Radical surgery is the mainstay of therapy for primary resectable, localized gastrointestinal stromal tumors (GIST). Nevertheless, approximately 40% to 50% of patients with potentially curative resections develop recurrent or metastatic disease. The introduction of imatinib mesylate has revolutionized the therapy of advanced (inoperable and/or metastatic) GIST and has become the standard of care in treatment of patients with advanced GIST. This article discusses the proper selection of candidates for adjuvant and neoadjuvant treatment in locally advanced GIST, exploring the available evidence behind the combination of preoperative imatinib and surgery.
Key points
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Preoperative (neoadjuvant) therapy in locally advanced GIST may facilitate resection with microscopically clear margins, decrease the risk of perioperative tumor spill, and decrease extent and morbidity of the surgical procedure.
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Existing evidence-based clinical practice guidelines suggest adjuvant imatinib for at least 36 months for patients with high-risk GIST (tumor >5 cm in size with high mitotic rate [>5 mitoses/50 high-power fields] or tumor rupture or a risk of recurrence that is >50%).
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Surgical removal of residual disease during imatinib treatment may allow for complete remission (in approximately 20%) in selected patients with GIST after response to therapy, probably prolonging durable remission.
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The time of the implementation of surgical treatment warrants further studies; mutilating surgery in metastatic GIST should be avoided, as systemic therapy is the mainstay of treatment in this setting and surgery is only adjunctive to tyrosine kinase inhibitors therapy.
Introduction: gastrointestinal stromal tumors general overview
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Morphologically and clinically they are a heterogeneous group of tumors, with a biological behavior that is difficult to predict, ranging from clinically benign to malignant. Radical surgery is the treatment of choice in primary resectable GIST. Nevertheless, approximately 40% to 50% of patients will develop recurrent or metastatic disease after curative resection. Understanding the molecular mechanisms of their pathogenesis demonstrated that most GISTs are associated with activating, constitutive, mutually exclusive mutations of 2 genes: KIT and PDGFRA (platelet-derived growth factor receptor-α). These are the early oncogenic events during GIST development and result in overexpression and activation of oncoproteins KIT and PDGFR. A significant subset of GIST is still diagnosed at a locally advanced, unresectable and/or disseminated stage of disease. Metastases preferably occur in the peritoneal cavity and/or the liver. Conventional cytotoxic chemotherapy treatment is ineffective in advanced cases of GIST. Radiotherapy is also of limited value in the management of GIST, mainly because these tumors are often located in close proximity with dose-limiting vital organs. However, advances in the understanding of molecular mechanisms of GIST pathogenesis have recently resulted in the development of a treatment modality that has become a model of targeted therapy in oncology. Imatinib mesylate is a tyrosine kinase inhibitor of KIT, BRC/ABL fusion protein, FMS (receptor for colony stimulating factor 1), Abl-related gene, and PDGFR-alpha and PDGFR-beta. It has revolutionized the treatment of advanced GIST and was the first effective nonsurgical treatment in inoperable and/or metastatic cases. Current survival in advanced GIST is strikingly superior to historical clinical data, with a reported median overall survival (OS) of 5 to 6 years and median progression-free survival (PFS) ranging from 2 to 3 years. In case of progression during imatinib treatment (which is mainly related to occurrence of new secondary KIT / PDGFRA mutations) there are currently several therapeutic strategies, such as escalation of the dose of imatinib to 800 mg daily, surgical removal of focally progressive lesions, and therapy with registered second-line drug sunitinib malate and third-line drug regorafenib (both are multitargeted tyrosine kinase inhibitors with anti-angiogenic properties). Recently, imatinib has been registered for adjuvant therapy in patients after resection of primary GIST with high risk of recurrence based on the results of 2 randomized trials (ACOSOG Z9001 and Scandinavian Sarcoma Group XVIII = SSGXVIII/AIO). Currently in selected cases of locally advanced GISTs, a strategy of neoadjuvant imatinib therapy has become a common approach.
In this review article we have focused on the evolving role of combined therapy with surgery and tyrosine kinase inhibitors in GIST management.
