Effect of capecitabine combined with irinotecan on the safety of colon cancer treatment, patients’ adverse reactions and quality of life

Purpose: To study the impact of the combination of capecitabine and irinotecan on the safety of colon cancer treatment, adverse reactions and wellbeing of patients. Methods: Colon cancer subjects (n =120) admitted to Guangzhou First People’s Hospital, Guangzhou, China were assigned equally to two groups (A and B) according to their order of admission, and they received intravenous infusion of irinotecan. In addition, group A patients were administered capecitabine, but those in B group were given tegafur, gimeracil and oteracil porassium. The patients in groups A and B were compared with respect to the incidence of unwanted effects, quality of life (QoL), and overall clinical efficacy of the treatments. Results: Cases of nausea and vomiting, delayed diarrhea and sensory neuropathy of the patients were significantly reduced in group A, relative to group B. Moreover, QoL score after treatment was markedly higher in group A than in group B, while the objective response rate (ORR) of colon cancer patients in group A was also significantly higher than that in group B (p < 0.05). However, no obvious difference in disease control rate (DCR) was observed between groups A and B (p > 0.05). Conclusion: Combined capecitabine and irinotecan therapy effectively improves clinical prognosis, reduces the incidence of adverse reactions, and is safe in colon cancer patients. Therefore, the combined treatment may be beneficial in the management of colon cancer.


INTRODUCTION
Colon cancer patients are often at the midway or advanced phases of carcinogenesis when diagnosed. Surgical treatment is generally used in clinical practice as the primary treatment modality for colon cancer. However, due to the sub-optimal degree of resection during surgeries, the patients also need to rely heavily on chemotherapy to improve their prognosis, which often brings toxic and side effects and symptoms e.g., diarrhea, thereby adversely affecting daily lives of patients [1][2][3]. Nowadays, people pay more attention to drug safety, and many new types of fluorouracil have been applied in clinical practice. Capecitabine, a fluorouracil drug, is an anti-tumor drug which improves overall efficacy, with less toxic and side effects on patients. Moreover, irinotecan, a popular drug for colon cancer, effectively facilitates enzymatic activity involved in metabolism of capecitabine. Therefore, these two drugs may exert good synergistic effects [4][5][6]. Based on this, the present study was on the influence of combined use of capecitabine and irinotecan in the treatment of 120 colon cancer subjects.

METHODS
A total of 120 colon cancer patients admitted to Guangzhou First People's Hospital, Guangzhou, China were assigned equally to two groups (A and B) according to their order of admission. There were no significant differences in the general profile of the two groups (p > 0.05).

Inclusion criteria
Patients and their families were informed about the scope of the research, and duly signed informed consent was obtained from them. Approval for this investigation was received from the Ethical Committee of Guangzhou First People's Hospital (approval no. 20181113), and the study followed the guidelines of Declaration of Helsinki as revised in 2013 [7]. Patients who were diagnosed with colon cancer after rectal touch, fibro-colonoscope and histopathologic examination were included in this study.

Exclusion criteria
Patients with mental disorders or who could not communicate with others; patients with other organic diseases, those aged over 75 years, patients with tumor metastasis, pregnant and lactating patients, and patients with expected survival period of less than or equal to 12 weeks, were excluded.

Treatments
Baseline examinations were carried out in all patients, including pathological examination, imaging examination (CT of thoracoabdominal region), blood routine examination, as well as liver and kidney function examination. Data on signs were recorded so as to confirm final treatment regimens for the patients.
Patients in both groups received intravenous infusion of irinotecan. In addition, the group A patients were administered capecitabine, while subjects in group B were given tegafur, gimeracil and oteracil potassium. The specific steps were as follows.

Irinotecan treatment
On the first day of chemotherapy, the patients were treated with 0.5 mg of atropine (Hunan Dongting Pharmaceutical Co. Ltd; National Medical Products Administration approval number: H43020586), and after 0.5 h, they received irinotecan (Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co. Ltd.; National Medical Products Administration approval number: H20113455) at a dose of 160 mg/m 2 via intravenous infusion within 1 h. One course of treatment lasted 3 weeks, and the patients were treated in six courses.

Capecitabine treatment
The patients orally took capecitabine (Lianyungang Runzhong Pharmaceutical Co. Ltd; National Medical Products Administration approval number: H2012345) at a dose of 750 mg/m 2 in the morning and evening after meals daily, and the drug administration was stopped for 1 week after every 2 weeks.

