The AXEPT trial (NCT01996306), which was conducted by the East Asia collaborative group led by Prof. Rui-Hua Xu from the Sun Yat-sen University Cancer, is a large-scale, multicenter, international phase III trial in patients with metastatic colorectal cancer refractory to first-line therapy. This trial was aimed to investigate the safety and efficacy of a modified capecitabine plus irinotecan (mXELIRI) regimen. The findings from this trial demonstrate that the mXELIRI regimen is effective and well-tolerated, and have recently been published online in the journal of Lancet Oncology, via the fast-publication tract.

Epidemiology and current treatment strategies for colorectal cancer
Colorectal cancer is the third most common cancer in the world. Over the past 10 years, the incidence of colorectal cancer in China has increased substantially. In 2015, the number of new colorectal cancer cases ranked fifth among all cancer types in China, and reached 260,000 in the urban population. Due to a lack of obvious symptoms during cancer onset, only 5-10% of all colorectal cancer patients were diagnosed and treated at an early stage. Detecting colorectal cancer at an earlier stage is imperative as it can be likely cured by surgery with a five-year survival rate of up to 90%. But for late stage inoperable cases, systematic chemotherapy is still the mainstay treatment, with a five-year survival rate of less than 10%.

Limitations for current chemotherapeutic regimens for metastatic colorectal cancer
The fluorouracil plus irinotecan (FOLFIRI) regimen is one of the recommended chemotherapeutic regimens in international guidelines for metastatic colorectal cancer. However, this regimen is inconvenient in administration because it mandates a 46-hour continuous infusion every two weeks, as well as pre-treatement implantation of central venous devices for infusion.

Capecitabine is a novel oral agent administrated in a three-week cycle, with a similar active component with that of fluorouracil. Compared with FOLFIRI, the XELIRI regimen requires only a 2- to 3- hour infusion every three weeks and does not need access to central venous devices, which makes it far more convenient to FOLFIRI. However, previous trials have shown a substantial toxicity of the XELIRI regimen in Western populations with metastatic colorectal cancer. Owing the dominance of Western investigators in the field of colorectal cancer treatment, the XELIRI regimen has never been adopted as a standard chemotherapeutic regimen in major international guidelines.

Innovative scientific hypothesis
Despite that Western investigators failed to demonstrate the feasibility of the XELIRI regimen, Prof. Xu has never stopped relevant exploration. On the basis of previous phase II trials by his research team, Prof. Xu raised a scientific hypothesis: a XELIRI regimen at a lower dosage level might not only have a lower toxic effect but also an improved efficacy. Consequently, Prof. Xu, Prof. Tae Won Kim from Asan Medical Center, and Prof. Kei Muro from Aichi Cancer Center, as principal investigators, led an Eastern collaborative research group and conducted the phase III AXEPT trial, in order to evaluate the safety and efficacy of the mXELIRI (capecitabine 800 mg/m2 twice daily and irinotecan 200 mg/m2, every three weeks) regimen.

The mXELIRI regimen is effective and well-tolerated
Between December 2013 and June 2017, a total of 650 patients refractory to first-line treatment of metastatic colorectal cancer was enrolled. Almost one third of the patients enrolled from China came from Sun Yat-sen University Cancer Center. The AXEPT trial found that patients treated with mXELIRI exhibited a non-inferior, and even numerically superior median survival to those with FOLFIRI (17 vs. 15 months). Additionally, the overall incidence of grade 3/4 adverse events was substantially decreased in the mXELIRI group that in the FOLFIRI group (54% vs. 72%). Notably, a markedly decrease in the incidence of neutropenia with mXELIRI was observed (from 45% to 20%).

mXELIRI is adopted a new standard of care
With the continuing improvement in survival of patients with metastatic colorectal cancer, it becomes imperative to improve the quality of life in these patients. For the first time, the AXEPT trial confirmed that the mXELIRI regimen has a comparable efficacy to the FOLFIRI regimen, and is better tolerated and more convenient in administration. Additionally, although the mXELIRI regimen has a similar cost with that of the FOLFIRI regimen, the former prolongs treatment interval and shortens hospital stay, and hence has a potential to improve patients’ compliance to treatment as well as lower travel expense.

The success of the AXEPT project shows that clinical colorectal cancer research in China has reached a new international frontier. This will undoubtedly provide valuable experience for clinical research practice in China as clinical research groups continue their efforts in the fight against cancer to provide better health care for more and more cancer patients.

Link to the article: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30140-2/fulltext