Introduction: gastrointestinal stromal tumors general overview
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Morphologically and clinically they are a heterogeneous group of tumors, with a biological behavior that is difficult to predict, ranging from clinically benign to malignant. Radical surgery is the treatment of choice in primary resectable GIST. Nevertheless, approximately 40% to 50% of patients will develop recurrent or metastatic disease after curative resection. Understanding the molecular mechanisms of their pathogenesis demonstrated that most GISTs are associated with activating, constitutive, mutually exclusive mutations of 2 genes: KIT and PDGFRA (platelet-derived growth factor receptor-α). These are the early oncogenic events during GIST development and result in overexpression and activation of oncoproteins KIT and PDGFR. A significant subset of GIST is still diagnosed at a locally advanced, unresectable and/or disseminated stage of disease. Metastases preferably occur in the peritoneal cavity and/or the liver. Conventional cytotoxic chemotherapy treatment is ineffective in advanced cases of GIST. Radiotherapy is also of limited value in the management of GIST, mainly because these tumors are often located in close proximity with dose-limiting vital organs. However, advances in the understanding of molecular mechanisms of GIST pathogenesis have recently resulted in the development of a treatment modality that has become a model of targeted therapy in oncology. Imatinib mesylate is a tyrosine kinase inhibitor of KIT, BRC/ABL fusion protein, FMS (receptor for colony stimulating factor 1), Abl-related gene, and PDGFR-alpha and PDGFR-beta. It has revolutionized the treatment of advanced GIST and was the first effective nonsurgical treatment in inoperable and/or metastatic cases. Current survival in advanced GIST is strikingly superior to historical clinical data, with a reported median overall survival (OS) of 5 to 6 years and median progression-free survival (PFS) ranging from 2 to 3 years. In case of progression during imatinib treatment (which is mainly related to occurrence of new secondary KIT / PDGFRA mutations) there are currently several therapeutic strategies, such as escalation of the dose of imatinib to 800 mg daily, surgical removal of focally progressive lesions, and therapy with registered second-line drug sunitinib malate and third-line drug regorafenib (both are multitargeted tyrosine kinase inhibitors with anti-angiogenic properties). Recently, imatinib has been registered for adjuvant therapy in patients after resection of primary GIST with high risk of recurrence based on the results of 2 randomized trials (ACOSOG Z9001 and Scandinavian Sarcoma Group XVIII = SSGXVIII/AIO). Currently in selected cases of locally advanced GISTs, a strategy of neoadjuvant imatinib therapy has become a common approach.
In this review article we have focused on the evolving role of combined therapy with surgery and tyrosine kinase inhibitors in GIST management.
Risk assessment of primary gastrointestinal stromal tumors
The treatment of choice in primary, resectable, localized GISTs is radical surgery with negative margins, but virtually all GISTs are associated with a risk of recurrence, and approximately 40% of patients with potentially curative resections will ultimately develop recurrent or metastatic disease. The identification of the risk factors for recurrence after primary surgery is crucial for reliable prognosis, follow-up schedule, and the selection of patients who may potentially benefit from the adjuvant therapy, aiming for a decrease in disease recurrences. The main criteria of aggressive behavior of GISTs are based on the presence of invasion of adjacent structures and/or the presence of metastases (overtly malignant cases), as well as on primary tumor site, size, and mitotic index. Several risk-stratification systems have been proposed in the recent years. In 2001, a Consensus Conference held at the National Institutes of Health (NIH) provided the first evidence-based definition and a practical scheme for the risk assessment in the clinical course of this disease. The risk categorization was based on evaluation of the tumor size and mitotic rate (evaluated per 50 high-powered fields [HPF] or mm 2 ) as the most reliable prognostic factors. Additional analysis in patients with primary tumor after complete macroscopic resection confirmed the significance of tumor anatomic location as the independent prognostic factor. Miettinen and Lasota created the classification for risk assessment in gastric, duodenal, intestinal, and rectal GISTs (National Comprehensive Cancer Network-American Forces Institute of Pathology [NCCN-AFPI]), which constituted the basis for new staging system of American Joint Committee on Cancer ( Table 1 ). It combines 3 crucial features (ie, size, site of origin, and mitotic index) and it reflects the fact that gastric GISTs show a much lower rate of aggressive behavior than jejunal and ileal GISTs of comparable size and/or mitotic rate. Recently it was established that tumor rupture (spontaneous or iatrogenic) is an additional important risk factor strongly associated with the increased recurrence rates. Therefore, in 2008 Joensuu and colleagues proposed another simplified classification system based on 4 prognostic factors (tumor size, site, mitotic count, and the presence of tumor rupture). Furthermore, completeness of resection is an independent prognostic risk factor; rather obviously patients with resectable primary GIST who undergo R0 resection have a significantly longer survival than patients undergoing incomplete resection.
