With the emergence of c-kit, the characteristic marker of gastrointestinal mesenchymal tumor (GIST) in 1998, and the successive introduction of molecularly targeted drugs such as imatinib and sunitinib, the treatment of GIST has entered the era of molecularly targeted therapy. A large number of clinical studies have provided an evidence-based basis for the treatment of GIST, and scholars at home and abroad have reached a number of consensus on the treatment of GIST. However, due to the differences in ethnicity, height and weight between Eastern and Western populations, it has been controversial whether the same drug dose can be used to treat GIST. In this paper, we will discuss the consensus and controversy of molecularly targeted GIST treatment in the East and West, taking into account the domestic and international literature.
In the future, whether it is the search for GIST treatment guidelines suitable for Eastern populations, the mechanism of primary and secondary drug resistance in GIST, individualized treatment guided by gene mutations, and the choice of third- and fourth-line treatment for GIST, a series of challenges remain to be tackled by global oncologists.
GIST Incidence and Gene Mutation
The incidence of GIST is similar in both Eastern and Western countries, with an overall increasing trend.
The incidence of GIST in Sweden (14.5 cases per million people) reported by Nilsson in 2005 is now widely quoted. Other Western countries including the United States, Spain, the Netherlands, and Iceland have reported incidence rates of 6.8-12.7 cases/million people in recent years, while the incidence rates of GIST from Taiwan and Hong Kong, China, are 13.7 cases/million people and 16.8-19.6 cases/million people, respectively, but national incidence statistics are not yet available for China, and the number of new cases is currently estimated to be 20,000-30,000 per year. The above data show that the incidence rates are similar in both eastern and western countries, with an overall increasing trend. However, more scholars believe that the increase in the incidence of GIST may be related to the increasing awareness and more patients being accurately diagnosed, rather than a true increase in incidence.
The frequency and type distribution of GIST mutations are similar between Eastern and Western countries
Mutations in the C-kit and PDGFRA genes are not only the main mechanism of GIST pathogenesis, but also predict the efficacy of molecularly targeted drugs for the treatment of advanced GIST.
The overall gene mutation rate of Western GIST reported by investigators in 2002 was 87.4%, among which the mutation rates of exon 11 and 9 were 67.5% and 11%, respectively. Our Prof. Shen Lin tested more than 200 Chinese GIST patients with similar mutation results as reported above, with an overall mutation rate of 89.9%. Combined with the results of small sample testing reported in Korea in 2004 and Taiwan in 2008, it can be seen that the rate of exon 9 mutations in GIST patients in Eastern countries is slightly lower, while the incidence of wild type is slightly higher.
It remains to be confirmed whether there are real differences in the types of mutations in GIST between Eastern and Western countries, but it is necessary to establish a uniform method and standard for detecting mutation status worldwide.
Sunitinib for GIST
Sunitinib second-line treatment for GIST improves survival, but adverse effects vary widely between East and West
In a phase III randomized controlled study of sunitinib second-line treatment of advanced GIST published in The Lancet in 2006, the time to disease progression (TTP) was significantly longer in the sunitinib-treated group compared to the placebo group (27.3 weeks versus 6.4 weeks), while OS reached 73.9 weeks. However, in terms of adverse effects, sunitinib differed in the treatment of GIST patients in Eastern countries.
In Western studies, the incidence of malaise and hand-foot syndrome in the sunitinib group was 34% and 13%, respectively, while in a phase I/II study of a group of Japanese GIST patients treated with sunitinib, the incidence of malaise and hand-foot syndrome was as high as 67% and 86%.
In a study of sunitinib for advanced kidney cancer comparing Asian and non-Asian patients, the incidence of malaise, hand-foot syndrome and mucositis were 45% versus 37%, 51% versus 23% and 47% versus 26%, respectively. The domestic phase IV clinical study of sunitinib has completed enrollment, but no formal data have been reported. The author summarized the adverse reactions in 39 patients treated with sunitinib in our center and found that the incidence of malaise and hand-foot syndrome was 41% and 71.9%, respectively. The above data showed that the incidence of adverse reactions in patients with GIST in Eastern countries treated with sunitinib was higher than that in Western patients, with malaise and hand-foot syndrome as the main manifestations.
