The first clinical application of postoperative chemoradiotherapy in resectable gastric cancer was reported in a randomized clinical study by Dent et al. in 1979, but the earliest clinical trials on chemoradiotherapy failed to demonstrate its benefits in resectable gastric cancer. in 2001, a large phase III randomized clinical trial (SWOG9008/INT0116) reported by the southwest oncology group (SWOG) was a landmark clinical study on the use of chemoradiotherapy in the treatment of gastric cancer. clinical trial (SWOG9008/INT0116) was a landmark clinical study of chemoradiotherapy in the treatment of gastric cancer.
This study has made chemoradiotherapy the standard of care for locally progressive gastric cancer in the United States. In 2005, a prospective controlled study in Korea, using the same chemoradiotherapy regimen as INT0116, further demonstrated that chemoradiotherapy provided a significant survival benefit for patients undergoing D2 radical surgery. survival advantage. Currently, the most classical form of chemoradiotherapy for gastric cancer is postoperative chemoradiotherapy, and more studies have been reported on it.
I. Postoperative chemoradiotherapy treatment plan
1.Fluorouracil plus formyltetrahydrofolate combined with regional radiotherapy: The INT0116 trial and a large single-group prospective controlled study in Korea demonstrated that chemoradiotherapy significantly improved the long-term survival of gastric cancer patients who underwent D0, D1 and D2 radical resection (R0 resection), respectively, using the same protocol. This regimen has become the standard of care for locally progressive gastric cancer in the United States.
Patients in the treatment group received 1 cycle of intravenous chemotherapy (fluorouracil plus formyl tetrahydrofolate) per month. In the INT0116 trial, 90% of patients underwent D0 and D1 radical surgery, and the 3-year overall survival rates were 50% and 41% (P=0.005) in the postoperative chemoradiotherapy group (281 patients) and 48% and 31% (P<0.001) in the surgery-only group (275 patients), respectively, and the disease-free survival rates were 48% and 31% (P<0.001), respectively. , whose 10-year follow-up analysis showed that postoperative chemoradiotherapy was ineffective for diffuse gastric cancer.
In the Korean trial, the 5-year overall survival rates were 57.1% and 51% in the D2 radical surgery post-chemotherapy group compared with the D2 surgery alone group (P=0.0198). The disease-free survival rates were 54.5% and 47.9%, respectively (P=0.0161). In recent years, several clinical studies on D2 radical surgery followed by the above-mentioned chemoradiotherapy regimen have shown that it is effective in reducing the local recurrence rate of gastric cancer patients. Therefore, for patients with locally progressive gastric cancer after R0 resection, this regimen is the first choice for postoperative chemoradiotherapy.
2.Cisplatin plus capecitabine combined with regional radiotherapy: Dutch scholars Jansen et al. conducted several phase I and II clinical trials to study the maximum tolerated dose of radiotherapy combined with cisplatin plus capecitabine, two chemotherapeutic drugs, in patients with gastric cancer after surgery. In the trials, 31 patients with gastric cancer in the human group received first 2 weeks of induction chemotherapy (capecitabine) after radical D1 and D2 surgery, followed by 1 week of interval and then 5 consecutive weeks of chemoradiotherapy (cisplatin plus capecitabine combined with 45 Gy of regional radiotherapy).
After a median follow-up period of 14.4 months, 11 patients died and 20 patients remained alive with tolerable chemotherapy toxicity. The ongoing phase III clinical research trial, the CRITICS study, will further investigate the protocol for modifying the optimal drug dose and elucidate its efficacy. Another phase III clinical trial, ARTIST, will compare the efficacy of chemoradiotherapy (capecitabine plus cisplatin combined with radiotherapy) to postoperative chemotherapy alone (capecitabine plus cisplatin) after radical D2 surgery, with a 3-year disease-free survival rate as the study endpoint.
3.Capecitabine combined with regional radiotherapy: Jansen et al. in the Netherlands studied the chemoradiotherapy regimen of single-agent capecitabine combined with regional radiotherapy after gastric cancer surgery: patients with gastric cancer first received induction chemotherapy (capecitabine) for 2 weeks after surgery, and then started a 5-week chemoradiotherapy after a 1-week interval, including oral escalating doses of capecitabine (650-1000 mg/m2 twice daily for 5 d) and 45 mg/m2 of cisplatin. , 5 d weekly) and 45 Gy of regional radiotherapy: the results showed that the highest dose of capecitabine in the trial was safe and well tolerated for patients with postoperative gastric cancer.
