Actual case experts comment on recurrence and metastasis of advanced gastric cancer in frail elderly

Commenting expert: Professor Xu Huimian, Professor Zhao Changlin, First Affiliated Hospital of China Medical University, Compiled by Professor Zhao Changlin, Dalian University Xinhua Hospital: Actual case of Professor Zhao Changlin｜Recurrence and metastasis of advanced gastric cancer in frail elderly patients, recurrence surgery + apatinib treatment, survival benefit (Click to read) "Actual case" is different from "Excellent Case Display" and "Case Sharing"
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The diagnosis and treatment process of clinically rare and more complicated cases and the problems and disputes involved in the diagnosis and treatment process are provided to colleagues for discussion, hoping to achieve the results of learning, communication, and improvement
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The diagnosis and treatment of this case includes two stages: diagnosis and treatment of primary gastric cancer and diagnosis and treatment of recurrence and metastasis of advanced gastric cancer.
Microsatellite instability (MSI) and mismatch repair genes (MMR) are involved in the diagnosis and treatment process.
Then the case comment Just start with MSI/MMR
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First, let’s talk about the significance and problems of MSI/MMR testing based on the case.
MSI/MMR are two different biological mutations.
MMR detection is achieved by immunohistochemistry (IHC).
IHC indicates that the negative expression of any MMR protein (MLH1, MSH2, MSH6, PMS2) is a mismatch repair gene defect (dMMR).
)
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If all 4 MMR proteins are positively expressed, it is called complete mismatch repair gene (pMMR)
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MSI detection uses PCR capillary electrophoresis to detect different sites of DNA microsatellites
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With the deepening of research on MSI/MMR, clinicians are also deepening their understanding of MSI/MMR
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The relationship between MMR and MSI is close, but there are also cases of inconsistency
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The reason is that the objects detected by the two methods are different, and the two detection methods are inconsistent in principle
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Due to factors such as detection accuracy and tumor heterogeneity, the coincidence rate between MMR-IHC and MSI-PCR is about 90%, but for patients with dMMR detected by IHC, they are truly MSI-H patients.
The ratio is low, resulting in dMMR and MSI-H not exactly the same
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Therefore, we cannot simply think of dMMR=MSI-H
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Many international studies have shown that the primary drug resistance of immunotherapy in "dMMR/MSI-H" patients is mostly due to misjudgment of MMR or MSI status
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These patients are not real "dMMR or MSI-H" patients, but "pMMR or MSS" patients
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Meta-research analysis showed that the detection rate of MMR evaluated by IHC alone was 88%~89%, and the detection rate of MSI evaluated by PCR alone was 95%~99.
7%.
The combined detection of the two methods can avoid misjudgment to the greatest extent
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Therefore, MMR-IHC cannot completely replace MSI-PCR
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It is worth emphasizing that, due to the obvious heterogeneity of gastric cancer, when judging the sensitivity of gastric cancer chemotherapy or primary drug resistance of immunotherapy, it is not appropriate to use IHC to detect MMR alone, but to combine MSI/MMR detection
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For patients with recurrence and metastasis of advanced gastric cancer, a single test of MSI/MMR may not be enough.
Sometimes a second test is required, and even metastatic lesions need to be detected
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Taking colorectal cancer (CRC) as an example, the functional status of MMR gene can affect the chemotherapy effect of fluorouracils in stage II colon cancer
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There is no controversy about the conclusion that patients with dMMR type II CRC cannot benefit from fluorouracil single-agent chemotherapy, but their prognosis is significantly better than that of pMMR patients
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Therefore, MMR-IHC should be done after stage II CRC to decide whether to perform adjuvant chemotherapy
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For patients with advanced gastric cancer and metastatic colorectal cancer (mCRC), when choosing nivolumab as the first-line treatment, MSI/MMR needs to be tested
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MSI/MMR detection can be used as a primary screening method for Lynch syndrome/Lynch syndrome-related tumors
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The first edition of the NCCN Guidelines for Gastric Cancer in 2021 has made an important update.
It is recommended that all newly diagnosed gastric cancer patients undergo routine MSI/MMR testing, but this is only a recommendation
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At this stage in China, due to national conditions and various reasons, it is unrealistic to recommend routine MSI/MMR testing for all newly diagnosed gastric cancer patients, and it is not under the control and control of clinicians
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There may still be a long way to go before MSI/MMR routine testing is truly performed on all newly diagnosed gastric cancer patients
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The MSI/MMR test was the first to be used in the diagnosis and treatment of CRC in the United States.
