Topic Written Talk｜Professor Zhao Changlin and Xu Huimian: Progress in comprehensive treatment of advanced gastric cancer (3)

Author: Reading the Idea of Dalian University Affiliated Xinhua Hospital XU Hui-mian First Affiliated Hospital of China Medical University has entered the preamble to surgical gastric surgery, concurrent chemotherapy, radiation therapy, targeted therapy, immunotherapy, interventional therapy combined therapy era.

Patients with advanced gastric cancer without R0 resection have a poor prognosis, with a survival time of 3 to 11 months.

Therefore, improving the overall survival rate of gastric cancer has a long way to go.

This article combines the new version of the gastric cancer guidelines and the high-level evidence of clinical studies on advanced gastric cancer at home and abroad in recent years, focusing on non-metastatic gastric cancer: the progress of comprehensive treatment of advanced unresectable gastric cancer.

1.
Non-metastatic gastric cancer: Unresectable reasons for advanced gastric cancer There are two main reasons for unresectable advanced gastric cancer: (1) Tumor factors: including the primary tumor has severely invaded, cannot be separated from the surrounding normal tissues or has been surrounded Large blood vessels; regional lymph nodes are fixed and fused into clusters; metastatic lymph nodes are not within the scope of surgery.

Although the tumor is affected by the above factors, it may be transformed into resectable after effective conversion therapy.

(2) Unresectable or refusal of surgery with contraindications for surgery: including poor general conditions, severe hypoproteinemia and anemia, malnutrition, and may not tolerate surgery: combined with serious underlying diseases, cannot tolerate surgery, etc.
; refusal of surgery.

The above situation is more common in elderly or elderly patients.

The unresectable reason for advanced metastatic gastric cancer is the recurrence or metastasis of gastric cancer after surgery and the loss of radical surgery.

It can be seen that although non-metastatic advanced unresectable gastric cancer and advanced metastatic unresectable gastric cancer are both unresectable gastric cancer, there are essential differences and different treatment strategies.
Therefore, a detailed analysis of unresectable advanced gastric cancer should be done The reason for this is to attach importance to the imaging examination before comprehensive treatment and give full play to the role of multidisciplinary diagnosis and treatment (MDT).2.
The importance of imaging examination and MDT assessment before comprehensive treatment.
Before comprehensive treatment, it should be combined with endoscopic ultrasound (EUS), multi-slice spiral CT enhanced scanning, magnetic resonance diffusion weighted imaging (MRI+DWI), or Positron emission computed tomography (PET/CT) and other imaging examination items, for patients with high lymph node metastasis, perform diagnostic laparoscopy and peritoneal cytology lavage, which is helpful to discover peritoneal implants that are difficult to detect by imaging examination Metastatic lesions such as metastasis.

The performance status (PS), tumor biological behavior, gene type of patients with non-metastatic unresectable gastric cancer by MDT [human epidermal growth factor receptor-2 (HER2), microsatellite highly unstable (MSI-H) /Mismatch repair defect (dMMR), microsatellite stable (MSS)/mismatch repair normal (pMMR), PD-L1 expression status (CPS score)] comprehensively evaluate, discuss comprehensive treatment strategies based on the evaluation results, and transform After successful treatment or failure of conversion treatment, patients make decisions about their next treatment.

(Figure 1 can be enlarged) Figure 1.
Comprehensive treatment of non-metastatic unresectable gastric cancer 3.
Non-metastatic gastric cancer: progress in comprehensive treatment of advanced unresectable gastric cancer 3.
1 Update of comprehensive treatment strategy for advanced unresectable gastric cancer first based on the patient's PS score At the same time, the basic strategy for comprehensive treatment of unresectable advanced gastric cancer was initially formulated.

For PS=0-1, MSS/pMMR, HER2-negative, PD-L1-negative unresectable gastric cancer patients, in addition to the transformational chemotherapy regimens already introduced, the 2020 version of CSCO Gastric Cancer Guidelines recommends concurrent radiotherapy and chemotherapy (Class 1A evidence) ); Level II recommends chemotherapy (Class 2B evidence), or radiotherapy (Class 2B evidence); Level III recommends chemotherapy + radiotherapy or concurrent radiotherapy and chemotherapy (Class 3 evidence).

MDT evaluates the possibility of surgery, such as R0 resection and sequential surgical treatment.

