According to the Chinese Society of Clinical Oncology (CSCO) 2018 guidelines for the management of gastric cancer, the first recommended regimen for first treatment (i.e., first-line therapy) in advanced gastric cancer is trastuzumab in combination with fluorouracil or platinum for those who are HER2 (i.e., human epidermal growth factor receptor 2)-positive; for those who are HER2-negative Those with HER2 negative choose a fluorouracil-based regimen in combination with platinum or paclitaxel.
How can advanced gastric cancer be treated after first-line therapy has failed? What is the choice between chemotherapy, targeted therapy, and immunotherapy …… in second- and third-line treatment?
Second-line therapy
| Class I Recommendation | Class II Recommended | Class III Recommended | ||
| HER2 positive | ECOG : score 0 to 1 | Clinical studies | Trastuzumab in combination with paclitaxel if platinum therapy has failed and trastuzumab has not been used previously (Class 1A/2A evidence) | Trastuzumab in combination with a second-line chemotherapy regimen other than an anthracycline is recommended if trastuzumab has not been administered previously, see Second-line therapy drug selection for HER2-negative gastric cancer (Class 3 evidence) |
| ECOG: 2 points | Clinical studies | |||
| HER2 negative | ECOG : 0 to 1 score | Single-agent chemotherapy [docetaxel or irinotecan or paclitaxel] (Class 1 evidence) |
Two-drug combination with paclitaxel or fluorouracil-based chemotherapy (Class 2B evidence) |
Cisplatin or oxaliplatin as base chemotherapy if prior platinum-free therapy has failed (Class 3 evidence) |
| Clinical studies | ||||
| ECOG: 2 points | Single agent paclitaxel (Class 1A evidence) | |||
| Clinical studies | ||||
(swipe left and right to see full table)
Third-line therapy (regardless of HER2 positive or negative)
| Class I Recommendation | Class II Recommended | Class III Recommended | |
| ECOG : 0~1 points | Apatinib (Class 1A evidence) | Single-agent chemotherapy (Class 3 evidence) | Single-agent PD-1 monoclonal antibody (Class 1A evidence) |
| Clinical studies | |||
| ECOG: 2 points | Clinical studies | Best supportive care | Single agent chemotherapy (category 3 evidence) |
Chemotherapy
The CSCO 2018 guideline’s aggressive recommended regimen for advanced gastric cancer is enrollment in a clinical study after failure of first-line therapy, and clinical studies are an important option after failure of first-line therapy.
Of course, if conditions do not allow for this, such as not being eligible for clinical study enrollment or not having a relevant clinical study in your area, you can also choose a different chemotherapy regimen based on ECOG score (i.e., physical status score), previous chemotherapy drug use, etc. Second-line treatment is mainly monotherapy, and chemotherapy drugs such as paclitaxel, docetaxel or irinotecan can be chosen. Of course, those with better physical status can also be considered to choose two-drug combination chemotherapy. However, in several studies, second-line treatment with a two-drug combination chemotherapy did not result in more survival benefit compared with single-drug chemotherapy.
By the time of third-line therapy, the benefit of chemotherapy is unclear.
Targeted therapy
In second-line therapy for advanced gastric cancer, the only targeted agent mentioned in the CSCO 2018 guidelines is trastuzumab. For HER2-positive patients, chemotherapy in combination with trastuzumab may be considered in second-line therapy when trastuzumab has not been used in first-line therapy. In the Japanese JFMC45-1102 study, patients with HER2-positive advanced or recurrent gastric cancer who progressed or recurred after prior chemotherapy (without trastuzumab) had a progression-free survival of 5.1 months and an overall survival of 17.1 months with trastuzumab combined with paclitaxel.
Ramucirumab, an anti-angiogenic targeted agent, has been marketed and approved in the United States for use after first-line chemotherapy for advanced or metastatic gastric cancer. The drug is not yet available in China, is in a phase III clinical study in China, and is not currently recommended in our guidelines.
In third-line therapy, the CSCO 2018 guidelines also recommend an anti-angiogenic targeted agent, apatinib, which is used without differentiating whether it is HER2-positive or not, but is only recommended for patients in good physical condition. In phase III clinical studies, in advanced gastric cancer after failure of second-line or higher chemotherapy, apatinib extended progression-free survival from 1.8 months to 2.6 months, with an overall survival of up to 6.5 months.
It is clear that there are not many targeted agents available for advanced gastric cancer after failure of first-line therapy.
Immunotherapy
At present, immunotherapy in gastric cancer is less developed than in other solid tumors, such as lung cancer, and monotherapy is only 10% to 15% effective. .
The 2 PD-1 monoclonal antibodies currently approved for advanced gastric cancer in the United States or Japan are nabolutumab (nivolumab) and pembrolizumab (pembrolizumab). Although these two drugs have been marketed in China, they have not yet received indications for use in gastric cancer. In the ATTRACTION-2 study, the use of nabolutumab significantly increased overall survival by more than 1 month (from 4.1 months to 5.3 months) in patients with advanced or recurrent gastric cancer who had failed at least two chemotherapy regimens. In those who progressed on two or more prior regimens, progression-free survival was 2 months and overall survival was 5.5 months on pablizumab monotherapy.
However, there are still many questions about the use of immunotherapy in gastric cancer, such as how to find people who are sensitive to the treatment.
Summary
In conclusion, clinical research is an important option for advanced gastric cancer after failure of first-line therapy, with limited options for chemotherapy and targeted therapy, and high expectations for immunotherapy, which in combination with other agents is the way to enhance immunotherapy. It is expected that advanced gastric cancer will have more options after first-line treatment. (This article is based on a report by Professor Yanqiao Zhang from the Cancer Hospital of Harbin Medical University at CSCO 2018)