What about the current status of MSI/MMR testing in the treatment of CRC in the United States? In 2019, the United States published the "Investigation Report on the Detection of MSI/MMR in the Treatment of MCRC Patients by American Doctors" [Eriksson,et al.
J.
Clin.
Med.
2019,8(4):558.
]
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151 doctors (including 91 medical oncologists, 15 surgeons and 45 pathologists) underwent an online survey
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The survey results show that 68.
9% of doctors will routinely submit MSI/MMR, and 29.
8% of doctors will selectively submit MSI/MMR
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The main obstacles to MSI/MMR testing are insufficient tissue sample size (48.
3%); patients refuse to do testing (35.
8%); patients are concerned about insurance premium overruns (31.
1%); appointment testing has not encountered any obstacles (27.
2%)
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Obstacles to MSI/MMR detection
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(Figure 1 can be zoomed in) Figure 1 Investigation report on MSI/MMR detection by American doctors in the treatment of mCRC patients: Obstacles to MSI/MMR testing Although American doctors have a high level of awareness and compliance with MSI/MMR testing, it seems that patients with MSI/MMR have a high level of awareness and compliance with MSI/MMR testing.
The MMR detection rate is not very satisfactory
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Due to different national conditions in China and affected by various reasons, the penetration rate of MSI/MMR testing for patients with stage II to IV CRC is far lower than that of the United States
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This is the case with CRC, let alone stomach cancer? This case was undergoing radical gastric cancer surgery in November 2019.
The doctor recommended MSI/MMR testing to the patient’s family, and explained the value of MSI/MMR testing for follow-up treatment.
The family did not tell the patient the truth about gastric cancer and the inconvenience to communicate with the patient MSI The value of the /MMR test is politely rejected for the first MSI/MMR test
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In clinical diagnosis and treatment, doctors have exercised their duty of notification and responsibilities, and respected the right of choice of patients’ family members.
This is something that is often encountered in clinical work and is beyond reproach
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For elderly patients with stage III gastric cancer after radical resection, ECOG PS 1 should not give up adjuvant chemotherapy if MSI/MMR status is not clear, or only dMMR is clear, but MSI-H is unknown
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Advanced gastric cancer is a general term for gastric cancer that covers T2N1M0～4bNanyM0.
It has the characteristics of different clinical manifestations, different heterogeneity, diverse molecular types, and different biological behaviors of tumors.
The treatment effect is still not satisfactory, the prognosis is poor, and it is easy to relapse.
And transfer
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Surgical surgery alone cannot achieve a radical cure in the biological sense, and a preliminary consensus has been reached in gastric cancer surgery
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At present, the standard mode, perioperative chemotherapy and adjuvant chemotherapy regimens for advanced resectable gastric cancer treatment at home and abroad have not yet reached a unified
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The Japanese and Korean guidelines recommend D2 surgery + adjuvant chemotherapy as the representative model; the new Chinese guidelines recommend D2 surgery + adjuvant chemotherapy for cT2-3N0-2M0, cIB-ⅡA stage resectable gastric cancer, and for cT3-4aN+M0, cⅢ For resectable gastric cancer, neoadjuvant chemotherapy + D2 surgery + adjuvant chemotherapy is recommended for perioperative chemotherapy
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However, most of the high-level evidence in the new Chinese guidelines comes from foreign research institutions such as Europe and the United States, and needs clinical verification and in-depth exploration in China
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The FLOT4 regimen (Docetaxel+Oxaliplatin+Fluorouracil) is the first choice for perioperative chemotherapy in advanced resectable gastric cancer in Europe and America
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In 2019, ESMO Korea announced the DOS program (Docetaxel+Oxaliplatin+S-1) researched by PRODIGY and in 2020 ASCO GI China announced the SOX program (Oxaliplatin+Tigio ) Perioperative chemotherapy can significantly increase R0 resection rate and pCR rate, prolong DFS and OS, and has good safety
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The ARTIST2 study and the RESOLVE study established the SOX regimen in adjuvant chemotherapy for advanced gastric cancer with positive lymph nodes
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The adjuvant chemotherapy regimens represented by SOX and XELOX are significantly better than S-1 single agent in the benefit of patients with DFS
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The 2020 version of the CSCO Gastric Cancer Guidelines recommends adjuvant chemotherapy for advanced gastric cancer stratified by TNM staging; 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
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2020 CSCO guidelines for adjuvant chemotherapy for gastric cancer