In addition, Dikken et al. selected this regimen as one of the treatment options for the postoperative chemoradiotherapy group after a comparative study of postoperative chemoradiotherapy versus postoperative chemotherapy for gastric cancer. The final efficacy of this regimen needs to be evaluated in further phase III clinical studies.
4. Postoperative ECF regimen (epirubicin, cisplatin and fluorouracil) plus regional radiotherapy: After the MAGIC trial was reported in 2006, perioperative ECF regimen chemotherapy became the first-line treatment option for gastric cancer in Europe. Australian scholar Leong et al. recently reported the results of a study in which they selected 54 patients with T3, T4 or N+ locally progressive gastric cancer who were given 3 courses of postoperative ECF regimen chemotherapy with 45 Gy radiotherapy and synchronized fluorouracil intravenous chemotherapy between courses 1 and 2, and the patients had an overall survival rate of 61.6% at 3 years postoperatively. A phase III clinical trial has been initiated to compare this regimen with the INT0116 regimen in combination.
5. Postoperative fluorouracil combined with whole abdominal radiotherapy (WAI): In a single-group uncontrolled study by Baeza et al, 52 patients with lymph node involvement or plasma membrane involvement of gastric cancer were selected for postoperative chemoradiotherapy, and patients received 21 Gy of whole abdominal radiotherapy and 24 Gy of shock radiotherapy to the tumor bed, with intravenous fluorouracil administered 5 d weekly during weeks 1 and 5 of radiotherapy [450-500 mg? mg?(m2)-1?d-1] or continuous intravenous infusion of fluorouracil [200-300 mg?(m2)-1?d-1] during radiotherapy;
The results showed that patients had an overall survival rate of 54% at 5 years after surgery. The high long-term survival rate of this trial provides a reference for us to seek the best postoperative adjuvant chemoradiotherapy for gastric cancer patients.
II. Preoperative chemoradiotherapy regimen
Preoperative chemoradiotherapy is an emerging chemoradiotherapy regimen in recent years. More than 50% of patients with progressive gastric cancer cannot achieve R0 resection by surgery and thus are not suitable for chemoradiotherapy after surgery. Compared with postoperative chemoradiotherapy, patients who have not undergone surgery can better tolerate the adverse effects of chemoradiotherapy, and preoperative chemoradiotherapy can not only reduce the tumor stage and provide the opportunity for R0 surgery, but also help reduce the tumor recurrence rate and improve the long-term survival rate of patients.
In addition, the anatomical structure of gastric cancer patients has not been changed before surgery, therefore, the localization of radiotherapy area in preoperative chemoradiotherapy is more accurate. In conclusion, the strategy of preoperative chemoradiotherapy for the treatment of progressive gastric cancer is a highly promising research direction, but due to the lack of results of large-scale phase III clinical trials, the best treatment protocol still needs to be explored in further randomized clinical studies.
1. Fluorouracil, formyltetrahydrofolate and cisplatin induction plus cisplatin and etoposide combined with regional radiotherapy: Stahl et al. compared the efficacy of 119 patients with locally advanced adenocarcinoma of the gastroesophageal junction who received preoperative chemotherapy and preoperative chemoradiotherapy, respectively, in a phase III clinical randomized controlled trial. In the trial, the chemoradiotherapy group underwent 12 weeks of preoperative induction chemotherapy (fluorouracil, formyltetrahydrofolate, and cisplatin) followed by 3 weeks of chemoradiotherapy, including intravenous chemotherapy (cisplatin and etoposide) and 30 Gy of regional radiotherapy.
Surgery 3 to 4 weeks after the end of chemoradiotherapy: the results of the study showed that for adenocarcinoma of the gastro-esophageal junction, the preoperative chemoradiotherapy group was compared with the preoperative chemotherapy group. The complete pathological remission rates in both groups were 15.6% and 2.0% (P=0.03), respectively, and the 3-year survival rates were 47.4% and 27.7% (P=0.07), respectively. Thus, this trial provides an evidence-based basis for the use of chemoradiotherapy in patients with adenocarcinoma of the gastroesophageal junction. However, the optimal dosing regimen remains to be further investigated.