Patients whose conversion therapy fails and cannot be resected with R0 are transferred to comprehensive treatment based on systemic drug therapy.

For patients with poor general conditions, PS=2, or patients who refuse surgery, the best supportive treatment/symptomatic treatment is recommended for level I (Class 1A evidence); the best supportive treatment/symptomatic treatment + chemotherapy alone is recommended for level II (MSS/ pMMR type)±radiotherapy (type 2A evidence), which can relieve clinical symptoms and improve the quality of life; for elderly patients who are frail or complicated with serious underlying diseases, after nutritional support, symptomatic treatment and medical treatment, the general status is improved, and the underlying disease is obvious For improvement, single-agent chemotherapy alone or reduced-dose two-agent chemotherapy (MSS/pMMR type) ± palliative radiotherapy can be considered, which can prolong the progression-free survival (PFS) of patients.

For patients with severe obstruction of the digestive tract, nutrition tube placement, stent placement, or gastrointestinal short-circuit surgery should be performed first to improve the general state and nutritional status of the patient, so that comprehensive treatment such as chemotherapy and radiotherapy can proceed smoothly.

(Figure 2.
1, 2.
2 zoom in) Figure 2.
1 2020 version of the guidelines for comprehensive treatment of unresectable advanced gastric cancer Figure 2.
2 2020 version of the guidelines for concurrent radiotherapy and chemotherapy 3.
2 Progress in comprehensive treatment of advanced unresectable gastric cancer 3.
2.
1 Progress in chemotherapy combined with concurrent radiotherapy and chemotherapy In 2018, Int J Radiat Oncol Biol Phys published a phase II study of S-1+cisplatin concurrent radiotherapy and chemotherapy (CRT) in the treatment of non-metastatic unresectable gastric cancer.
The study included 30 patients with non-metastatic unresectable gastric cancer and were given S -1+cisplatin simultaneous CRT+S-1+cisplatin consolidation chemotherapy was decided after 10 months of R0 resection.

The effective rate of treatment was 65.
%, of which 10 cases had R0 resection, the pathological complete remission (pCR) rate was 13.
3% (10/30), and the median survival time (OS) was 25 months.

Conclusion: Simultaneous CRT can benefit both in the down-stage rate and pCR rate of non-metastatic unresectable gastric cancer.
It can be used as an effective treatment for non-metastatic unresectable gastric cancer.

(Figure 3 can be enlarged) Figure 3.
Non-metastatic unresectable gastric cancer: the efficacy of S-1 + cisplatin concurrent chemoradiation-Phase II study A study published in J Natl Compr Canc Netw in 2018 shows that CRT can improve non-metastatic gastric cancer Survival rate of patients with metastatic unresectable gastric cancer. Based on the National Cancer Database (NCDB) unresectable stage I to III gastric cancer patients who did not undergo surgery, 1479 received CRT treatment and 3316 received chemotherapy alone (CT).

Conclusion: Compared with the CT group, the OS rate of the CRT group was significantly higher than that of the CT group.

(Figure 4 can be enlarged) Figure 4.
CRT can improve the survival rate of patients with non-metastatic unresectable gastric cancer.
Int J Radiat Oncol Biol Phys published a report on CT+CRT+CT in the treatment of non-metastatic unresectable gastric cancer in 2017.
the study.

The enrolled patients were non-metastatic gastric cancer (GC)/gastroesophageal junction adenocarcinoma (EGJA) (n=36) with underlying medical diseases/refusing surgery, and were treated with CT+synchronous CRT+CT.

The results showed that the objective response rate (ORR) rate was 83%, the clinical complete response (cCR) rate was 36%, the median OS was 28.
8 months, and the 2-year OS rate was 52%.

Conclusion: Due to basic medical diseases/patients with non-metastatic and unresectable GC/EGJA patients who refuse surgery, this regimen is tolerable, safe and effective, and can prolong the survival time of patients.

(Figure 5 can be zoomed in) Figure 5.
The efficacy of CT+synchronous CRT+CT for non-metastatic unresectable gastric cancer-Phase II study 3.
2.
2 Progress of systemic chemotherapy Non-metastatic unresectable gastric cancer systemic chemotherapy regimen adopts advanced metastatic gastric cancer chemotherapy Program.

