Moving east with increasing risk
James Fleck, MD, PhD: Anticancerweb 16 (01), 2022
In 1271, Marco Polo, his father and uncle, left Italy on a journey along the Silk Road. The Polo party began this historic journey in Acre (now Israel) and Jerusalem, moving eastward as shown on the map. In 1274, they arrived in the capital of China, Dadu (present-day Beijing), where Marco Polo learned the Chinese language and met Kublai Khan, developing a strong collaborative relationship between Eastern and Western cultures. After a period of 24 years, Polo returned to Venice, having traveled nearly 15,000 miles.
Gastric cancer is the 5th most diagnosed malignant tumor in the world, reaching 1,089,103 new cases in 2020. The mortality rate of gastric cancer assumed the 4th position globally, accounting for 768,793 deaths in 2020, leading to a case fatality rate of 70.6%. Gastric cancer epidemiology gets worse as we move eastward. In both Iran and Afghanistan, gastric cancer is the 2nd malignant tumor in incidence and the 1st in mortality, leading to a case fatality rate around 90%. Let's take the Silk Road and plot the incidence and mortality rate from gastric cancer. We will use the age-standardized rate (ASR) to equalize the age distribution currently observed in some of the countries that made up the Polo's long journey. In the figure shown below, there is an increasing trend in gastric cancer incidence as we move eastward, reaching 478,508 new diagnosed cases in China during the year of 2020. As far as we know, Marco Polo did not go to Japan, but gastric cancer has continued to move eastward and currently 138,470 Japanese new cases are diagnosed annually. Together, China and Japan account for more than half of the gastric cancer diagnosed worldwide. Fortunately, Japan has stopped some of the trends seen along the Silk Road. Despite the high incidence of gastric cancer observed in Japan, a great deal of effort has been made in early diagnosis and improvements in both gastric cancer surgery and adjuvant treatments, which have reduced its mortality rate (ASR = 8.2). When compared to Silk Road countries, Japan has reduced the case fatality rate to an extraordinary 33.2%, which has not been achieved anywhere in the eastern or western world.
Eastern guidelines for the treatment of advanced gastric cancer emphasize the importance of preoperative laparoscopy, gastrectomy + total omentectomy + D2 lymphadenectomy. The Japanese Gastric Cancer Association has described 23 distinct lymph node stations and defines D2 lymphadenectomy as comprising lymph node dissection at stations 1, 3, 4, 5, 6, 7, 8a, 9, 11p and 12a. In general, a D2 dissection represents a sample of at least 15 lymph nodes. Training of surgeons in D2 gastrectomy is the cornerstone to achieve better results in the treatment of gastric cancer, and a Marco Polo-type diplomatic intervention should be implemented to establish a cooperative effort between Eastern and Western surgeons, aiming at a worldwide standardization of the surgical approach in advanced gastric cancer. Adjuvant chemotherapy should also be considered as standard in the treatment of advanced gastric cancer, improving patient outcomes. The ACTS-GC was a Japanese prospective trial where patients with histologically confirmed stage II and III gastric cancer were randomly assigned to undergo surgery + adjuvant fluoropyrimidine derivative S1 or surgery alone. The overall survival after five-year follow-up was 71.7% in the S1 group and 61.1 % in surgery-only group (HR = 0.669). However, S1 cannot be found in western world. Fortunately, the CLASSIC South Korea trial also evaluated adjuvant chemotherapy after D2 dissection, using the worldwide available doublet capecitabine and oxaliplatin. After a medium follow-up of 62.4 months, the estimated 5-year disease-free survival was 68% in the adjuvant capecitabine and oxaliplatin group versus 53% in the surgery alone group. Estimated 5-year overall survival was 78% in the adjuvant group versus 69% in the observation group (HR 0·66, P=0·0015).
Western efforts have been focused in perioperative chemotherapy. The FLOT4 is a German prospective randomized phase 2/3 trial. In the FLOT4 trial, resectable advanced gastric cancer patients were assigned to three preoperative and three postoperative cycles of epirubicin, cisplatin plus either fluorouracil infusion or oral capecitabine (ECF/ECX) as a control group or four preoperative and four postoperative cycles of docetaxel, oxaliplatin, leucovorin and fluorouracil infusion (FLOT) as an experimental group. Overall survival was increased in the FLOT group (HR = 0.77). Medium overall survival was 50 months in the FLOT arm and 35 months in the ECF/ECX arm. Most of the gastric cancer patients were not treated with D2 dissection and the study also included gastro-esophageal junction adenocarcinoma. Although, different studies should not be directly compared, the western gastric cancer patients seems to have a worse outcome.
A comprehensive assessment of the difficulties and opportunities to improve outcomes in advanced gastric cancer should be pursued along the Silk Road. Sharing advances would be desirable and very welcome across the world..