There is no pharmacokinetic analysis of sunitinib in GIST patients of different races, and there is no final conclusion about whether there is a correlation between differences in adverse reactions and race, height and weight. However, a renewed phase I/II clinical study of sunitinib in China would be important to explore the appropriate dose of sunitinib treatment for Chinese GIST patients.
Sunitinib intermittent dosing is still the currently recommended standard of administration
Sunitinib 50 mg/d (4 weeks of dosing with 2 weeks of intermittent dosing) is the recommended dosing regimen for advanced GIST. George reported at the 2008 American Society of Clinical Oncology (ASCO) annual meeting that intermittent administration of sunitinib caused significantly higher instability of drug exposure than continuous dosing, and that continuous administration of sunitinib 37.5 mg/d for advanced GIST achieved the longest median OS (107 weeks) to date in a non-concurrent control. However, whether continuous dosing can replace traditional intermittent dosing has yet to be confirmed in randomized controlled studies.
Imatinib for GIST
Imatinib 400 mg/d is not controversial as first-line standard of care
Imatinib has been widely used as first-line treatment for advanced GIST since 2000.
62005, US0033 and other studies confirmed that first-line treatment of advanced GIST with imatinib 400 mg/d significantly improved survival, while increasing the dose did not improve efficacy or survival. Therefore, the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO) and the Chinese GIST treatment guidelines recommend imatinib 400 mg/d as first-line standard treatment for advanced GIST, but high-dose imatinib should be given as first-line treatment for those with exon 9 mutations. Currently, a controlled study of nilotinib versus imatinib in the first-line treatment of advanced GIST is underway, and its ability to replace imatinib as a new first-line treatment drug deserves attention.
The dose should be increased to 600 mg/d after failure of 400 mg/d in our patients
The EORTC62005, US0033 studies confirmed that a dose increase to 800 mg/d after failure of imatinib 400 mg/d treatment resulted in further tumor control in about 1/3 of patients with tolerable adverse effects. The progression-free survival (PFS) periods for patients after dose increase in both studies were 11.3 weeks and 5 months, respectively.
The ability of Eastern patients to tolerate imatinib 800 mg/d is controversial due to differences in height and weight from Western patients.
Professor Shen Lin reported on the study of increasing dose of imatinib for advanced GIST in China at the ASCO Gastrointestinal Oncology Conference 2010. The results showed that increasing the dose to 600 mg/d after failure of imatinib 400 mg/d treatment resulted in a patient PFS of 17 weeks, which was similar to the results of two western studies; however, patients could not benefit again from increasing the dose to 800 mg/d after failure of 600 mg/d treatment, and also tolerated poorly due to severe weakness, edema, and gastrointestinal reactions.
Therefore, our GIST treatment guidelines recommend that patients with GIST should preferentially increase the dose to 600 mg/d after failure of imatinib 400 mg/d treatment.
Adjuvant treatment with imatinib improves RFS in those at moderate to high risk of recurrence
In 2007, the Z9001 study showed a significant improvement in the 1-year recurrence-free survival (RFS) rate in GIST patients with tumors >3 cm in length who were given imatinib adjuvant therapy for 1 year after complete tumor resection (98% vs. 83%). In the same year, Prof. Wenhua Zhan reported the results of a multicenter study of imatinib adjuvant therapy for those at moderate to high risk of recurrence at ASCO, with a 1-year RFS rate of 96.08%. Both the NCCN guidelines and ESMO guidelines recommend imatinib adjuvant therapy for 1 year after surgery for those at moderate to high risk of recurrence, but note that the timing of adjuvant therapy for those at high risk of recurrence has not been conclusively confirmed.
Professor Shen Lin reported at the 2009 ASCO annual meeting that 3 years of postoperative adjuvant treatment with imatinib for those at moderate to high risk of recurrence improved the 1-year and 2-year RFS rates, suggesting that extending the duration of adjuvant treatment may further improve survival.
Chinese GIST treatment guidelines recommend at least 2 years of postoperative adjuvant treatment with imatinib for those at high risk of recurrence and 1 year for those at intermediate risk of recurrence. The ongoing SSGX VIII study (1 and 3 years of adjuvant therapy) and the ACOSOG expansion study (2 and 5 years of adjuvant therapy) will help further confirm the appropriate time frame for adjuvant therapy.