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(Figure 2 can be enlarged) Figure 2 2020 CSCO gastric cancer adjuvant chemotherapy regimen This case is an elderly patient with stage III gastric cancer after radical resection, pT4aN1M0, invaded nerves, and tumor thrombi were seen in the vessels
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ECOG PS 1
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In the case of refusing MSI/MMR testing, he agreed to accept SOX regimen adjuvant chemotherapy
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One cycle of adjuvant chemotherapy is mainly due to the intolerance of Tiggio's gastrointestinal adverse reactions
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In the intermittent period of adjuvant chemotherapy, continuous abdominal distension, lack of diet accompanied by nausea or vomiting and stagnation of food, gastroparesis and gastric retention occur, symptomatic supportive treatment is given, and adjuvant chemotherapy is postponed for 20 days
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Considering the serious adverse reactions of the digestive tract in elderly patients and the cardiotoxicity of gastroparesis and fluorouracils, it is not suitable to use SOX or XELOX regimens
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Based on the 02GO2 study, with reference to the DOS and FLOT4 regimens, we tried to withdraw Tiggio's docetaxel + oxaliplatin two-agent chemotherapy in the second to third cycles; in the fourth cycle, docetaxel single-agent chemotherapy was used
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It should be said that the treatment of elderly patients with stage III gastric cancer after radical resection is reasonable and moderate
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At the stage of diagnosis and treatment of recurrence and metastasis of this case, the patients and their families were fully communicated and agreed to perform the MSI/MMR status and BRAF V600E detection of the primary gastric cancer before the radical resection, and the MSI/MMR status of the metastasis after the operation
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This is a wise choice for both doctors and patients, and it is not easy to take this step
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The MMR-IHC of the primary lesion was MLH1(-), PMS2(-), suggesting dMMR; MSI-NGS (second-generation sequencing) was MSI-H; BRAF V600E was detected as mutant
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The MSI-H/dMMR status of the primary tumor and the BRAF V600E mutation are clarified, which provides a reference for subsequent treatment and assessment of prognosis
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How to treat the negative expression of MLH1 and PMS2 in IHC? Combining this case, talk about how to diagnose Lynch syndrome/Lynch syndrome-related tumors and sporadic gastric cancer? Under normal circumstances, MLH1 and PMS2, MSH2 and MSH6 are coupled together.
The MSH2 protein first recognizes and binds the mismatched DNA sequence, and forms a dimer with MSH6, and then MLH1 and PMS2 form a heterodimer.
, Adjust base mismatches to complete DNA repair
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How to treat the negative expression of MLH1 and PMS2 in IHC? There are two situations: (1) Germline mutations from MLH1 and PMS2 genes cause Lynch syndrome/Lynch syndrome-related tumors; (2) Methylation in the promoter region of MLH1 gene or BRAF V600E gene mutations, resulting in Because the MLH1 gene is silent, the PMS2 protein coupled with it is negatively expressed, which is a sporadic tumor
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Therefore, for patients with gastric cancer, only the negative expression of MLH1 and PMS2 proteins shown by IHC cannot diagnose Lynch syndrome/Lynch syndrome-related gastric cancer.
Further testing of BRAF V600E gene status or MLH1 gene promoter region methylation status, or MMR is needed.
Gene germline mutation detection can be diagnosed as Lynch syndrome or Lynch syndrome-related tumors
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Lynch syndrome/Lynch syndrome-related tumor diagnosis process
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(Figure 3 can be enlarged) Figure 3 Lynch syndrome/Lynch syndrome-related tumor diagnosis process At present, the U.
S.
Food and Drug Administration (FDA) has not approved the use of MLH1 gene promoter region methylation detection and MMR gene germline mutation detection technology The clinical germline screening for Lynch syndrome is limited to clinical research in the laboratory
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Therefore, it is necessary to be cautious to perform germline screening for Lynch syndrome in patients with a strong family history
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It is worth emphasizing here that, as a clinician, you should not diagnose Lynch syndrome only based on the MLH1(-) and PMS2(-) displayed by IHC in patients with gastric cancer
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About 50% to 80% of Lynch syndrome occurs in the colorectal, accounting for about 2% to 3% of all colorectal cancers
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Lynch syndrome-related endometrial cancer accounts for about 2% of all endometrial cancers
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The average age of diagnosis of Lynch syndrome-related gastric cancer is 56 years old.
It is common in small intestinal adenocarcinoma.
It accounts for about a percentage of all gastric cancers.