| Parameters | Lower Risk | Higher Risk |
|---|---|---|
| Surgery | R0 | R1, tumor rupture |
| Localization | Stomach | Small or large intestine |
| Size (cm) | ≤5 | >5 |
| Mitotic index | ≤5/50 HPF | >5/50 HPF |
| Gene mutation | PDGFRA | KIT, wild-type (nn-PDGFRA, non-KIT) |
| Type of KIT mutation | Duplications/insertions in exon 11 | Exon 11 deletions (especially involving codons 557–558), exon 9 |
Taking into account that some of prognostic features (such as mitotic index and tumor size) are continuous (not categorical) variables, prognostic nomograms for prediction of tumor were developed. Joensuu and colleagues’ prognostic contour maps resulting from nonlinear modeling may be appropriate for estimation of individualized outcomes. The comparison of different classification systems shows that patients with intermediate risk have a clinical course more similar to the low-risk group, which implies that only the high-risk patients would likely benefit from adjuvant therapy after primary tumor resection.
In addition to the clinicopathological factors mentioned previously, KIT and PDGFRA mutational status may also have a prognostic significance in primary GIST. However, currently available data are insufficient to incorporate the kinase mutation status into the risk stratification of primary tumors. Several studies have indicated a more favorable prognosis for patients carrying exon 11 point mutations or insertions, as well as PDGFRA exon 18 mutations, whereas tumors harboring KIT exon 9 duplications as well as KIT exon 11 deletions (especially involving codons 557 and/or 558 or in homozygous state) were associated with more aggressive behavior. Recent analysis of clinicopathologic and molecular data from 1056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European Contica GIST database confirmed the independent prognostic significance of the KIT deletions involving codons 557 and/or 558, especially in GIST of gastric origin. Population-based series of patients with primary resectable GIST confirmed more favorable outcomes of PDGFRA mutations and KIT exon 11 duplication mutations or deletions of 1 codon. Further developments in molecular analysis (such as inclusion genomic index) may further optimize the individual risk assessment and inclusion criteria for adjuvant therapy after primary tumor resection.
Primary localized gastrointestinal stromal tumors
Neoadjuvant Strategy
Locally advanced GISTs are defined as those tumors that can potentially benefit from neoadjuvant treatment with imatinib through a decrease in size and vulnerability. If the tumor is localized at a critical anatomic site, such as the gastroesophageal junction, juxtapancreatic duodenum, or lower rectum, the surgical procedure can be downsized from an extensive multiorgan or full-organ resection to a more limited surgical procedure, without compromising local radicality. Very large tumors also can be potential candidates for preoperative therapy, because they tend to be extremely fragile and hypervascular, with a substantial risk of intraoperative rupture and/or bleeding.
