The roundtable focused on gastric cancer immunotherapy, and experts discussed the optimization of treatment processes and modes to enhance the efficiency and attenuation of immunotherapy

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01

Professor Wang Caixia: The results of GC immunotherapy research are mixed, and strict indications are particularly critical

With nearly 1 million new cases each year, GC is the fifth most common cancer worldwide and the third leading cause of
cancer death.
Because early GC symptoms are insidious, most patients are locally advanced or advanced at the time of diagnosis, less than 50 percent of patients diagnosed can be completely resected by surgery, and the current expected survival for palliative care GC patients is barely more than one year ^[2,3].

In recent years, immunotherapy has brought new hope for the treatment of advanced GC, and new explorations have been made
for the perioperative treatment of locally advanced GC.
But results on immunotherapy are mixed
.

Hi-Microsatellite instability/mismatch gene repair deficiency (MSI-I/dMMR) patients are the advantageous group of immunotherapy benefits, and immunomonotherapy is more effective
than chemotherapy.
Chinese and foreign guidelines consistently recommend that immunotherapy is the preferred regimen for patients with MSI H/dMMR, regardless of the number of lines; Regardless of the number of lines and HER-2 status, immunotherapy is an option for other patients, especially first-line therapy, and combination therapy with immunotherapy should be the first choice
.
In addition, HER2 as an important therapeutic target for gastric cancer, a number of clinical studies of anti-HER-2 drugs combined with immunotherapy are in full swing, it is believed that in the near future, the drug layout and clinical outcomes of the whole course of treatment for HER-2-positive gastric cancer patients will have major changes (Table 1).

Worry - There are multiple failed phase III clinical studies
in advanced gastric cancer.
For patients with potentially curable locally advanced GC, reliable immunotherapy strategies are still exploratory
.
In addition, many phase II clinical trial treatment options are complex, immunotherapy and two-drug regimens (using oxaliplatin or cisplatin combined with capecitabine or tegio-io or fluorouracil), three-drug regimens (platinum-containing two-drug combination with paclitaxel or docetaxel or epirubicin), and antiangiogenic drugs have reported preliminary results
.
However, whether the treatment plan requires the screening of molecular markers is also the direction of neoadjuvant immunotherapy ^[4,5].

At present, biological agents "a hundred schools of thought", related drawbacks and advantages gradually emerge, in clinical practice, doctors strictly control the indications for medication is particularly important
.

Table 1 Clinical studies of HER-2 drugs combined with immunotherapy ^[6]

02

Professor Liu Lian: GC "immunotherapy" has emerged, and follow-up research needs to be deepened and expanded

With the update of CheckMate 649 and ORIENT 16 research data, immunotherapy has gradually occupied an important position
in the first-line treatment of advanced gastric cancer.
However, current treatments cannot solve the problem
of first-line immunotherapy for all or most gastric cancers.

First, there are still many limitations
in how to choose the beneficial population of immunotherapy.
Defined by the combined positive score (CPS), both large studies have demonstrated that patients with CPS≥5 are likely to benefit significantly from
immune combination chemotherapy.
The population with CPS<5, including CPS 1~4 and CPS<1, did not benefit significantly<b12>.
However, due to the dynamic changes in the expression of PD-L1 and the gap between different PD-L1 monitoring technologies, the scope of adaptation can be appropriately expanded ^[7,8].

Second, the evidence for immune combination chemotherapy is limited to single-immune combination chemotherapy regimens, and although PD-L1 monoclonal antibody combined with CTLA-4 monoclonal antibody or combination chemotherapy has been tried in this year's study, no positive results have been presented; Neither CheckMate 649's simple double exemption nor Moonlight's study of double immune combination chemotherapy have shown significant efficacy over chemotherapy
.
This suggests that the strategy of immunotherapy in combination with chemotherapy needs to be further explored ^[9,10].

Third, whether the efficacy of double immunity therapy will be impaired due to excessive toxic side effects, and whether it can reduce toxic side effects by targeting two targets at the same time, need more research to verify
.

In addition, there are still many unsolved problems, such as whether immunotherapy is cross-line application after the progress of first-line immunotherapy combined with chemotherapy, and traditional indicators such as PD-L1, MSI-H, and TMB cannot predict drug susceptibility problems in all patients, which need to be further explored and solved
through basic research, clinical research and translational research.
On the one hand, through the combination of treatment strategies and whole-process management of drugs with multiple mechanisms of action, on the other hand, it is necessary to dig deep into the mechanism and strive for accurate prediction, so that immunotherapy can enter the road of precision treatment and bring more benefits
to patients.