No authoritative report has been published, suggesting that Lynch syndrome-related gastric cancer is a rare tumor
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Although the NCCN colon cancer guidelines were released in 2019, 1% of BRAF V600E mutation patients with negative MLH1 protein expression in colon cancer may still have Lynch syndrome
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However, this extremely rare situation occurs only in patients with BRAF V600E mutations with negative expression of MLH1 protein in colon cancer, and has not been found in patients with BRAF V600E mutations with negative expression of MLH1 protein in other cancers
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The 79-year-old gastric cancer patient in this case showed MLH1(-) and PMS2(-) on IHC, while NGS showed BRAF V600E mutation.
There is no strong family history.
Lynch syndrome or Lynch syndrome-related gastric cancer can be ruled out, and the diagnosis is sporadic gastric cancer
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The treatment strategy of sporadic gastric cancer is different from that of Lynch syndrome or Lynch syndrome-related gastric cancer
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MSI/dMMR stage III gastrointestinal tumors can benefit from adjuvant chemotherapy? At present, it is still controversial whether patients with MSI stage III gastric cancer and stage III CRC can benefit from adjuvant therapy
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The "Meta-analysis of individual patient data on the value of MSI as a biomarker for gastric cancer" published in September 2019 included 1556 patients with resectable gastric cancer from four studies of MAGIC, CLASSIC, ITACA-S and ARTIST, of which 121 were MSI-H (7.
8%), to analyze the relationship between the MSI status of gastric cancer and the prognosis of chemotherapy/surgery
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Compared with surgery alone, MSS/MSI-L gastric cancer patients with chemotherapy + surgery benefited from both DFS and OS, while MSI-H gastric cancer patients did not benefit from chemotherapy (Pietrantonio et al.
Journal of Clinical Oncology, 2019,37(35) :3392.
)
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MSI means MSI-H/MSI-L
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In this meta-analysis, patients with MSI-L gastric cancer benefited from chemotherapy plus surgery
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However, this meta-analysis of multi-country and individual patient data did not analyze the relationship between gastric cancer MSI-H/MSI-L and the prognosis of chemotherapy/surgery, but analyzed the relationship between MSS/MSI-L status and the prognosis of chemotherapy/surgery, and did not analyze the relationship between To further analyze the relationship between MSI-H/MSI-L status and the prognosis of chemotherapy/surgery in the subgroups of stage and Ⅲ patients, it is inevitable that the subgroup sample size is small and the data is unbalanced and biased, resulting in the limitation of insufficient statistical power Sexual issues
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Therefore, it is not yet possible to draw a positive conclusion that patients with MSI-H stage III gastric cancer cannot benefit from adjuvant chemotherapy, and further exploration is needed
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On December 23, 2020, Cohen R, et al.
J Clin Oncol published online "MSI stage III colon cancer can benefit from oxaliplatin-containing adjuvant chemotherapy: a meta-analysis of 12 randomized clinical trials
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"
(Figure 4 can be enlarged) Figure 4 Meta-analysis of MSI stage III colon cancer benefiting from oxaliplatin-containing adjuvant chemotherapy This meta-analysis included 5457 cases from 12 randomized clinical trials who underwent MSI status testing III Among patients with stage colon cancer, 609 cases (11.
2%) were MSI; 4848 cases (88.
8%) were MSS
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To evaluate the effect of FP + oxaliplatin on DFS and OS in patients with MSI stage Ⅲ colon cancer and the prognostic value of FP + oxaliplatin in the treatment of patients with MSI stage Ⅲ colon cancer
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Among the 4250 patients who received FP+Oxaliplatin treatment, 461 were MSI and 3789 were MSS
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Conclusion: MSI stage Ⅲ colon cancer can benefit from adjuvant chemotherapy containing oxaliplatin.
Compared with MSS stage Ⅲ colon cancer, patients with MSI stage Ⅲ colon cancer N1 group have better OS
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The results of PETACC-8 and NCCTG N0147 were confirmed, and the prognosis of BRAF wild-type and BRAFV600E mutant MSI stage III colon cancer patients was not significantly different
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In July 2019, a French researcher (Taieb, et al.
Ann Oncol.
2019.
7.
3) published an online research report on “The MSI/dMMR phenotype of stage III colon cancer suggests better survival after adjuvant chemotherapy”
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(Figure 5 can be enlarged) Figure 5 MSI/dMMR phenotype of stage III colon cancer recurred after adjuvant chemotherapy, 2630 patients with stage III colon cancer who relapsed after receiving adjuvant chemotherapy from 7 clinical trials.
