multi-center studies. The current study examined IRIS therapy in a single Institution. This study found that IRIS therapy had an RR of 14.8%. This result differs little from the results of a multi-center study of IRIS therapy (3). The RR for FOLFOX/FOLFIRI therapy is reported to be 45%-56% (6-8), so IRIS therapy dose have a lower RR than FOLFOX/FOLFIRI therapy. Nevertheless, the results of the current study indicated an overall survival time of 26.7 months in contrast to a reported 10.8-23.1 months for FOLFOX/FOLFIRI therapy (6-10). These results are comparable. IRIS therapy is less effective at shrinking the tumor, but it is fully capable of not exacerbating disease.
Several studies have described that adjuvant chemotherapy after surgery for colorectal cancer to be effective (11, 12). Similarly, IRIS therapy was used as adjuvant chemotherapy for nine of the current patients, some of whom had stage II cancer. Colorectal cancer recurred in four of the patients, two of whom died. Additional cases need to be accrued and studied to determine the efficacy of IRIS therapy as adjuvant chemotherapy.
With regard to the adverse events associated with FOLFOX/FOLFIRI therapy, studies have reported finding leukopenia in approximately 70% of patients (6, 13). IRIS therapy in the current study resulted in leukopenia in 40% of patients. There were few (17.8%) grade 3 or more serious adverse events which might hamper the continuation of therapy. IRIS therapy is a therapeutic regimen with satisfactory tolerability (14, 15).
Kaplan-Meier curve for overall survival for 81 patients.
IRIS as adjuvant chemotherapy.
Over the past few years, a handful of studies in the area of chemotherapy to treat colorectal cancer have reported that combining chemotherapy with molecularly targeted drugs increases the efficacy of that therapy (8-10, 16, 17). Studies have reported that combining bevacizumab with IRIS therapy increases its efficacy (15, 18). Therapeutic outcomes should further improve in the future.
Conclusion
At this Hospital, the response rate to IRIS therapy was 14.8%. This figure is somewhat lower than the response rate to the standard therapies of FOLFOX/FOLFIRI therapy, but IRIS therapy resulted in an overall survival time of 26.7 months, which is comparable to the survival time reported for FOLFOX/FOLFIRI therapy. In addition, IRIS therapy had a low incidence of serious adverse events and allowed patients to continue receiving treatment for a prolonged period on an outpatient basis. In the future, IRIS therapy may become a key regimen for chemotherapy to treat colorectal cancer.
Adverse events.
Acknowledgements
The Authors wish to thank Miss Risa Kojima, a secretary who helped with the preparation of this article.
- Received April 4, 2014.
- Revision received June 16, 2014.
- Accepted June 17, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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