Gastric cancer is the most common malignant tumor of the digestive tract, with about 934,000 new cases per year worldwide, ranking the second most common tumor, and about 700,000 deaths, ranking the fourth most common tumor. Gastric cancer has obvious geographical characteristics, especially in East Asia (Japan, China and Korea), which is a high incidence area and accounts for about 2/3 of the global total; in China, more than 300,000 new patients are diagnosed each year, accounting for 1/3 of the global total; 260,000 deaths, accounting for 23.24% of all tumor deaths.
Due to the low rate of early diagnosis of gastric cancer, nearly 40% of patients lose the opportunity of surgery at the time of diagnosis, and even for patients who undergo radical surgery, nearly 50% of them will have recurrence and metastasis after surgery, so most of them have to receive chemotherapy (citing data from Professor Qin Shukui’s article).
To date, fluorouracil-based drugs remain the cornerstone of chemotherapy for gastric cancer. How to actively develop more convenient and safe oral agents without compromising the efficacy is the goal pursued.
In recent years, the results of a series of large clinical studies have led to the recognition of new fluorouracil-based oral agents in the treatment of progressive gastric cancer, which have increasingly shown their promising future. ), several fluorouracil-based oral formulations have come to market. The price is getting more expensive, whether it brings improved clinical efficacy, numerous evidence-based data how we can screen.
In 1966, experts in the former Soviet Union synthesized the first fluorouracil-based oral drug FT207, or tegafur, which is a precursor drug for 5-FU and is metabolized by P450 enzymes to 5-FU after oral administration. The blood concentration of tegafur reaches its peak two hours after taking tegafur capsules, and the blood concentration is 1/4 of the peak 24 hours later. 5-Fluorouracil and uracil blood concentration reaches its peak 30 minutes after administration, and then gradually decreases.
The effective concentration of the drug appears in blood, tumor, stomach, intestine, lung, breast, bile duct and other tissues. The concentration of 5-fluorouracil in tumor is higher than that in blood and normal tissues around tumor, and the concentration in gastric cancer tissue is 8.2 times of blood concentration and 3.2 times of normal stomach wall. The drug and its metabolites are mainly excreted through urine. It has definite efficacy in treating progressive gastric cancer, and there is a lack of results of large-scale multicenter clinical studies as high-level evidence, as well as low price.
Roche has further improved the structure of fluorouracil-based drugs and developed a new fluorouracil-based oral drug, capecitabine (Xeloda). The drug is absorbed orally and firstly formed into two intermediate products, deoxyfluorocytidine and deoxyfluorouracil, by the action of carboxylesterase and cytidine deaminase in liver and tumor tissues, and finally transformed into 5-FU in tumor cells through the catalysis of thymidine phosphorylase (TPase), which exerts selective local anticancer effects.
After that, 5-FU is then degraded to a-fluoro-b-alanine (FBAL) and excreted by the action of DPD, dihydropyrimidinase and b-acyl-ureido-propionic acidase, where DPD is the rate-limiting enzyme of this catabolic process. Oral capecitabine is highly bioavailable and can be absorbed intact via the small intestine, which mimics continuous intravenous infusion of 5-FU and avoids the barrier problems of parenteral administration, providing an exceptional basis for optimal use of capecitabine in gastric cancer chemotherapy.
In addition, due to the high concentration of TPase in tumor tissues, capecitabine can be selectively activated in tumor tissues, which greatly improves the concentration and antitumor effect of the drug in cancer cells, significantly reduces the systemic toxic effects, and achieves efficient cell-targeted therapy. (By comparing the above bolded words, we can understand that both capecitabine and tegafur have higher concentration in gastric cancer tissues than blood concentration)
S-1 is a new type of oral fluorouracil drug, whose main components are FT207 and 2 modulators: gimeracil (CDHP) and oteracil (Oxo). The composition ratio is FT207:CDHP:Oxo=1:0.4:1 (molar ratio). FT207 has excellent oral bioavailability, and after oral absorption, it is transformed into 5-FU by liver P450 enzymes and then enters the blood circulation to exert anti-tumor effects. CDHP can inhibit the activity of dihydropyrimidine dehydrogenase (DPD) and reduce its decomposition of 5-FU, which helps maintain CDHP can inhibit the activity of dihydropyrimidine dehydrogenase (DPD), reduce its catabolism of 5-FU, and help maintain the drug concentration of 5-FU in blood and tumor tissue.
In contrast, Oxo acts by specifically inhibiting orotate ribosyltransferase (ORTC) in intestinal mucosal cells, reducing the phosphorylation of 5-FU in intestinal tissues (the result of phosphorylation is the main cause of gastrointestinal side effects), thus reducing the gastrointestinal toxicity of FT207.
