Stomach cancer, an evil name that I’m sure no one is unfamiliar with. As one of the top five prevalent tumor diseases worldwide, stomach cancer claims at least hundreds of thousands of lives each year. When it comes to the surgical and adjuvant treatment of gastric cancer, scientists never stop. For them, 2019 has been both a year full of good news and no shortage of disappointments. Some new treatment options have finally succeeded after a decade of trials, while others have faltered.
Next, let’s take a look back at the past year and see the groundbreaking research made by medical practitioners!
The dust has settled and laparoscopic surgery is no less effective than open surgery
Laparoscopic surgery is a minimally invasive procedure that has become the “trendy choice” for all types of shell surgery in recent years because of its smaller incisions, faster recovery, and less pain than traditional open surgery. But what are the results of laparoscopic surgery for gastric cancer treatment?
In a 2019 clinical study, researchers at Southern Medical University and others convened 1,056 patients with locally progressive gastric cancer (T2-4aN0-3M0) for laparoscopic and open surgery, looking at a combination of 3-year disease-free survival, 3-year overall survival, and recurrence patterns. The results showed that the 3-year disease-free survival rates were 76.5% and 77.8% in the laparoscopic and surgical groups, respectively, while the 3-year overall survival (83.1% vs. 85.2%) and recurrence pattern (18.8% vs. 16.5%) did not differ between the two groups. This implies that in patients with locally progressive gastric cancer, the use of laparoscopic distal resection of the tumor is no less effective than open surgery. However, as the tumor stage became more advanced, a significant difference in survival began to emerge between the laparoscopic and open surgery groups.
Based on these findings, the 2019 edition of the CSCO Guidelines for the Management of Gastric Cancer has been updated to recommend the surgical option of laparoscopic distal gastrectomy in the progressive portion of gastric cancer. However, medical resources and levels of care vary widely across the country and need to be performed in experienced centers. In addition, we note that this study did not consider patients treated with neoadjuvant chemotherapy or radiotherapy. How would the effect of laparoscopic surgery be exerted in them? We do not yet know, and new studies are still underway.
The icing on the cake fails, adjuvant radiation regimen after D2 radical surgery
Patients with gastric cancer often consider whether they should have postoperative adjuvant radiation therapy after undergoing D2 radical surgery, which removes the lesion and clears surrounding tissue such as lymph. In fact, this is a problem that has plagued clinical academia. More than five years ago, Korean scholars tried “capecitabine with radiotherapy” as an adjuvant treatment option, but it failed. Recently, a second similar study was initiated by Korean scholars.
The new study included patients with stage II-III pathologic gastric cancer with positive lymph nodes, using the length of “median tumor-free survival” as the primary measure. Patients received adjuvant chemotherapy with S-1 (trade name “esvan”), adjuvant chemotherapy with SOX (“oxaliplatin” and “esvan” combination), and adjuvant chemotherapy with SOXRT (SOX regimen). SOXRT regimen (SOX regimen + radiotherapy). The 3-year disease-free survival rates for these three groups were 64%, 78% and 73%, respectively. This shows that the efficacy of SOX and SOXRT is indeed better than that of S-1 alone. However, we also noted that the SOXRT regimen, even with the addition of radiation therapy, did not significantly improve patient survival compared with the SOX regimen.
So this study actually demonstrates that adjuvant radiotherapy regimens after D2 radical surgery are a failure and unnecessary. Combined radiotherapy did not further improve survival, regardless of whether the patient had lymph node metastases. However, the study did not include patients with esophagogastric junction (EGJ) cancer and T4b patients, and it is not known whether these two groups would benefit from adjuvant radiotherapy. For these two groups, the current clinical studies are based on neoadjuvant chemotherapy or radiotherapy.