At present, most clinical studies done at home and abroad exclude gastric cancer patients older than 70 years old or PS≥2, and this part of the population accounts for 30% to 50% of new cases, and cannot tolerate surgery or combined basic medical diseases.
How to make a treatment plan for the frail elderly who refuse surgery? The 02GO2 study (abstract 4006) announced at the 2019 ASCO annual meeting explored the optimal dose of OxCap regimen in elderly and frail patients with advanced gastroesophageal cancer, and explored the guidance of dose individualization based on the objective evaluation indicators of the patient’s baseline.
Comprehensive evaluation of overall utility treatment (OUT), comprehensive clinical benefit, tolerability, and quality of life. The study included a total of 514 patients in 61 cancer centers in the UK from 2014 to 2017, and they were randomly assigned to the dose group A (Ox 130 mg/m2, d1, Cap 625 mg/m2 bid, d1-21, q21d), group B (80% of the dose of group A) or group C (60% of the dose of group A).

The OUT evaluation was carried out in the 9th week.

The main study endpoint is that the PFS of group B and C is non-inferior to group A.

The results showed that PFS in group B was not inferior to group A (HR=1.
09, CI 0.
89~1.
32), and low-dose PFS in group C was not inferior to standard-dose group A (HR=1.
10, CI 0.
90~1.
33).

The OUT of group C was better than that of group A and group B, and the incidence of adverse reactions was the lowest.

This study provides a basis for reduced-dose chemotherapy for patients with non-metastatic unresectable gastric cancer who cannot tolerate surgery or who refuse surgery.

The 2020 version of the CSCO Gastric Cancer Guidelines is based on the 02GO2 study.
It is recommended that reduced-dose two-drug chemotherapy can be used for advanced gastroesophageal cancer over 70 years of age or in frailty.

 (Figure 6 can be zoomed in) Figure 6.
02GO2 study: Exploring the optimal dose of chemotherapy for patients with advanced gastroesophageal cancer in the elderly and infirm.
Professor Xu Ruihua at the 2019 ASCO annual meeting reported "S-1 combined with oxaliplatin vs.
S-1 Combined cisplatin as the first-line treatment of advanced diffuse or mixed GC/EGJA Phase III clinical study (SOX-GC)".

576 patients with advanced diffuse or mixed GC/EGJA were enrolled and randomly divided into S-1 combined with oxaliplatin (SOX) group at 1:1 (S-1: 40-60 mg, bid, d1-14, q3w; oxaliplatin: 130 mg/m2, d1, q3w) and S-1 combined with cisplatin (SP) group (S-1: 40-60 mg, d1-14, q3w; cisplatin: 60 mg/m2 , D1, q3w).

The results of the study showed that the OS of the SOX group and the SP group were 13 months and 11.
8 months, and the PFS was 5.
7 months and 4.
9 months, respectively.
The SOX group prolonged the survival time of the patients. The incidence of adverse reactions in the SOX group, such as fever, anemia, nausea and vomiting, and loss of appetite, was lower than that in the SP group.
The overall toxicity was lower, safety and tolerability were better, but ≤ Grade 2 sensory neurotoxicity (41.
6 % Vs.
12.
2%) and the incidence of abnormal liver function was higher than that of the SP group.

Conclusion: The SOX regimen is superior to the SP regimen and can become the standard first-line treatment regimen for patients with advanced diffuse or mixed GC/EGJA.

With reference to the conclusions of Lauren tissue classification of gastric cancer and SOX-GC research, non-intestinal or mixed non-metastatic unresectable GC/EGJA can be the first choice for SOX.

(Figure 7 can be enlarged) Figure 7.
SOX-GC-replacement SP study: advanced diffuse or mixed gastroesophageal junction adenocarcinoma standard first-line treatment plan FOFIRINOX regimen for the first-line treatment study of gastroesophageal adenocarcinoma reached the primary endpoint And the toxicity can be tolerated.

The ORR in HER2-negative patients was 61%, and the ORR in HER2-positive patients was 85%.

The research has elevated the status of irinotecan to the first line, providing a new option for the first-line treatment of gastroesophageal adenocarcinoma.

The 2020 version of the CSCO guidelines updated the second-line single-agent/two-agent chemotherapy regimen for advanced metastatic gastric cancer (Figure 8 can be enlarged).

The updated comprehensive treatment of advanced metastatic gastric cancer: The third-line treatment plan will be explained in detail in the article on the comprehensive treatment of advanced gastric cancer recurrence.