03

Professor Jun Wang: Prevention-Assessment-Multidisciplinary Management-Treatment-Follow-up, Multi-link Reduction of Immunotherapy irAEs

Immunotherapy is highly specific for tumor-specific
antigens by stimulating a host immune response to destroy localized and metastatic cancer cells.
At present, immunotherapy has become a new way of GC treatment, and its therapeutic indications are increasing
.
However, while immunotherapy improves the efficacy of GC, it may also lead to immune system disorders due to its specific mechanism of action and the occurrence of immune-related adverse events (irAEs).

Therefore, proper understanding of the toxic side effects of immunotherapy and appropriate management are critical to patient outcomes ^[11].

The safety management of immunotherapy mainly includes five aspects
.
First, prevention
.
Before initiating immunotherapy, identify the risk group
for adverse events.
Patients with a history of autoimmune disease, chronic viral infection, and organ dysfunction are at high risk
.
For example, patients with thymoma, tuberculosis, hepatitis B, etc.
, need anti-tuberculosis or antiviral intervention before considering immunotherapy
.
Second, assessment
.
Baseline testing of patients is necessary to distinguish between underlying disease and toxic side effects
prior to immunotherapy.
In the process of immunotherapy, clinicians should continuously improve their ability to discriminate, and at the same time, familiarize patients with relevant precautions and pay close attention to symptom changes, which can help reduce the risk of
toxicity.
Third, multidisciplinary monitoring
.
Essential
to reduce the impact of toxicity.
irAEs involve multiple systems and organs, and strengthening the monitoring and cooperation of related disciplines for the performance of different systems and organs is conducive to preventing the occurrence
of toxic side reactions.
Fourth, deal with irAEs
.
Different toxicity levels have different response measures, which require doctors to fully grasp the patient's condition, cooperate with multidisciplinary monitoring, and carry out timely and effective treatment
.
Fifth, follow-up
.
It is recommended to carry out follow-up monitoring every 3~6 months after the end of treatment, and the monitoring items include general condition, biochemical examination and imaging examination
.
If irAEs reappear during follow-up monitoring, they can be treated according to the principles described above (Figure 1) ^[12,13].

Fig.
1 Safety management of immunotherapy ^[12,13].

04

Professor Li Minghuan: Further clarify the population that may benefit from radiotherapy, and gradually optimize the perioperative treatment mode of GC

At present, radical surgery is the only cure for gastric cancer, and distant metastasis, peritoneal metastasis, and local regional recurrence are the three major modes of recurrence of gastric cancer after surgery, and they are also the main causes of
patient death.
Gastric cancer itself is a malignant tumor with high heterogeneity, and different primary lesion sites, lymph node dissection range, staging, pathological classification, perioperative treatment mode and other factors all affect
the recurrence of tumors.
Over the past few decades, postoperative adjuvant radiotherapy has been shown to improve the long-term prognosis
of gastric cancer patients.
In the past two decades, the research on neoadjuvant therapy for gastric cancer has also achieved initial results, but there are still controversies
in terms of program selection and applicable population.
The role and status of radiotherapy in tumor treatment have become increasingly prominent and have become one of the important means for the treatment of
malignant tumors.
However, patients with gastric cancer should be clear when choosing radiotherapy ^[14].

At present, there is no strong evidence
for routine adjuvant radiotherapy in patients after gastric cancer surgery.
Although some studies have shown that postoperative radiation therapy may be beneficial in patients with lymph node stage N3 or metastases > 25%, people with later N stage are at high risk of distant metastases or peritoneal metastases
.
Jee Suk Chang et al.
reviewed the recurrence pattern of 382 N3 patients who underwent radical D2 resection, with a median follow-up time of 56.
3 months, 63.
4% of patients experienced recurrence, 44.
0% of patients had the first single-site recurrence, of which peritoneal recurrence reached 20.
7%, which was the most common single-site recurrence
.
Therefore, laparoscopic exploration prior to treatment to exclude peritoneal metastases is essential in these patients ^[15].

The clinical evidence of gastric cancer with neoadjuvant radiotherapy is mostly concentrated in the lower esophageal and gastroesophageal junction cancers, and the clinical evidence of related distal gastric cancer is lacking
.
From the available studies, neoadjuvant radiotherapy can improve the rate of R0 resection and pathological complete response (pCR), and the safety is better than adjuvant radiotherapy
.
However, the comparison of neoadjuvant chemoradiotherapy and adjuvant chemotherapy needs to wait for the release of the results of three clinical trials such as TOPGEAR ^[16].

The optimization of the treatment model is also worth considering
.
In the past, postoperative adjuvant chemoradiotherapy has been a sandwich mode of "chemotherapy + radiotherapy + chemotherapy", which has been shown to have no significant impact on the survival prognosis of patients compared with adjuvant chemotherapy, while patients will achieve better survival outcomes after full course chemotherapy followed by radiotherapy and enhanced local control ^[16]
.