Preoperative or postoperative chemotherapy? A decade of research gives new recommendations
Should chemotherapy for gastric cancer be given before, or after, surgery? This question has been hotly debated by scholars in the East and West. Last year, Korean and Chinese scholars simultaneously published their respective findings, which may provide a basis for resolving the debate. It is worth mentioning that this study by Chinese scholars has been initiated a full decade ago, which can be described as a decade of sharpening the sword.
The Chinese and Korean studies were actually very similar in that they both focused on D2 radical surgery, comparing the effects of preoperative versus postoperative chemotherapy, with the main metrics being 3-year progression-free survival and 3-year disease-free survival. The main differences were the staging of the patients, which was more advanced in the Chinese study group, and the types of drugs they tested, which were less consistent.
However, the final conclusions of the two studies were very similar. They both demonstrated that neoadjuvant chemotherapy before surgery better improves 3-year disease-free survival (benefit of about 6%), helps achieve tumor downstaging, and improves R0 resection rates (that is, no significant lesions remain after surgery even when viewed under a microscope). Therefore, the guidelines have been updated in light of these findings. For locally progressive gastric cancer with relatively advanced staging, we should preferentially recommend that patients regress their tumor with chemotherapy before undergoing D2 radical surgery.
In addition, Chinese scholars have compared the advantages and disadvantages of postoperative chemotherapy with SOX (oxaliplatin + esvam) and XELOX (oxaliplatin + capecitabine), and the results are indistinguishable, which may also rewrite the treatment guidelines in the future.
How well the treatment works may have something to do with the “microsatellites” in your body
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“Microsatellite” may sound like an aerospace term at first, but it actually refers to a number of repeating fragments of DNA in your body. There has been early academic speculation that microsatellite instability (MSI) may be associated with the outcome of gastric cancer treatment, but there is insufficient evidence.
In 2019, a new study was conducted to address this speculation on a large scale. The three main types of microsatellite states in the patients tested were MSI-H, MSI-L, and MSS. The results show that the treatment effect may vary greatly depending on the microsatellite status in the patient. Specifically, patients with MSI-H had higher 5-year disease-free survival and overall survival rates (both nearly 20% higher). In addition, MSI-H patients treated with surgery alone have a good prognosis even without adjuvant chemotherapy, whereas preoperative chemotherapy may be harmful. In contrast, people with MSI-L and MSS types are more likely to benefit from a “chemotherapy + surgery” regimen.
Based on these findings, microsatellite status (MSI) has been recognized as a key factor in determining whether a patient needs preoperative or postoperative adjuvant chemotherapy. 2019 edition of the CSCO guidelines require that all patients with advanced gastric cancer considered for immune checkpoint inhibitor therapy be tested for MSI or mismatch repair status. The testing should be more aggressive for locally progressive gastric cancer. For patients with MSI-H or mismatch repair deficiency, physicians should consider surgery alone or consider perioperative immunotherapy clinical studies.
Starting the journey, perioperative immunotherapy research is on the rise
Immunotherapy has demonstrated initial efficacy and safety in studies related to perioperative gastric cancer, and larger studies are underway.
In 2019, a study of Fulbright’s PD-1 monoclonal antibody HLX10 for neoadjuvant treatment of gastric cancer was officially launched after adjusting the protocol. This study is only for PD-L1-positive (CPS ≥10) cT3 and N positive patients with locally progressive gastric cancer, excluding patients with adenocarcinoma of the esophagogastric junction, with 3-year event-free survival as the primary study.
In the trial, patients were randomized to receive SOX in combination with HLX10 or placebo for a total of 3 weeks followed by D2 radical surgery. In the adjuvant phase, the former was treated with HLX10 monotherapy for up to 17 cycles. The latter completed 5 weeks of SOX adjuvant chemotherapy. The study design reflects the strong combination of the neoadjuvant phase and the emphasis on immune protection of the tumor microenvironment in the postoperative adjuvant phase.
While the results are not available to date, it is believed that it will provide fuller evidence on the timing, population screening, and combination strategies for perioperative immunotherapy in gastric cancer.