 Figure 8.
The 2020 CSCO guidelines update the second-line single-dose/two-drug chemotherapy regimen for advanced metastatic gastric cancer 3.
2.
3 Progress in targeted drug therapy The proportion of HER2-positive gastric cancer patients in my country is only 10%-15%.

The 2020 version of CSCO Gastric Cancer Guidelines recommends first-line treatment for HER2-positive gastric cancer: trastuzumab + chemotherapy regimen is changed from "cisplatin + fluorouracil/capecitabine" to "cisplatin/oxaliplatin + fluorouracil/capecitabine" "Bin" (Class 1A evidence); Level II recommends trastuzumab + oxaliplatin/cisplatin + Tiggio/Capecitabine (Class 2B evidence).

Cancel the recommendation of the second-line application of trastuzumab in patients with HER2-positive gastric cancer.

Therefore, once trastuzumab + chemotherapy develops drug-resistant disease, its follow-up treatment options are limited.

Margetuximab is a novel Fc domain optimized immune-enhancing monoclonal antibody that targets to block the HER2 protein.
It is called "optimized Herceptin" and has similar blocking HER2 binding and anti-proliferation properties to trastuzumab.
Effect, while mobilizing innate immunity and adaptive immunotherapy for HER2-positive GC/GEJA resistant to trastuzumab.

In July 2020, "Lancet Oncoloy" published the results of a phase II study (CP-MGAH22-0, NCT02689284) on the efficacy and safety of margetuximab combined with pembrolizumab in the treatment of patients with HER2-positive advanced gastric cancer.

The object of study was advanced unresectable or metastatic HER2-positive gastric cancer that had at least received trastuzumab + chemotherapy treatment.

The median follow-up time was 19.
9 months.

The results showed: (1) Among the overall patients, ORR was 18%, disease control rate (DCR) was 53%, median PFS was 2.
7 months, and median OS was 12.
5 months; (2) In HER2 positive and PD -L1 positive double positive subgroup of patients, ORR was 44%, DCR was 72%, median PFS was 4.
8 months, median OS was 20.
5 months; (3) HER2 amplification (HER2amp) positive/HER2 In the (IHC3+) positive/PD-L1 positive triple-positive subgroup, the ORR was 60% and the DCR was 80%.

20% of patients had treatment-related adverse events (TRAE) ≥3 grade, of which anemia (4%) and infusion reactions (3%) were the most common, and there were no treatment-related deaths.

Currently, the Phase II/III MAHOGANY (NCT04082364) study is evaluating the efficacy of margetuximab combined with immune checkpoint inhibitor ± chemotherapy as the first-line treatment of HER2-positive GC/GEJA patients.
The results are waiting to be seen.

3.
2.
4 Progress of immunotherapy MSI-H gastric cancer patients accounted for 22%, of which stage IV MSI-H gastric cancer patients accounted for only 3%. The 2019 ESMO meeting reported the results of the KEYNOTE-062 study (Pembrolizumab in the first-line treatment of MSI-H (CPS≥1 or 10) advanced GC/EGJA) results.

Fifty patients with MSI-H advanced GC/EGJA were enrolled, of which 32 patients had CPS ≥10, 14 patients in the pembrolizumab single-drug group, and 19 patients in the chemotherapy group.

The results of the study showed that for the first-line treatment of MSI-H advanced GC/EGJA, pembrolizumab as a single agent was significantly better than chemotherapy.
The HR of the two groups of patients were 0.
29 and 0.
21, respectively.
It is especially emphasized that there is almost no survival curve crossover.
Phenomenon, although the sample size is not large, the study proves that MSI-H gastric cancer is the dominant population for immunotherapy.

There were 17 cases in the pembrolizumab + chemotherapy group compared with 19 cases in the chemotherapy alone group.

The results of the study show that the ORR of pembrolizumab + chemotherapy can reach 64.
7%.
Although the median OS is not reached, from the current trend of OS, pembrolizumab single agent or pembrolizumab + chemotherapy, Both showed an absolute survival advantage over chemotherapy alone.

In the KEYNOTE-062 study, a subgroup analysis was carried out for Asian patients, and it was found that the therapeutic effect of Asian subgroup patients was more obvious than that of European and American patients, and PD-L1 positive patients were more significant.

(Figure 9 can be enlarged) Figure 9.
KEYNOTE-062 study: Pembrolizumab first-line treatment of MSI-H (CPS≥1 or 10) advanced GC/EGJA4.
Summary of gastric cancer with high heterogeneity, non-metastatic and unresectable gastric cancer The condition is more complicated and the treatment is more difficult.

