Universally, paclitaxel is used as second-line chemo in the treatment of gastric cancer. Ramucirumab is an antagonist of vascular endothelial growth factor receptor 2 (VEGFR2), the combination with paclitaxel can further improve the therapeutic effect. But it is not yet available in the Chinese Market. Previous combined chemotherapies as 2nd line were not successful, although clinical studies have been reported. Previous Phase II clinical studies of combination of irinotecan and cisplatin or S-1, have failed, this may be because of the platinum or fluorouracil drugs that have failed in the 1stline. There is no cross-resistance observed between raltitrexed and fluorouracil. This study was designed to compare the efficacy and safety of second-line palliative chemotherapy with paclitaxel plus raltitrexed and paclitaxel alone in patients with metastatic gastric adenocarcinoma who failed to receive fluorouracil treatment as 1st line.
In the present study, the combination doses of PTX was adjusted to 240 mg/m2 with the dosing frequency and interval of three-weekly d1, d8, and d15 to meet the primary endpoint of PFS. The adjusted dose for treatment was found well tolerated despite of the higher cumulative paclitaxel dose with shorter infusion schedules (30 minutes vs. 3 hours for paclitaxel) delivered without premedication for unselected patients with metastatic gastric cancer. In this study, we chose 135 mg/m2 PTX and 3 mg/m2 raltitrexed as study group with the aim to explore whether combination regimen is superior or not in comparison to the single-drug regimen.
As usual, the ORR is low in each group but the DCR was found 56.2% and 36% in combination and in single PTX group. Although the OS and PFS was similar not only in ITT but also in PP population, but the absolute increased OS time of ITT was 4.1 months. Subgroup analysis also suggested that if the pathological type is poor RP regimen maybe more favorable (p = 0.09),and if the disease combined with ascites or peritoneal involved or disease metastasis sites more than 2, RP regimen is more beneficial (p = 0.05).
The hematological toxicity of RP group and control group was similar. The incidence of hepatotoxicity was higher in the experimental group because of the combination of raltitrexed.
The survival time of paclitaxel monotherapy group was shorter than 3–4 months reported in previous literatures, probably because this study chose the use of paclitaxel once every three weeks. Clinical study of second-line every three week paclitaxel-albumin in gastric cancer also showed worse efficacy than weekly use. Another reason is that the paclitaxel dosage in this study has chosen the lower limit of the three-week standard dosage regimen, considering the comparability between the experimental group and the single drug group. The application of low-dose paclitaxel in China conforms to the fact that Chinese patients have low physique. Even if lower doses of paclitaxel were chosen in this study, a certain proportion of hematological toxicity was observed. Fortunately, the addition of an antineoplastic agent in the combination group did not significantly increase the hematological toxicity and was well tolerated.
The author thinks that appropriate dosage and usage of paclitaxel and antimetabolites may play greater role in 2nd line therapy of AGCs. Paclitaxel combined with raltitrexed group still saw a trend of improvement in efficacy with favorable tolerance and good safety, especially in individual sub-groups; it is worth carrying out a randomized controlled study for this subgroup in the future.