Gastric cancer is one of the common malignant tumors of the digestive system, and most patients are already at an advanced stage of the disease at the time of diagnosis. Worldwide, the number of deaths from gastric cancer accounts for the second highest number of tumor deaths each year. The annual mortality rate of gastric cancer in China is 25.21% per 100,000 population, which is the first among all kinds of malignant tumors.
Surgery, chemotherapy, radiotherapy and biologic targeted therapy are the four major treatments for malignant tumors. Since gastroscopy screening is not yet popular in China, many patients are already at advanced stage when they are found. Although 50-60% of these patients have the chance of radical resection, they will eventually face recurrence or metastasis after surgery; even for early stage gastric cancer, most of them have lymphatic metastasis and still have the risk of recurrence or metastasis after surgery; the efficacy of surgery alone for gastric cancer is limited, and the main treatment for advanced patients or those with recurrence or metastasis after surgery is chemotherapy; advanced patients can be changed from inoperable to operable through preoperative neoadjuvant chemotherapy Therefore, individualized and standardized comprehensive treatment for gastric cancer is still the best way to improve the survival. Ma Ning, Department of Medical Oncology, Henan Provincial People’s Hospital
I. Perioperative treatment of resectable gastric cancer
According to the results of the classical MAGIC trial, i.e. 3 cycles of ECF (epi-amycin/cisplatin/fluorouracil) regimen each before and after surgery, the lesion size was significantly reduced in the treatment group (n=250) compared with surgery alone (n=253) (p=0.001), the proportion of T3/T4 was 48% vs. 62% (p=0.009),N2/N3 ratio was 16% vs. 26% (p= 0.01), although the R0 resection rate suggested no difference in pathological complete remission, 5-year survival (36% vs 23%, p=0.009), and progression-free survival time were significantly prolonged (p<0.001), Meta-analysis results showed that perioperative chemotherapy was beneficial to enhance overall survival, regardless of gender, age, PS status, and tumor location (proximal, distal), ECF as preoperative and postoperative adjuvant chemotherapy regimen has been largely agreed upon.
Postoperative adjuvant chemoradiotherapy treatment for resectable gastric cancer
The SWOG 9908/INT0116 multicenter trial is a landmark clinical trial. The trial enrolled patients with T3 and/or lymph node metastasis of gastric cancer or combined gastroesophageal cancer. After undergoing surgical resection with negative margins, 603 patients were randomized into the observation group and the postoperative combined radiotherapy group with 1 cycle of intravenous chemotherapy per month for a total of 5 cycles, and combined with 45 Gy simultaneous radiotherapy in the 2nd and 3rd cycles. In the combined radiotherapy group, the proportion of local recurrence as first recurrence was significantly lower (19% vs. 29%), median survival was significantly longer (36 months vs. 27 months), disease-free survival (27 months vs. 19 months, P<0.009), and overall survival (35 months vs. 27 months, P=0.006) was significantly improved. The status of postoperative adjuvant chemotherapy for gastric cancer was thus established.
III. Postoperative adjuvant chemotherapy for resectable gastric cancer
S-1 is a new type of oral fluorouracil drug, which is composed of tegafur FT-207, Gimost CDHP and Otilacid Oxo, formulated in capsule form with molecular weight 1:0-4:1, each capsule contains either FT-207 20mg or 25mg, which is activated by P450 enzyme in liver to produce 5-FU and then activated to FdUMP for anti-cancer effect. CDHP inhibits DPD to prevent 5-FU from being degraded and increases the production of fluorouracil deoxynucleotides (FdUMP) from 5-FU. Gimostat (CDHP) inhibits dihydropyrimidine dehydrogenase (DPD) 180-fold more than uracil in UFT. Otilacil (Oxo) blocks phosphorylation of 5-FU and its high distribution concentration in the gastrointestinal tract, which affects the distribution of 5-FU in the gastrointestinal tract, thus reducing attenuating the toxicity of 5-FU to the gastrointestinal tract.