Therefore, the reasons for unresectable should be analyzed in detail, and the imaging examination and evaluation before comprehensive treatment should be emphasized to give full play to the role of MDT.

Comprehensive evaluation of tumor biological behavior, gene type, CPS score.

Based on the patient's clinical characteristics, PS stratification, histopathological classification, and molecular classification, it is very important to develop individualized comprehensive treatment strategies for patients with non-metastatic, unresectable gastric cancer.

Surgery, concurrent radiotherapy and chemotherapy, chemotherapy drugs and programs should be selected rationally.
With the development and clinical research and application of new targeted drugs and immunotherapy drugs, it is believed that the treatment bottleneck of non-metastatic unresectable gastric cancer can be resolved and recurrence can be reduced.
Rate and transfer rate, and improve the goals of PFS and OS.

Progress in comprehensive treatment of advanced gastric cancer (4)-Progress in comprehensive treatment of recurrence of advanced gastric cancer (1) will be released in the near future, please read it.

Prof.
Changlin Zhao National Class III Professor, Chief Physician, Doctor of Medicine, Master Supervisor Director of the Department of Gastrointestinal Oncology, Xinhua Hospital Affiliated to Dalian University Head of Dalian Colon and Rectal Cancer Diagnosis and Treatment Base, Chinese Anti-Cancer Association, Standing Committee of Liaoning Colorectal Cancer Professional Committee, Chinese Anti-Cancer Association Member of the Standing Committee of the Liaoning Provincial Gastric Cancer Professional Committee Member of the Standing Committee of the Liaoning Base of the Abdominal Tumor Committee of the Chinese Medical Education Association Member of the Standing Committee of the Liaoning Provincial Tumor Marker Professional Committee Member of the Standing Committee of the Liaoning Provincial Tumor Biology and Targeted Therapy Professional Committee Member of the Liaoning Provincial Chemotherapy Professional Committee Member of the Chinese Medical Association Liaoning Provincial Tumor Branch Member of the Eighth and Ninth Committees of the Science Society Chinese General Surgery Literature (Electronic Edition) Editorial Board Member of the Chinese Electronic Journal of Colorectal Diseases Special Expert Reviewer, National Natural Science Foundation of China Project Reviewer, National Health Commission, Science and Technology Project Reviewer, National Ministry of Education Science and Technology Project review expert, Professor Xu Huimian, National Second-Class Professor, Special Allowance Expert of the State Council, Doctoral Supervisor, Visiting Professor of Dalian University, Director of the Cancer Center of the First Affiliated Hospital of China Medical University, Director of the Oncology Branch of the Chinese Medical University 11th Chairman of the Chinese Anti-Cancer Association The chairman of the gastric cancer professional committee and other academic consultation experts of the Central Health Care Committee have long been committed to exploring the law of tumor metastasis and optimizing the work of clinical standard diagnosis and treatment.
They have made outstanding contributions to improving the level of tumor prevention and treatment in Liaoning Province and even the whole country.
Won the 10th Chinese Physician Award, Outstanding experts of the Liaoning Provincial Government, the first Liaoning famous doctor and other honorary titles successively presided over and undertook to publish 161 domestic core journal papers based on the Natural Science Foundation projects and 19 national, provincial and ministerial scientific research projects such as "863" and "973", included in SCI Published 93 papers, with a cumulative impact factor of more than 300, edited 2 monographs on gastric cancer.
In 2001 and 2006, it won the second prize of National Science and Technology Progress Award and a number of provincial and ministerial science and technology progress awards.
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Professor Xu Huimian's comment | Imaging and ctDNA Monitoring the efficacy and prognosis of comprehensive treatment of potentially resectable CRLM 2.
Professor Zhao Changlin: My opinion on the comprehensive treatment of colorectal cancer liver metastasis combined with lung metastasis 3.
Professor Zhao Changlin: "Same function but different effect" APOLLO study is dynamic monitoring of drug resistance by ctDNA liquid biopsy New evidence for the efficacy of advanced cancer patients 4.
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Special talks | Professor Changlin Zhao, Professor Huimian Xu: Progress in comprehensive treatment of advanced gastric cancer (1) 6 .
Thematic Written Talk｜Professor Zhao Changlin and Xu Huimian: Progress in comprehensive treatment of advanced gastric cancer (2)