Thus, based on the spectacular activity of imatinib on metastatic GIST, neoadjuvant therapy seems an attractive treatment strategy in locally advanced and/or marginally resectable GIST. Although current European (European Society of Medical Oncology [ESMO]) and US (NCCN) guidelines recommend this neoadjuvant strategy in selected cases, it seems that is not yet fully implemented in routine practice. This neoadjuvant cytoreductive and tumor cell inactivating treatment in localized GIST aims to facilitate resection with microscopically clear margins, to decrease the extent and morbidity of the surgical procedure, and to minimize tumor micrometastases, thus increasing the patient’s chance for cure. Neoadjuvant therapy can reduce the need for extensive, multiorgan resections and diminish the intraoperative risk of rupture of devitalized tumor and spillage of active tumor cells into the peritoneal cavity (which is closely related to the risk of disease dissemination). Furthermore, it decreases the necessity of blood transfusions as a consequence of intraoperative tumor bleeding. Fig. 1 illustrates a locally advanced gastric GIST, detected due to gastrointestinal bleeding, which responded to imatinib 400 mg daily, resulting in a significant shrinkage of tumor. This enabled a complete tumor removal via wedge resection.
When used as a neoadjuvant treatment, imatinib is administered until maximal response is achieved. The duration of treatment can vary between 6 and 12 months. Usually, after 6 to 9 months, when 2 consecutive images (mostly computed tomography [CT]) show no further tumor regression, this is considered the point of maximal response. At that moment, a plateau in tumor shrinkage is reached, whereas the risk of developing secondary resistance to imatinib therapy is still very low. A study by Tirumani and colleagues confirmed that the best response to neoadjuvant imatinib is reached after approximately 28 weeks of treatment, with a plateau response at 34 weeks. Therefore, continuation of imatinib beyond this time span is probably not beneficial.
To avoid missing the optimal timing for surgery, careful response assessment should be undertaken. In selected cases, especially if mutational status was not determined in advance, this assessment should include imaging with PET/CT, as this modality may more adequately predict short-term treatment responses. Moreover, there is clear evidence that treatment with imatinib should always be followed by surgical resection. In the BFR-14 trial, Blesius and colleagues demonstrated that patients with potentially resectable GIST who are treated with imatinib alone (ie, without resection) have a similar disease-free survival (DFS) and OS to that of patients with metastatic GIST. Thus, imatinib cannot replace surgery.
Imatinib can generally be stopped safely the day before surgery and restarted (when indicated) as soon as postoperative oral food intake is restored. However, some centers prefer to stop the drug 1 week before surgery and do not restart it until 1 week after surgery.
Although preoperative therapy has become a common approach in individualized GIST cases, formal evidence from clinical trials regarding the outcome of neoadjuvant treatment with imatinib is limited. Several articles report on small series of patients treated with imatinib before tumor resection, but they often have a mixed population of patients with primary, nonmetastatic GIST, as well as patients with metastatic GIST operated for residual disease. The largest cohort of patients with GIST treated with neoadjuvant imatinib followed by resection was a series of 161 patients from 10 sarcoma centers of the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG). This study reported excellent safety data and long-term results, with a 5-year DFS (calculated from date of resection) and OS (calculated from start of preoperative imatinib) of 65% and 87%, respectively. Only 1% of patients progressed during preoperative therapy. Microscopically radical resection (R0) was obtained in 83.2% of cases. Postoperative complications were recorded in 15% of cases, but only 3% required surgical intervention. One patient died postoperatively after total gastrectomy. Tielen and colleagues analyzed a series of 57 patients with locally advanced GIST treated with neoadjuvant imatinib, with a median treatment duration of 8 months. Microscopically radical resection (R0) was possible in 84% of patients. Five-year DFS and OS of 77% and 88% were reported, respectively. Median tumor size of 12.2 cm before treatment was reduced to 6.2 cm after imatinib treatment. No tumor rupture was recorded. Goh and colleagues analyzed 37 patients preoperatively treated with imatinib, and concluded that radical resection was possible in 33 (89%) cases. Postoperative complications were recorded in only 4 (11%) of cases. A Dutch study presented data of 57 patients with locally advanced GIST who underwent surgery after a median time of 8 months of treatment with imatinib. Tumor perforation did not occur in any of the patients and R0 resection was achieved in 84% of cases. Forty-four patients did not develop recurrence during follow-up. Recent reports indicate the possibility of successful laparoscopic resection of locally advanced gastric or esophageal GIST treated with neoadjuvant imatinib.