(FT207 plus 2 modulators, the price is far higher than FT207, there is the benefit of reducing the gastrointestinal toxicity of FT207, the problem now is that FT207 does not have a lot of side effects)
Who is better It also makes sense to compare which is better, capecitabine or S-1, for progressive gastric cancer applications. In 2007, Kang et al. (Kang Y, Lee J, Min Y, et al. 2007) reported a phase II clinical study comparing capecitabine with S-1 in the treatment of advanced gastric cancer in the elderly, with 91 cases enrolled.
Results: PR was 29.5% and SD 38.6% in the capecitabine group; CR was 2.2%, PR 26.7%, and SD 40.0% in the S-1 group; TTP was 4.8 months vs. 4.2 months and MST was 10.0 months vs. 7.9 months for both, and both had milder toxic effects. Preliminarily, oral capecitabine or S-1 chemotherapy alone has good efficacy and tolerability as a first-line treatment option for elderly patients with advanced gastric cancer. So whether tegafur as the root should be eliminated, the efficacy and price advantage make us concerned .
Gastric cancer was treated with tegafur orally combined with herbal formula, and the data are reported as follows.
1.Data and methods
1.1 General data There were 18 patients in the group, all of them were advanced gastric cancer, 7 males and 11 females; age 58-93 years old, age distribution: 1 case over 90 years old, 6 cases 80-89 years old, 7 cases 70-79 years old, 3 cases 60-69 years old, 1 case under 60 years old Average age 78 years old, all of them were diagnosed as gastric adenocarcinoma by gastroscopic pathology, and distal shift was found by imaging, among them liver metastasis at the time of consultation Among them, 5 cases had liver metastasis, 10 cases had abdominal metastasis, and 3 cases had bone metastasis at the time of consultation, all of which were not operated. There were no obvious abnormalities in blood routine, liver and kidney function, electrocardiogram, etc. before treatment, and they resolutely requested comprehensive treatment with Chinese medicine.
1.2 Treatment: Chinese herbal medicine prescription: Astragalus membranaceus 40 g, Poria 10 g, Atractylodes macrocephala 20 g, Atractylodes macrocephala 20 g, Cichorium sanguinis 15 g, Cordyceps sinensis 6 g, Glycyrrhiza glabra 5 g. If stomach pain is obvious, add Yuanhu 10 g, vomit a lot of white sputum and saliva, add Sempervisia 10 g, constipation, add Horsetail 30 g, Citrus aurantium 10 g, gastrointestinal bleeding, add Yunnan Baiyao and Omeprazole, take daily;
At the same time, each patient should take 200mg of tegafur (FT-207) and 5mg of gastroflucan orally 3 times a day after meals for 10 days, and continue to take it for 10 days after the blood picture is normal. The total monthly cost is within 300 yuan.
1.3 Observation index: remission time of main symptoms, duration of asymptomatic, survival time; and toxic side effects.
2. Results
2.1 Efficacy 18 patients were enrolled during the period from May 2005 to October 2008, 3 patients progressed within 2 treatment cycles, showing an increase in obstruction and inability to eat and take medication, interrupting treatment and judged to be ineffective; 15 patients were able to continue to take medication, and statistical analysis was performed until October 30 this year, 15 patients had obvious remission of major symptoms, 10 cases of choking sensation from eating As of October 30 of this year, the statistical analysis showed that 15 patients had obvious relief of their main symptoms, and 10 patients with choking sensation after taking the medication had obvious relief, which made the treatment continued and greatly enhanced the confidence of the patients and their families;
The pain of 12 patients with epigastric pain was relieved; 5 patients with gastrointestinal bleeding were controlled; 15 patients were able to continue the treatment according to the program because of the clinical benefit within one treatment cycle, the shortest duration of asymptomatic was 3 months in one case, 6 months in one case, 8 months in three cases, 10 months in two cases, 12 months in three cases, 15 months in two cases, 23 months in three cases, and until October this year As of October this year, there were 6 cases continuing the treatment.
2.2 Toxic side effects The toxic side effects of this therapy are mild, mainly nausea in the gastrointestinal tract, and the majority of patients can continue to take it with the addition of gastroflucan. Hematologic toxicity was mild, with a few patients showing a mild decrease in white blood cells and hemoglobin, but no significant adverse effects were observed.
3. Discussion
3.1 Patients with advanced gastric cancer are in poor physical condition, especially the elderly patients enrolled in this group, who have difficulty in tolerating “regular” chemotherapy, so it is valuable to find an effective treatment plan. However, there are too few cases and no controls in this group, so the standard design is flawed, but how to deal with such patients. There are several questions for your consideration
①What clinical indicators are used to determine the efficacy of this group of patients
②What is the maximum duration of continuous administration of tegafur? At present, we have observed 26 months, and no effect on liver and kidney function has been observed, but mild bone marrow suppression has occurred, which can be recovered after one week of discontinuation.
③How to establish a control group if it is to be established without violating ethics.
④How to determine the best efficacy-price ratio.