References:
1. Fosco Maraini: Marco Polo: Italian Explorer, Britannica, January 4th, 2022
2. Global Cancer Observatory: International Agency for Cancer Research (IARC), World Health Organization (WHO), 2020
3. Japanese Gastric Cancer Association: Japanese Classification of Gastric Carcinoma: 3rd English Edition, Gastric Cancer 14: 101 – 112, 2011
4. Japanese Gastric Cancer Association: Japanese Gastric Cancer Treatment Guidelines, Gastric Cancer14: 113 – 123, 2011
5. Sasako M, Sakuramoto S, Katai, H, at al: Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer, J Clin Oncol 33: 4387 – 4393, 2011
6. Noh SH, Park SR, Yang HK, at al: Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial, Lancet Oncol 12: 1389 – 1396, 2014
7. Al-Batran S E, Homann N, Pauligk, C, et al: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma (FLOT4): a randomized phase 2/3 trial, Lancet 393: 1948 – 1957, 2019
8. Photo by Egor Myznik on Unsplash
The association of gradually higher incidence of Gastric Cancer moving eastward is very impressive and allows comparison even with Marco Polo's adventures. However, the main point here is the valuable lessons that differences between these countries could show. According to IARC, in 2020, China had 3,4 more cases (478.508 versus 138.470), but 8,1 more deaths (373.789 versus 46.024) from Stomach Cancer than Japan. The Japan fatality rate of 33.2% speaks by itself when compared to the China's 78,1% (which is, by the way, very similar to those in Brazil, 78,3%, despite the much lower incidence). As showed in the text above, the Japan success could be credited to factors as training of surgeons in D2 gastrectomy and adjuvant chemotherapy. Maybe it's time to Silk Road bring to West some knowledge about how to fight Gastric Cancer.
Notably, there is a delay in the formulation of RCTs related not to prognosis, but to treatment stratified by the population at risk, mainly dictated by treatments such as chemotherapy associated with immunotherapy, or other combinations that may establish a therapeutic result.
The lower mortality rate of gastric cancer amongst the Japanese population in comparison not only to its neighboring countries, but also to the western population, is a collective effort that should not be overlooked. In fact, we as health professionals should take a note from Marco Polo's book and integrate these practices, making the way back from the Silk Road in order to maximize better outcomes of gastric cancer in the rest of the world.
It is noticed that gastric cancer is very present as one advances to East Asia. However, in Japan this number is decreasing due to early diagnosis and improvements in surgery and adjuvant treatment.
The fact that gastric cancer is one of the most diagnosed malignant tumors in the world, and its mortality rate and lethality rate reach high numbers, reveal the importance of paying attention to this neoplasm. The epidemiology of gastric cancer worsens as we move eastward, with China and Japan accounting for more than half of gastric cancers diagnosed worldwide encourages plans like Japan's for earlier diagnosis and improvements in both gastric cancer surgery. and in adjuvant treatments to reduce mortality rates. Interestingly, Eastern countries re-evaluate their gastric cancer measures to improve data on gastric cancer in the region.
Japanese medicine has shown impressive efficiency and progress in recent decades, from robotic surgery to the development of new drugs and procedures. The need for dialogue between Eastern and Western medical cultures is undeniable. However, I also find it interesting why the incidence is higher as we move further east. Could it be the diet? genetic differences? differential radiation? Anyway, an excellent read.
It's interesting to notice how different countries have developed very different approaches with varying results, being the janapese case the gold standard in gastric cancer treatment. What still lacks is the identification of modifiable rick factors in those populations that makes the prevalence of gastric cancer so high in those countries, and where those countries healthcare systems is failing in the provision of lifestyle education and screening programs.
The issue of differing gastric cancer incidence and mortality across the world is in part a matter of money and communication (as those who pioneered the Silk Road might have thought thousands of years ago). Differences in language and culture hinder the sharing of knowledge, which, if improved, would still be limited by economic inequality.
International cooperation seems to be the way to solve problems in different aspects of human history. Historically, western and eastern medicine have followed autonomous paths, it is past time for us to unite knowledge in order to practice the best medicine we are able to provide our patients.
China and Japan together account for more than half of all stomach cancers diagnosed in the world. Although the incidence of gastric cancer in Japan is high, fortunately, many efforts have been made in early diagnosis and improved gastric cancer surgery and adjuvant therapy, thus reducing the mortality rate.
In the fight against gastric cancer, bridging Eastern and Western cultures is crucial, as rising incidence and mortality rates are observed along the east, particularly in China and Japan. Promising results have been seen with early diagnosis and adjuvant chemotherapy in Japan. To combat gastric cancer effectively, efforts to raise awareness, promote screening, and educate communities about risk factors and prevention strategies are vital. Collaboration among healthcare professionals, researchers, and communities can lead to a better understanding of the disease, improved treatment options, and ultimately, a reduction in gastric cancer incidence and mortality rates.
It's important to realize that the increase in incidence in the countries further east of the Silk Road (Mongolia, China, and Japan) does not similarly track with the mortality rates of other countries. Part of this disproportional increase in mortality can be attributed to advancements in preoperative care and an increased adherence to cancer screenings. Moreover, the instituted postoperative treatment has been demonstrated as a significant factor in changing these patients' prognosis.
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