Only 3 small, nonrandomized phase II trials are available evaluating neoadjuvant therapy with imatinib in locally advanced GIST ( Table 2 ). In the Radiation Therapy Oncology Group (RTOG), the National Cancer Institute, and the American College of Radiology Imaging Network (ACRIN)–RTOGS-0132/ACRIN 6665 phase II trial, 31 patients with primary, localized GIST received imatinib at the dosage of 600 mg daily preoperatively for 8 to 12 weeks and in case of objective response or stable disease they underwent elective surgery, followed by 2 years of adjuvant imatinib. Results of this trial confirmed the safety of this approach and a high percentage of relapse-free survival was observed after surgery. Two-year DFS and OS rates were 83% and 93%, respectively, but discontinuation of adjuvant imatinib decreased the outcome to 5-year DFS and OS rates of 57% and 77%, respectively. This study may have also identified gene expression signatures that are predictive for response to imatinib. The German phase II CST1571-BDE43 study is the largest trial on neoadjuvant treatment with imatinib. After 6 months of imatinib, only 1 patient was inoperable at planned surgery and 26 (64%) of 41 patients had less extensive surgery than initially planned before administration of imatinib.
| Eligibility Criteria | Trial Design | Patient Numbers, n | Endpoints and Results | |||||
|---|---|---|---|---|---|---|---|---|
| DFS/RFS | OS | ORR | PFS | Toxicity/SAE | ||||
| Phase II RTOG-S0132/ACRIN 6665 | Cohort A: Locally advanced GIST ≥5 cm Cohort B: potentially resectable metastatic/recurrent GIST KIT-positive | Nonrandomized Neo-adj. imatinib 600 mg/d. for 8–12 wk and adj. imatinib for 2 y [R0 resection: 67%] | Total: n = 52 Cohort A: n = 30 Cohort B: n = 22 | 5-y. RFS: 57% | 2-y. OS: 92% 5-y. OS: 77% | — | 2-y. PFS: 80.5% | Grade 3: 29% Grade 4: 16% Grade 5: 4% |
| Phase II MD Anderson Cancer Center | GIST at size ≥1 cm KIT-positive | Nonrandomized Neo-adj. imatinib 600 mg/d. for 3, 5 or 7 d and adj. imatinib for 2 y | n = 19 | 1-y. DFS: 94% 2-y. DFS: 87% | — | — | — | — |
| Phase II APOLLON CST1571-BDE43 | Locally advanced GIST KIT-positive | Nonrandomized Neo-adj. imatinib 400 mg/d. for 6 mo [R0 resection: 87%] | n = 41 | 3-y. RFS: 85% | Mean OS: 74.9 mo Mean OS: 83% | — | Mean PFS: 67% Mean TTP: 64 mo | — |
| EORTC STBSG collaborative series | Locally advanced, nonmetastatic GISTs KIT-positive | Retrospective study Neo-adj. imatinib 400 mg/d. for median time of 40 wk [range: 6–190 wk] [R0 resection: 83%] | n = 161 | 5-y. DFS: 65% | 5-y. OS: 87% 5-y. DSS: 95% Median OS: 104 mo | 80% | — | — |
These results imply that neoadjuvant therapy with imatinib increases the possibility of complete tumor resection and decreases the need for extensive and/or multivisceral resections. The median time of preoperative imatinib in the EORTC STBSG data was 10 months. With longer neoadjuvant therapy, approximately 80% of cases demonstrate objective response to imatinib therapy. This is higher than the response rates reported in the phase II RTOG 0132 trial, in which a maximum of 12 weeks of preoperative imatinib only was used. Goh and colleagues as well as Doyon and colleagues reported similar data. Furthermore, neoadjuvant imatinib seems to be a safe treatment strategy. In the EORTC STBSG series only 3% of patients were reported to require surgical reintervention due to postoperative complications.