2.Fluorouracil, cisplatin and paclitaxel induction plus fluorouracil and paclitaxel combined with regional radiotherapy: In a single-group uncontrolled clinical study by Ajani et al, gastric cancer specialists at MD Anderson Cancer Center in Texas, 41 patients with locally resectable gastric cancer received paclitaxel-based chemoradiotherapy before surgery, and the treatment regimen consisted of 1 to 2 courses of induction chemotherapy (fluorouracil, cisplatin and paclitaxel) and 5 weeks of chemoradiotherapy (45 Gy of radiotherapy plus fluorouracil and paclitaxel); finally 40 patients (98%) underwent surgery and 32 (78%) had R0 resection; the complete pathological remission rate was 20% and partial remission rate was 15%; after a median follow-up period of 36 months. 28 patients (68%) were still alive.
3. Induction with fluorouracil, formyltetrahydrofolate and cisplatin plus fluorouracil combined with regional radiotherapy: In a single-group clinical study by Ajani et al. 33 patients with limited gastric cancer were selected to receive 1 to 2 courses of induction chemotherapy (fluorouracil plus formyltetrahydrofolate plus cisplatin) before surgery, followed by 5 weeks of chemoradiotherapy, including 45 Gy of regional radiotherapy and simultaneous fluorouracil intravenous chemotherapy, with the course The results showed that 28 patients (85%) underwent surgical treatment, 23 with R0 resection, with a complete pathological remission rate of 30%. The partial pathological remission rate was 24% and the 2-year survival rate was 54%.
4. Fluorouracil and cisplatin induction plus fluorouracil and paclitaxel combined with regional radiotherapy: A multicenter phase II clinical trial conducted by Ajani et al. evaluated the efficacy of preoperative chemoradiotherapy for gastric cancer based on four chemotherapeutic media: fluorouracil, folinic acid, cisplatin, and paclitaxel.
In the study, 43 patients with gastric cancer received one to two courses of induction chemotherapy (fluorouracil and cisplatin) followed by sequential chemoradiotherapy (45 Gy of regional radiotherapy plus fluorouracil- and paclitaxel-based intravenous chemotherapy) preoperatively and surgery at the end of the course; finally, 36 patients (83%) underwent surgery and 27 (63%) were resected R0, with a complete pathological remission rate of 26%, and the median survival time for all patients was 23.2 months.
III. Chemoradiotherapy combined with intraoperative radiotherapy
Intraoperative radiotherapy, i.e., radiation therapy to the area defined for radiotherapy during surgery. Compared with external radiation therapy, intraoperative radiation therapy under direct vision can reduce the area that patients receive radiotherapy and increase the dose of tumor irradiation, while organs that are dose-limiting and do not need to be irradiated can be moved away from the radiotherapy area, with the ultimate goal of reducing the local recurrence rate of tumor and thus improving the long-term disease-free survival rate of patients.
Intraoperative radiotherapy for gastric cancer is mostly combined with postoperative external irradiation therapy, mainly for patients with high risk of local tumor recurrence. However, the implementation of intraoperative radiotherapy requires an operating room equipped with mobile radiotherapy equipment; meanwhile, its complicated operation process and prolonged operation time make the clinical research of this treatment method relatively limited at present.
1.Intraoperative radiotherapy plus postoperative fluorouracil, cisplatin, docetaxel and formyltetrahydrofolate combined with regional radiotherapy: Fu et al. compared the difference in efficacy between intraoperative radiotherapy sequential postoperative chemoradiotherapy (46 cases) and postoperative chemoradiotherapy alone (51 cases) in 94 patients with locally progressive gastric cancer, the former received 12～15 Gy of intraoperative radiotherapy after completion of gastrectomy and lymph node dissection in D2 radical surgery prior to GI reconstruction. The former received 12-15 Gy of intraoperative radiotherapy and 39.6 Gy of postoperative radiotherapy with concurrent chemotherapy (fluorouracil, cisplatin, docetaxel, and formyltetrahydrofolate) after completion of chemoradiotherapy, followed by 4-6 additional courses of chemotherapy (fluorouracil, cisplatin, docetaxel, and formyltetrahydrofolate): the results showed that the addition of intraoperative radiotherapy significantly improved the rate of local tumor recurrence control (TRC) in patients with gastric cancer who received D2 radical surgery combined with postoperative chemoradiotherapy. local tumor recurrence control rate (median follow-up 24 months, 77% vs. 63%, P=0.05).
2. Preoperative fluorouracil combined with regional radiotherapy plus intraoperative radiotherapy: In a single-group clinical trial by Lowy et al. 23 patients with locally progressive gastric cancer. After receiving preoperative fluorouracil-based chemoradiotherapy (for 5 weeks, including 45 Gy of radiotherapy plus simultaneous fluorouracil intravenous chemotherapy), 19 patients (83%) underwent D2 radical surgery with intraoperative radiotherapy, of whom 18 were R0 resected; 2 (11%) achieved complete pathologic remission and 12 (63%) achieved apparent partial pathologic remission after surgery.