In 2008, NEJM published the results of a phase III trial of postoperative adjuvant therapy with S-1 in Japan. 1059 patients with stage II-III gastric cancer after radical D2 surgery were included in ACTS-GC and randomized to the S-1 monotherapy group and the surgery-only control group. subgroup analysis S-1: surgery-only group, 3-year overall survival (80.1% vs. 70.1%, HR=0.68, p=0.003 ), 3-year progression-free survival (72.2% vs 59.6%,HR=0.62, P<0.001). The improvement in overall survival was strongly associated with the high rate of gastroscopic screening, complete surgical radical resection, and the use of S-1 in Japan.
IV. Chemotherapy for advanced or metastatic gastric cancer
1.Paclitaxel
In the classic V325 study, 445 patients with untreated advanced gastric cancer were randomized into two groups, 1 group DCF (TXT/DDP/FU), 1 group CF (DDP/FU). 67% vs 56% disease control rate, 5.6 months vs 3.7 months progression-free time (P=0.001), median overall survival time 9.2 months vs 8.6 months for DCF vs CF (P= 0.02), and based on the results of this study NCCN guidelines included the DCF regimen as standard of care for metastatic or locally progressive gastric cancer with a level of evidence grade 1 stance. However, the evolution of the modified regimen has become the new standard of care because of ethnic differences between the East and West resulting in greater side effects in the Eastern population.
On 2008/9/10, the NCCN guidelines stated that albumin-bound paclitaxel, synthesized using albumin nanotechnology, could be used for the treatment of advanced NSCLC, especially for people with hypersensitivity to paclitaxel. This year, albumin-conjugated paclitaxel was also officially launched in China for the treatment of advanced breast cancer, and the treatment dose was almost doubled compared with regular paclitaxel, 260 mg/m2 vs 175 mg/m2, and the OS was significantly prolonged when used as a second-line drug, 56.4 weeks vs 46.7 weeks, P=0.0024, and the incidence of toxic side effects, especially allergic reactions, was significantly reduced, P<0.001. improvement may be the main reason for the increased efficacy, but it also provides a new therapeutic possibility for the application in gastric cancer.
2. Capecitabine
CAPE is an oral fluorouracil analog that converts to 5-fluorouracil in tumor tissue. two phase III trials, REAL and MA17032, established its efficacy and safety in the treatment of gastric cancer. the REAL-2 trial was a randomized multicenter phase III trial comparing CAPE with FU and L0HP with DDP in advanced gastric and esophageal cancers. 1003 cases of histopathologically confirmed adenocarcinoma, squamous carcinoma, and squamous carcinoma were treated with CAPE. pathologically confirmed adenocarcinoma, squamous or undifferentiated carcinoma were enrolled and randomized into 4 groups receiving EPI-based chemotherapy regimens, ECF, EOF, ECX, EOX, with a median follow-up of 17.1 months and an efficiency rate of 41% vs 42% vs 46% vs 48%, respectively, with no significant difference, but the CAPE-containing group seemed to have a somewhat higher efficiency rate with an OS of 9.9 months vs 9.3 months vs 9.9 months vs 11.2 months, PFS 6.2 months vs 6.5 months 6.7 months vs 7.0 months, respectively, all without statistical difference, but EOX had an OS prolongation advantage over ECF, P=0.02. REAL conclusion, treatment of advanced gastroesophageal cancer is that CAPE is no worse than FU and LOHP is no worse than DDP. Therefore, capecitabine combined with platinum oxalate becomes a new choice for the treatment of gastric cancer.
3.S-1
JCOG9912 compared CPT-11+DDP (N=236), S-1 (N=234), FU CIV (N=234), and the results showed that CPT-11+DDP did not show advantages compared with 5-FU CIV, recalcitrant toxic reactions led to treatment failure, S-1 showed significant non-inferiority compared with 5-FU CIV, and all study samples had controlled toxicity, satisfactory RR, TTF, PFS, NHS (ambulatory survival), and prolonged OS compared to 5-FU CIV. Conclusion: S-1 should be the standard chemotherapy agent for the treatment of patients with non-surgically resected/recurrent gastric cancer. 2009ASCOabstr4514 updated data, median survival in the FU, CP, and S-1 groups were 10.8 months vs 12.3 months vs 11.5 months, 1-year survival 44% vs 53% vs 48%, and 2-year survival 14% vs 18% vs 21%, respectively, with the CP and S-1 groups showing a statistical advantage over the FU groups all showed statistical advantages (test of superiority). CONCLUSION: S-1 alone can be used as a new standard of care in the AGC1 line.