The results of multivariate analysis showed that, Among patients with stage III colon cancer who recurred after adjuvant chemotherapy, the survival rate (SAR) after recurrence of MSI/dMMR phenotype III colon cancer was significantly better than that of MSS/pMMR phenotype III colon cancer
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These research results from stage III colon cancer provide a reference for formulating comprehensive diagnosis and treatment strategies for MSI stage III gastric cancer
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We look forward to the results of meta-analysis and high-level evidence evaluating the impact of adjuvant chemotherapy on the prognosis of patients with MSI stage III gastric cancer
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The treatment of recurrence and metastasis of advanced gastric cancer is very difficult, the progress of comprehensive treatment is relatively lagging, and there is a lack of large-sample prospective research data
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Regarding the treatment of recurrence and metastasis of advanced gastric cancer after radical resection, there is no unified and standardized treatment strategy in the world
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In the 2020 version of the CSCO guidelines, the level I recommendation for comprehensive treatment of local recurrence of advanced gastric cancer is still treated as recurrent and metastatic gastric cancer or participating in clinical trials
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(Figure 6 can be enlarged) Figure 6 2020 version of the CSCO guidelines for advanced gastric cancer local recurrence comprehensive treatment of advanced gastric cancer postoperative recurrence or single metastasis patients who undergo recurrence surgery can survive up to 25.
8 months, and the metastasis resection + radical resection+ Systemic drug treatment can prolong the survival time of patients and improve the quality of life
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The CLASS series of studies provide high-level evidence-based evidence for global gastric cancer laparoscopic surgery and form the Chinese standard for minimally invasive surgery
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In this case, laparoscopic surgery was used for both primary and metastatic radical surgery in the frail elderly patient with resectable gastric cancer, which reached the NED goal, with little trauma and quick recovery
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The MSI/MMR status and BRAF V600E detection of the patient's primary tumor, the imaging examination and MDT after recurrence and metastasis are fully evaluated, and it plays an important role in mastering the indications for re-laparoscopic radical surgery + postoperative treatment
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How to treat the elderly and frail patients with recurrence and metastasis of MSI-H/dMMR stage III gastric cancer? There is no authoritative "diagnosis and treatment guide" to follow
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Adjuvant treatment after radical resection for recurrence and metastasis of stage Ⅲ gastric cancer is different from that of non-metastatic and resectable stage Ⅲ gastric cancer
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So what is the difference? Taking metachronous potentially resectable colorectal cancer liver metastases as an example, patients who have successfully resected liver metastases from conversion therapy need to receive adjuvant therapy for 6 months, and proven effective programs (including combined molecular targeted drugs) should be the first choice of adjuvant The treatment plan, the non-metastatic resectable stage III CRC postoperative adjuvant treatment but no combination of molecular targeted drugs, this is the biggest difference
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The AHEAD-G203 study is a prospective, multi-center, non-interventional clinical study.
Half of the patients have first-line and second-line advanced gastric cancer
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The results of the study show that apatinib can bring clinical benefits to patients with advanced gastric cancer whether it is in the third-line, first-line or second-line treatment
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This patient with MSI-H/dMMR stage III gastric cancer recurrence and metastasis needs adjuvant treatment after re-radical resection
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In the case of MSI-H resectable gastric cancer that does not benefit from chemotherapy after surgery, and the patient is old and weak, in the case of ECOG PS 2, apatinib or navuliyu should be selected according to the third-line treatment plan for recurrent and metastatic gastric cancer Monoclonal antibody treatment, and explain the efficacy and adverse reactions of the drug to patients and their families, especially for patients who are close to the elderly, to explain the cardiotoxicity of immunotherapy
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After weighing the efficacy and adverse effects of the drug, apatinib was selected as the adjuvant treatment.
Clinical practice has proved that it is safe and effective, and the patient is benefited in terms of survival and quality of life
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Finally, I will conclude the case review with a passage made by Academician Fan Daiming when he gave a report on "Reshaping of Medical Culture" at the 4th National Cancer Center Colorectal Cancer International Summit Forum and Academician Forum in 2019
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“I don’t pay attention to the overall condition of the patient and the characteristics of the disease.
I memorize the NCCN guidelines by rote, and I am a bad oncologist; I have NCCN guidelines brochures in my white coat pockets
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In the entire diagnosis and treatment process of patients, it is necessary to refer to the guidelines for cancer diagnosis and treatment, and to pay more attention to the overall situation of cancer patients and individualized diagnosis and treatment, and strive to be "tailor-made" and "tailor-made" for cancer patients
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This is the essence of medical culture
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