3. Preoperative chemotherapy (fluorouracil, formyltetrahydrofolate, adriamycin and cisplatin) plus intraoperative radiotherapy plus postoperative regional radiotherapy: Weese et al. investigated the therapeutic efficacy of preoperative chemotherapy sequential intraoperative radiotherapy sequential postoperative external irradiation therapy in patients with locally progressive gastric cancer.
In the study, 15 patients with locally progressive gastric cancer received preoperative chemotherapy (fluorouracil, formyltetrahydrofolate, adriamycin, and cisplatin) in a four-drug combination before surgery, and those with intraoperative exploration for transmural tumors or positive lymph nodes received intraoperative radiotherapy at a dose of 10 Gy during gastrectomy, followed by a total of 45 Gy of external irradiation 4 weeks after surgery, and finally 9 patients received After a median follow-up period of 27 months, 10 patients (67%) remained recurrence-free at the end of the follow-up period. The results showed that this treatment protocol not only decreased the tumor stage preoperatively, but also reduced the local recurrence rate and prolonged the long-term survival time of patients.
IV. Research prospect and outlook
In 2001, the results of the clinical study of INT0116 were reported, which made the adjuvant treatment method of chemoradiotherapy a hot topic in gastric cancer research. For preoperative chemoradiotherapy for gastric cancer, there is a lack of results of large phase III clinical trials to support its long-term survival advantage, and the strategy of preoperative chemoradiotherapy for progressive gastric cancer is still a highly promising research direction.
Currently, chemotherapy is still used as the first-line adjuvant treatment for gastric cancer before and after surgery in Europe and Japan, and whether chemoradiotherapy, as a relatively new treatment strategy, can improve the long-term survival rate of gastric cancer patients compared with chemotherapy still needs to be further explored. chemoradiotherapy. An ongoing phase III clinical trial, the ARTIST trial, will compare the difference between postoperative capecitabine- and cisplatin-based chemoradiotherapy and chemotherapy for gastric cancer in terms of disease-free survival at 3 years after radical D2 surgery.
In addition, the application of novel radiotherapy techniques has led to more targeted treatment of gastric cancer, and recent studies of various radiotherapy sensitizers have aimed to find the best chemoradiotherapy combinations. For example, Intensity Modulated Radiation Therapy (IMRT), a new radiotherapy technique, is a revolutionary radiotherapy technique that has emerged in recent years. It has solved the problem of uneven radiation dose within the tumor in traditional 3D conformal radiotherapy, especially for the protection of sensitive tissues, and IMRT is the best choice for current radiotherapy techniques.
A cohort study conducted by German scholars Boda-Heggemann et al. showed that IMRT combined with Xelox chemotherapy regimen had a better long-term survival advantage compared with conventional three-dimensional conformal radiotherapy (3D-CRT) combined with fluorouracil and formyltetrahydrofolate. Several reports have shown that IMRT significantly reduces radiotherapy-induced nephrotoxicity compared with 3D-CRT in patients treated with chemoradiotherapy after gastric cancer surgery. As for the use of radiotherapy sensitizers. The latest NCCN guidelines clearly indicate that patients with gastric cancer given radiotherapy need to be supplemented with fluorouracil-based radiation sensitizers. Various new radiotherapy sensitizers, such as docetaxel, luteolin, gefitinib, and arabinosine, have also been shown to be effective in the treatment of gastric cancer patients in various studies.
The long-term survival rate of gastric cancer patients after surgery is the main criterion to determine the efficacy of the chosen treatment. Despite the breakthroughs in chemoradiotherapy research, there are still many barriers to the application of chemoradiotherapy regimens for the adjuvant treatment of locally progressive gastric cancer worldwide, and even in the United States, most patients with locally progressive gastric cancer are still not treated with chemoradiotherapy. treatment in Oregon, USA. It was found that only 36.8% of patients with locally progressive gastric cancer were treated with chemoradiotherapy even after the report of INT0116 in 2001.
In conclusion, chemoradiotherapy as an adjuvant treatment for gastric cancer. It can significantly improve the long-term survival rate of patients with resectable gastric cancer, but the optimal chemoradiotherapy regimen still needs to be further studied by scholars in the field. With the progressive research in the future, the treatment of chemoradiotherapy in gastric cancer will enter a brand new era!