The SPIRITS phase III trial (2008asco abstr 66) established the 1st-line status of S-1+DDP for the treatment of AGC. Single agent group S-1 40-60mg bid d1-28 ,Q6w×4; SP combination group S-1 40-60mg bid d1-21,CDDP 60mg/m2 iv d8,Q5w×5, primary endpoint OS, median follow-up 34.6 months, patient characteristics balanced in both groups; toxic effects tolerated in both groups, no treatment-related deaths; S-1 vs SP median overall survival 11 months vs 13 months (p=0.0366), 1-year survival 46.7% vs 54.1%, 2-year survival 15.3 % vs 23,6%, progression-free survival 4.0 months vs 6.0 months (p<0.0001), overall response rate 31% vs 54% (p=0.0018). the SPIRITS trial suggested that SP could be the standard of care for progressive gastric cancer.
4. Irinotecan
IRI (CPT-11) is a synthetic CPT derivative, which belongs to the same topoisomerase I inhibitor as the CPT and hydroxycamptothecin (HCPT) extracted from the hippophae tree in China in the 1970s, and the CPTs form a stable complex with TOPOI-DNA, which prevents the DNA single-stranded cut from rejoining and replicating, thus stopping cancer cell reproduction. From 1994 to 2002, there were 5 reports of monotherapy for AGC with a total of 161 cases and an RR of 19% (14%~23%).
A phase II clinical trial using CPT-11 + DDP for AGC was conducted in Japan in 1999. CPT-11 (70 mg/m2) day 1 , 15 , CDDP (80 mg/m2) d 1,Q 4 W. N=44. ORR=48% for IP regimen, RR=27% for patients with prior chemotherapy, RR=59% for patients without chemotherapy, and high efficiency for patients with liver, lung, and lymph node metastases. Overall ITT had an overall survival of 272 days and 322 days in 29 patients treated with 1st-line therapy, so CPT-11+DDP is included in the US NCCN guidelines with evidence-based grade 2B.
5. VM-26
VM-26 is a semi-synthetic derivative of onychotoxin, whose mechanism of action is to cut the DAN double chain bound to topoisomerase II. VP-16 is also one of the semi-synthetic derivatives of ghostwort, which is commonly used in chemotherapy for gastric cancer. The cytotoxic effect of VM-26 has been reported in the literature to be 5-10 times higher than that of VP-16. In the clinical treatment of gastric cancer, VM-26, DDP and 5-FU, three synergistic drugs, were combined for the first time to form a VDF regimen for the treatment of intermediate and advanced gastric cancer in the Department of Oncology of provincial medicine, and the efficiency rate reached 71%, and the difference was significant when compared with the commonly used EDF (VP-16 + DDP + 5-FU) regimen (efficiency rate 48.8%). Because of its high effectiveness and low cost, it has broken the phenomenon of “the more expensive treatment” in tumor treatment and become the best choice for advanced stage, especially for relapsed and drug-resistant gastric tumors.
V. Targeted therapy
The 2009 Annual Meeting of American Oncology reported the results of the ToGA trial: a phase III study of trastuzumab (H) plus to standard chemotherapy (CT) in the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Advanced gastric cancer is an incurable disease that requires new, less toxic therapeutic approaches. The literature reports that HER2 overexpression is present in 6-35% of gastric and gastroesophageal cancers. Trastuzumab (Herceptin), a monoclonal antibody to HER2, in combination with conventional chemotherapy can provide a survival benefit in patients with HER2-positive early-stage and metastatic breast cancer. the ToGA trial was the first randomized, prospective, multicenter phase III clinical trial to investigate the efficacy and safety of trastuzumab in patients with HER2-positive gastric cancer. In this trial, HER2 status in tumor tissue was centrally tested in 3807 patients: 22.1% were HER2-positive (abstract #4556). 594 patients were randomized in a 1:1 ratio across Europe, Latin America, and Asia. Baseline characteristics were balanced across groups. median overall survival was significantly higher in the H+CT group than in the CT group: 13.5 months, 11.1 months, respectively (p=0.0048, HR 0.74, 95% CI 0.60, 0.91). The overall response rate was 47.3% in the H+CT group and 34.5% in the CT group (p=0.0017). Safety was similar in both groups, with no unexpected side effects in the H+CT group. There was no significant difference in symptomatic congestive heart failure between the two groups. Asymptomatic left ventricular ejection fraction decline was 4.6% in the H+CT group and 1.1% in the CT group. CONCLUSION: The first randomized trial investigating anti-HER2 therapy for advanced gastric cancer showed that the H+CT regimen was superior to the CT-only regimen. The overall survival benefit suggests that trastuzumab is a new, effective and well-tolerated treatment for patients with HER2-positive gastric cancer.