Treatment with tegafur, gimeracil and oteracil potassium
The patients took tegafur, gimeracil and oteracil porassium (Qilu Pharmaceutical Co. Ltd.; National Medical Products Administration approval number: H20100151) at a dose of 20 mg/m 2 daily and orally in the morning and evening, after meals. The drug was discontinued for 1 week after every 2 weeks.
The patients were given specific treatment measures based on their conditions during the study, so as to protect their gastrointestinal function.

Incidence of adverse reactions
Adverse reactions consisted of myelosuppression, nausea and vomiting, delayed diarrhea and sensory neuropathy. According to the Common Terminology Criteria for Adverse Events of US National Cancer Institute (NCI), toxic and side reactions in patients were classified as grade I (mild reactions), grade II (obvious reactions but no effect on life), grade III (severe reactions and effect on life), and grade IV (severe reactions and serious effects on life). The number of patients in each of the different grades was recorded [8].

QOL
This was determined with the Karnofsky performance score (KPS). The higher the score, the better the quality of life [9].

Overall efficacy
Patients' conditions were classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) according to the WHO Response Evaluation Criteria [10]. where DCR = disease control rate of GC; ORR = overall response rate; CR = complete response; PR = partial response; and SD = stable disease.

Statistical analysis
The selected data processing software used in this study was SPSS20.0, while GraphPad Prism 7 was selected for drawing graphs. Measured data were analyzed with Student's t-test, while counting data were analyzed using ꭓ 2 test. Value of p < 0.05 indicated statistically significant differences. Table 2 shows that there were no marked differences in cases of myelosuppression between patients in groups A and B (ꭓ 2 = 1.600, p = 0.206).

Incidence of nausea and vomiting
Nausea and vomiting occurred in 27 patients (45.0 %) in group A, relative to 40 patients (66.7 %) in B group i.e., cases of nausea and vomiting were markedly lower in group A (ꭓ 2 = 5.711, p = 0.017), as shown in Figure 1. Table 3 shows that cases of delayed diarrhea were markedly reduced in group A, relative to B group (ꭓ 2 = 4.227, p = 0.040).    Table 3 shows that the KPS score after treatment in group A was higher that the score in B group (p < 0.001).

Overall treatment efficacy
The ORR of the patients was markedly higher in group A than in B, but DCR values were comparable, as shown in Table 3.

DISCUSSION
At present, due to limited medical techniques in the treatment of colon cancer in China, patients still have to face the problems of severely reduced QOL after undergoing surgeries and systemic chemotherapy required to improve their prognosis. Chemotherapeutic drugs produce a variety of adverse effects in patients. These effects further lead to multiple complications in patients during chemotherapy. Therefore, it is of great significance to apply safer drugs in clinics [11,12]. Capecitabine is a novel antineoplastic agent, and a selective intra-tumoral activated fluorouracil urethane.
Studies have shown that its therapeutic efficacy is superior to those of conventional fluorouracil-    [13,14].
In this study, the incidences of nausea and vomiting, delayed diarrhea as well as sensory neuropathy in group A were markedly lower in group A than in group B, indicating that relative to tegafur, gimeracil and oteracil porassium, capecitabine has mild effect on the gastrointestinal tract, because it rapidly neutralizes foreign bodies when fighting against tumors, and it exerts less stimulation of gastrointestinal function, resulting in lower incidence of nausea and vomiting.
In this study, ORR was markedly higher in group A than in B group because the combination of irinotecan and capecitabine exerted enhanced efficiency in antitumor effect. Irinotecan impairs the synthesis of tumor cell nucleic acid, while capecitabine slows down the recombination of tumor cell nucleic acid [15][16][17]. Therefore, the lesions disappeared faster in group A.
Moreover, the results of this study revealed that QOL after treatment was markedly increased in group A, relative to B group, suggesting that safe and effective chemotherapeutic drugs are essential for optimizing patients' quality of life. In a study by Hiroi [18], it was reported that the KPS score in a group administered capecitabine plus irinotecan was 78.1 ± 5.26 points after treatment, which was significantly higher than the corresponding score in the control patients who received combination of apecitabine, tegafur, gimeracil and oteracil porassium. This indicates that the combination of capecitabine and irinotecan can effectively improve patients' QOL.

CONCLUSION
Combined treatment with capecitabine and irinotecan significantly relieves adverse reactions, improves QOL, and has high level of safety in colon cancer patients. Therefore, the combined treatment has merits over current treatment strategies.