Clinical Study of Combining Chemotherapy of Oxaliplatin or 5-Fluorouracil/Leucovorin with Hydroxycamptothecine for Advanced Colorectal Cancer

Discussion

L-OHP, the third generation platinum analogue, conjugates DNA to form N-Pt-N combo. N-Pt-N combo can cause DNA tridimensional structure handicap and twist to prevent DNA from synthesizing and repairing more effectively, as a result, cells begin to die. The rate of L-OHP conjugating DNA is that of decuple cisplatin and there isn’t complete cross drug resistance between L-OHP and cisplatin^[5]. L-OHP is still effective for ACRC patients who have developed resistance to DDP and 5-Fu. The dose of L-OHP has significant correlation with RR of chemotherapy and PFS in ACRC patients^[6]. Topoisomerase I (TOPO I) is one of necessary enzymes in the course of cell proliferation and new target against malignant tumors. The HCPT, TOPO I and DNA in the incision integrate a triple complex which can cause double chains rupture and copy stop when DNA is copying. Because the mechanism of the triple complex is different from that of other cytotoxic agents, it is not easy to induce cross drug resistance when the HCPT is used with other anticancer agents. And it is effective for cancer cells with resistance to other chemo-drugs^[7,8]. The curative effect of HCPT has direct correlation with content of TOPO I in tumor tissue. The HCPT is suit to treat colorectal cancer as TOPO I expresses highly in colorectal cancer tissue. There were literatures to report there is anticancer activity in the sort of agents of camptothecine ^[9], and the HCPT promotes apoptosis and inhibits tumor cells growing and forming blood vessels by inhibiting TOPO I^[10,11]. The combination of HCPT and 5-Fu can inhibit colorectal cancer cells^[12,13] and promote treatment effect of colorectal cancer. The combination of HCPT and L-OHP can inhibit colorectal cancer cells owing to L-OHP enhancing action of inducing apoptosis of HCPT to colorectal cancer cells^[14].

Now, Tournigand et al.^[13,15] found that RR shown in the 2 groups of the patients with ACRC treated with FOLFOX regimen and FOLFIRI regimen as first-line treatment is 54% and 56%, respectively. But if FOLFOX is chosen as second-line treatment after FOLFIRI regimen or FOLFIRI is chosen as second-line treatment after FOLFOX regimen, the RR of the patients with the different regimens are 15% and 4%, respectively. FOLF-OX is chosen as a second-line regimen after CPT-11^[16]. Lu et al.^[17] found that the RR was 36.8% when the HLF regimen was used for the patients with ACRC. But Zhao et al.^[18] found that the RR was merely 13.3% when the HLF regimen was used in 30 patients with ACRC. Yang et al.^[19] found that the RR was 38.9% when the OH regimen was used in 36 patients with ACRC after 5-Fu/CF regimen. In our study, we treated 37 patients with ACRC using the OH regimen and 22 patients with ACRC using the HLF regimen, and the RR of the patients in the two groups was 32.4% and 22.7%, respectively. The result of the OH regimen was a little less than the reports above all, yet HLF regimen’s wasn’t as much as the reports above all. We think that the different results of the treatment maybe derived from the facts of producing procedures of agents, proportion of initial treatment and retreatment of the patients and number of metastatic organs. The efficacy is almost equal between the regimens of the OH and the HLF. The OH regimen was better to prolong OS and promote one-year survival compared with the HLF regimen, yet the HLF regimen was better to prolong the PFS than the HLF regimen. There were no significant differences in PFS, OS and one-year survival between the two groups. The number of the cases wasn’t enough in our study. If we can continue to cumulate cases and follow-up, the significantly different result will probably occur in the survival analysis. It was showed that the OH and the HLF regimens maybe be helpful to alleviate clinical symptoms and enhance quality of life of the ACRC patients.

The main dose-limiting toxicities were bone marrow suppression and digestive tract symptom in 2 groups. The incidence rates of the side effects in the OH group were as the following: 51.8% (87/168 cycles) of leucopenia, which was less than that reported by Yang et al.^[19] and Yang et al.^[20], 78.6% (132/168 cycles) of nausea and vomiting, 55.8% (48/86 cycles) of diarrhea, both above those reported by Yang et al.^[19] and Yang et al.^[20], 37.5% (63/168 cycles) of peripheral neuropathy, which was less than that reported by Yang et al.^[19] To treat the peripheral neuropathy, 10% calcium gluconate 10 ml and 25% magnesium sulfate 4ml were used to abate peripheral neuropathy on the day and the day before the treatment with the L-OHP^[21]. The incidence rates of the side effects in the HLF group were as the followings: 55.3% (52/94 cycles) of leucopenia, which was less than that reported by Zhao et al.^[18]; the rate of nausea and vomiting was 60.6% (57/94 cycles), it was as much as the report of Zhao et al.^[18], 51.1% (48/94 cycles) of diarrhea, which was obviously more than that reported by Zhao et al.^[18] The peripheral neuropathy wasn’t observed in the HLF group. The digestive tract symptoms in the two groups were both more serious than those reported in the literatures because the HCPT used in our study was the powder agent and its purity and content in per unit was higher than its water solution agent^[22]. The nadir of WBC were both found from day 2 to day 14 after chemotherapy in 2 groups, therefore, we recommend that the hemogram should be checked every other day after administration for those patients with low basic hemogram, the elder patients and the patients with grade II-IV leucopenia until the last cycle of chemotherapy. If the trend of leucopenia was found, the G-CSF was used in time. If diarrhea occurred over 3 times during chemotherapy, the treatment should be paused. If over grade III diarrhea was hard to control, the treatment should be stopped and the diarrhea should be treated, and the infection, electrolyte disturbance and acid-base disequilibrium as a result of the diarrhea should be prevented and treated in time. It should be noticed that the rate of diarrhea combined with grade III-IV leucopenia were both more than 60.0%. The diarrhea maybe derived from the damage of intestinal mucosa, and the serious leucopenia often occurred after diarrhea. We recommend that it is necessary to use G-CSF for elder and the valetudinarianism besides using routine treatment above all, once over grade III diarrhea occurs. The routine treatment to prevent diarrhea in our study didn’t work in 2 patients combined with grade IV leucopenia and bloody diarrhea in the OH group and the bloody diarrhea got remission after increasing the amount of inhibin and giving the transfusion for several times. According to our statistical analysis, the leucopenia, digestive tract symptoms and peripheral neuropathy appeared more in the OH group than those in the HLF group, so we recommend that hemogram should be watched strictly, and the infection should be prevented, especially those combined with diarrhea. It was helpful for alleviating lingering toxicities to control acute nausea and vomiting actively.

The results of OH and HLF regimens were affirmatory for patients with ACRC. There were no significant differences in short-time effect and survival between 2 groups. The OH and HLF regimens were helpful to alleviate clinical symptoms, and enhance quality of life of the ACRC patients. They may be chosen as the second-line treatment, especially for those who have developed resistance to the FOLFOX regimen or for those who can’t tolerate the chemotherapy of regimen with CPT-11. Leucopenia, nausea and vomiting, diarrhea and peripheral neuropathy appeared more in the OH group, but the serious peripheral neuropathy wasn’t observed after the calcium gluconate and magnesium sulfate were supplied prevently. Anemia and thrombocytopenia shown in 2 groups were almost equal. It is important to ensure the medical safety by predominating the indication of chemotherapy strictly, preventing and treating the bone marrow suppression and diarrhea after administration of chemo-drugs actively.