VI. Treatment of malignant peritoneal effusion
Malignant peritoneal effusion is a common complication of advanced tumors, among which about 1/2 are caused by gastric cancer. The appearance of malignant peritoneal effusion in lung cancer patients indicates that the disease has entered an advanced stage, which seriously affects the survival quality of patients and has a poor prognosis. Generally, the treatment adopts abdominal puncture and fluid release and intracavitary drug injection to reduce abdominal distension, abdominal pain and other symptoms and to prevent the formation of ascites again. Effective control of ascites plays an important role in the comprehensive treatment of advanced gastric cancer. According to the different disease characteristics of patients, provincial medical oncology department adopts intraperitoneal injection of biological agents such as recombinant human p53 adenovirus injection (rAd/p53), tumor necrosis factor, combined with cisplatin, fluorouracil and other chemotherapeutic drugs, using biological agents – chemotherapeutic drugs sequential/synchronous administration mode, abdominal local/systemic synchronous treatment mode, abdominal thermal perfusion therapy and other rich treatment forms to treat advanced gastric cancer The clinical efficiency is close to 90%, which is higher than that of conventional treatment, and the quality of life of patients has been greatly improved, while the side effects are mild, which is at the advanced level in the province.
Treatment of gastric cancer metastases
Perigastric lymph nodes and liver metastasis are common metastatic sites of advanced gastric cancer. In this regard, the purpose of surgical resection of isolated metastases can be achieved through palliative chemotherapy, but of course, the timing of surgery is very important; intervention, radiofrequency, microwave and particle implantation can be used as the best supportive treatment and the positive and effective supplement of late palliative treatment, which can significantly improve patients’ quality of life; stent placement and gastroscopic injection of biological agents can achieve the effect of direct reduction of tumor volume; through the abdominal thermal The efficacy of chemotherapy, biotherapy and even radiotherapy and local minimally invasive treatment can be enhanced directly by the abdominal thermal perfusion system.
VIII. Summary
Dr. Zhou Yun, chief physician of the Department of Oncology of Henan Provincial People’s Hospital, has been engaged in basic and clinical research of gastrointestinal tumors for a long time, and is a well-known oncologist in China. In the process of treatment, our department truly follows the principle of individualized treatment, flexibly applying anthracyclines, paclitaxel and topoisomerase inhibitors in combination with chemotherapy, and the original double platinum regimen; according to the characteristics of patients’ diseases, we combine P53 adenovirus gene therapy, TNF biological therapy, intraperitoneal thermal perfusion therapy, systemic and local synchronous chemotherapy, etc., and the treatment forms are abundant; according to the characteristics of pathological types, we choose different biological targeting drugs, such as trastuzumab, and the treatment of gastric cancer. The most effective combination of the simplest and basic drugs according to the patients’ economic ability; minimally invasive treatments such as intervention, stent placement, radiofrequency, microwave, particle implantation and immune cell therapy for metastatic gastric cancer patients; the most advanced EGFR, k-RAS mutation and other mutations at home and abroad. The most advanced EGFR, k-RAS mutation and amplification gene testing is available at home and abroad, and some patients can get the opportunity of free testing. For patients, how to make individualized choices to achieve the highest efficacy, lowest toxicity, longest survival and most economical cost is the main goal, and this is where our department’s strength lies!