05

Professor Wang Caixia concluded:

Globally, the prevalence of GC is rising, patients benefit from traditional treatment methods to a limited extent, immunotherapy is a pioneering way to break the bottleneck and move the treatment towards a more effective and rational model, which has changed the treatment of
gastric cancer.
It is worth noting that the instability of malignant tumor cells and the dynamic changes of their microenvironment may make the immunotherapy effect of a single pathway limited, and the development of combination therapy for multiple molecular pathway-mediated immunomodulatory mechanisms and continuous optimization of neoadjuvant chemoradiotherapy treatment mode will achieve better survival outcomes
.

Expert profiles

Professor Wang Caixia

Doctor of Medicine, Chief Physician, Master Supervisor, Well-known Expert

Director of the Department of Chemotherapy, Cancer Center

Provincial Hospital Affiliated to Shandong First Medical University

Chairman of Oncology Precision Medicine Physician Branch of Shandong Medical Association

Chairman of the Biological Targeted Therapy Professional Committee of Shandong Gerontology and Geriatrics Society

Head of the Immunotherapy Collaboration Group of Oncology Precision Medicine Physician Branch of Shandong Medical Association

Member of the Cancer Support and Rehabilitation Group of the Oncology Branch of the Chinese Medical Association

Expert consultant of the "standardized diagnosis and treatment of lung cancer" project of the National Health Commission

Member of the 6th Council of the Chinese Society of Gerontology and Geriatrics

External expert of Shandong Province Adverse Drug Reaction Monitoring Center and Drug Abuse Monitoring Center

Vice Chairman of the Multidisciplinary Comprehensive Oncology Professional Committee of Shandong Medical Association

Standing director of Shandong Gerontology and Geriatrics Society

Vice Chairman of the Neuroendocrine Oncology Professional Committee of Shandong Medical Association

Vice Chairman of the Biotherapy Branch of Shandong Anti-Cancer Association

Director of the Medical and Health Work Committee of Shandong Province of the Peasants' and Workers' Party

Expert profiles

Prof.
Lian Liu

Director of the Department of Medical Oncology, Qilu Hospital, Shandong University, Professor, Doctoral Supervisor

Chief physician

Deputy Director of the Department of Oncology, Qilu Medical College, Shandong University

Chairman of the Tumor Molecular Markers and Targeted Therapy Committee of Shandong Immunology Society

Chairman of the Immunotherapy Committee of Shandong Clinical Oncology Society President of the Oncology Ethics Branch of Shandong Medical Ethics Society

Member of CSCO Immunotherapy/Thyroid Cancer/Cancer Nutrition Therapy Expert Committee

Member of the Internal Medicine Group of the Gastric Cancer Professional Committee (CGCA) of the Chinese Anti-Cancer Association

Member of the Standing Committee of the Cancer Chemotherapy Committee of the Chinese Health Science and Technology Promotion Association

Standing director of Shandong Immunology Society

Vice Chairman of the Organoid Committee of Shandong Medical Association/Multidisciplinary Committee of Urogenital Tumors

Vice Chairman of the Oncologist Branch of Shandong Medical Association

Vice Chairman of the Cell Therapy Technology and Standards Committee of Shandong Society of Pharmaceutical Biotechnology

Vice Chairman of the Science Education/Tumor Microecology Special Committee of Shandong Society of Immunology

Vice Chairman of the Lung Cancer Committee of Shandong Medical Education Association

Vice Chairman of the Cancer Metastasis Committee of Shandong Research Hospital Association

Vice Chairman of the Integrative Oncology Committee of Shandong Pain Medical Association

Vice Chairman of Oncology Precision Medicine Branch of Shandong Geriatrics Association

Data verifier of the Center for New Drug Evaluation of the State Food and Drug Administration

Expert of the National Doctoral and Master's Thesis Review of the Degree Center of the Ministry of Education

Correspondence review expert of the National Natural Science Foundation of China

Shandong Science and Technology Expert Database Fund Final Review Expert

Expert of science and technology project review in Zhejiang Province, Jiangsu Province and Beijing Municipality

Expert profiles

Professor Wang Jun

Deputy Director of Oncology, Chief Physician, Ph.
D.
, Doctoral Supervisor, Deputy Director of Shandong Lung Cancer Institute

Director of Chinese Society of Clinical Oncology

Vice Chairman and Secretary-General of the Immunotherapy Expert Committee of the Chinese Society of Clinical Oncology

Vice Chairman of the Patient Education Expert Committee of the Chinese Society of Clinical Oncology

Member of the Expert Committee of Non-Small Cell Lung Cancer of the Chinese Society of Clinical Oncology

Director of Shandong Society of Immunology

Visiting Professor, MD Anderson Cancer Center, University of Texas, USA

Communication review expert of the National Natural Science Foundation of China

He has presided over 3 projects of the National Natural Science Foundation of China, 2 projects of the Natural Science Foundation of Shandong Province, the author of "Guidelines for the Management of Toxicity Related to CSCO Immune Checkpoint Inhibitors" and "Guidelines for the Clinical Application of CSCO Immune Checkpoint Inhibitors", 3 monographs as editor-in-chief/chief translator, published more than 40 SCI papers as the first/corresponding author, and won 3 second prizes for scientific and technological progress / achievements at the military and provincial levels

Expert profiles

Professor Lee Myung-hwan

Doctor of Oncology, Chief Physician

Director of the second ward of abdominal radiotherapy, Shandong Provincial Cancer Hospital

Professor of Shandong University, doctoral supervisor

Qilu health and health leading talents

The first outstanding young and middle-aged health care expert in Shandong Province

Member of the Standing Committee of Radiation Oncology Branch of Shandong Anti-Cancer Association

Youth Committee Member of Radiation Oncology of Chinese Anti-Cancer Association

Member of the Radiotherapy Professional Committee of Shandong Medical Association

Top 10 young scientists in Shandong Cancer Hospital

References: (swipe to view)

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Cao Maomao, Li He, Sun Dianqin, et al.
Epidemiological trend of gastric cancer in China from 2000 to 2019 [J].
Chinese Journal of Digestive Surgery,2021,20(01):102-109

2.
Ferlay J,Colombet M,Soerjomataram I,et al.
Cancer statistics for the year 2020:An overview[J].
Int J Cancer,2021.
[Online ahead of print].

3.
 Shitara K, Honma Y, Omuro Y, et al.
Efficacy of trastuzumab emtansine in Japanese patients with previously treated HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: A subgroup analysis of the GATSBY study[J].
Asia Pac J Clin Oncol,2020 Feb,16(1):5-13.

4.
Chen Bojin, Hu Xingyi, Zhao Jingwen, et al Research progress of immunotherapy in neoadjuvant therapy for gastric cancer[J].
Cancer Prevention and Treatment Research,2022,49(07):727-732

5.
Sun J, Li X, Chen P, et al.
From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer[J].
J Inflamm Res,2022,15:4061-4085.

6.
Wang Yakun, Shen Lin.
Inventory of gastric cancer treatment progress in 2020[J].
Electronic Journal of Comprehensive Oncology,2021,7(01):1-5

7.
Ji Gang, Wei Jiangpeng, Lu Qiang.
2022 V3 edition of NCCN Clinical Practice Guidelines for Esophageal and Esophageal and Gastric Junction Cancer[J/OL].
Chinese Clinical Journal of Thoracic and Cardiovascular Surgery:1-10[2022-10-05].

8.
Chen Junliang, Wang Fenghua.
2021 CSCO gastric cancer diagnosis and treatment guidelines for metastatic gastric cancer[J].
Chinese Journal of Oncology,2022,49(07):325-330

9.
Liu T, Bai Y, Lin X, et al.
First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis[J].
Int J Cancer, 2022 19.

10.
C.
Pauligk, T.
O.
Götze, P.
C.
Thuss-Patience, et al.
Al-Batran,1443P Modified FOLFOX versus modified FOLFOX plus nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction – Safety Results from AIO-STO-0417: A randomized phase II trial of the German Gastric Group of the AIO[J].
Annals of Oncology, 2020,31(4): S908.

11.
 Sang W, Zhang Z, Dai Y, et al.
Recent advances in nanomaterial-based synergistic combination cancer immunotherapy[J].
Chem Soc Rev,2019,48 (14):3771-3810.

12.
 Sanmamed MF, Chen L.
A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization[J].
Cell,2019,176(3):677.

13.
 Kichloo A, Albosta M, Dahiya D, et al.
Systemic adverse effects and toxicities associated with immunotherapy: A review.
World J Clin Oncol,2021,12(3):150-163.

14.
Rongshou Zheng, Siwei Zhang, Hongmei Zeng, et al.
Cancer incidence and mortality in China, 2016[J].
Journal of the National Cancer Center,2022, 2(1):1-9.

15.
Chang JS, Lim JS, Noh SH, et al.
Patterns of regional recurrence after curative D2 resection for stage III (N3) gastric cancer: implications for postoperative radiotherapy[ J].
Radiother Oncol,2012,104(3):367-73.

16.
Cai Gang, Wang Shubei, Chen Jiayi Current status and challenges of radiotherapy in the whole process management of gastric cancer[J] China Oncology,2022,32(07):581-587

Typesetting: Hu Haiyan

Editor: Wang Lina

Reviewed: Lina Wang

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