The proper candidates for preoperative imatinib are those patients who may benefit from tumor downstaging before operation; that is, patients in whom preoperative therapy with imatinib enables an organ-sparing resection with negative margins, avoiding mutilating surgery, intraoperative tumor rupture, and/or extensive blood loss ( Box 1 ). Obviously, this neoadjuvant strategy is especially attractive in surgically demanding tumor sites, such as distal rectum, gastroesophageal junction, duodenum or esophagus, where preservation of vital functions is pivotal. Resection of advanced primary tumors at these sites may be related to significant morbidity and functional defects. In some selected cases, downstaging of the primary tumor may sometimes even allow laparoscopic surgery instead of open surgery through an extensive midline laparotomy. Of course, these patients must be selected carefully by multidisciplinary assessment to optimize clinical outcomes. Before starting neoadjuvant therapy, a biopsy is obligatory (preferentially core-needle biopsy) and ideally the selection process should also be based on tumor genotyping results. The assessment of molecular status before neoadjuvant therapy is obligatory according to current ESMO guidelines, but this may sometimes be difficult on a small biopsy sample. Nevertheless, it is clear now that the presence of primary gain-of-function mutations in KIT or PDGFRA genes strongly correlates with outcome of imatinib therapy in advanced GIST. The mutational status of the primary tumor is related to PFS and it predicts the probability of response to imatinib. Tumors harboring exon 11 KIT mutations demonstrate the best response to imatinib (70%–85% objective response rate) and these patients have the longest overall and PFS. On the other hand, several clinical and laboratory studies confirmed that tumors with exon 18 PDGFRA D842V mutations are insensitive to imatinib, whereas other PDGFRA -mutant GIST show variable response. In GIST harboring exon 18 PDGFRA D842V mutations (which are relatively frequent in the stomach) neoadjuvant treatment with imatinib is futile, as these tumors are not sensitive to this drug. Furthermore, it has been demonstrated that patients with advanced and metastatic GIST harboring KIT exon 9 mutations may benefit from an increased imatinib dose (escalated to 800 mg daily). This indicates that patients with this mutation may be undertreated, when applying standard 400-mg daily dosage, but so far no clinical trial explored the outcome of an increased imatinib dose in this subset of patients in a neoadjuvant setting.
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Locally advanced tumor, not a priori amenable for surgery without mutilating/multivisceral operation (eg, abdominal-perineal resection, pelvic evisceration, Whipple procedure, esophagogastric resection)
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When a negative resection margin of the organ of origin is difficult to obtain, a high risk of tumor rupture can be expected or complication due to the extensive surgery can be foreseen
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When function-sparing resection, minimizing the extent of surgery and reducing postoperative morbidity and mortality can be expected after tumor shrinkage (wedge resection instead of total gastrectomy with splenectomy, local excision instead of Whipple procedure, one cavity approach instead of abdominal-thoracic resection).
Based on assessment of size, location, and mitotic index, most primary GISTs treated with preoperative imatinib are considered high-risk or intermediate-risk tumors. This makes them candidates for adjuvant treatment with imatinib. According to current guidelines, imatinib should be administered postoperatively for 36 months (see also the next section). The EORTC STBSG series demonstrated the significant difference in DFS in favor of patients receiving imatinib, especially in patients with small-bowel GIST, who have an intrinsically higher risk of developing recurrence.
Adjuvant Strategy
Postoperative recurrence of moderate and high-risk GIST is frequently observed. This led to the idea of using imatinib as an adjuvant treatment after primary surgery to prevent or delay recurrence and thus prolong survival. In 2008, imatinib was registered for use in adjuvant therapy after resection of primary GIST at significant risk of relapse. This was based on the results of clinical trials demonstrating a significant reduction in the risk of recurrence. However, the data did not provide a clear guidance as to optimal duration of treatment.
The role of imatinib in the adjuvant treatment setting has been evaluated in several phase II and III clinical trials: ACOSOG Z9000 and Z9001 (conducted by the American College of Surgeons Oncology Group), SSGXVIII/AIO (conducted by the Scandinavian Sarcoma Group and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie XVIII), RTOG S0132 (conducted by the Radiation Therapy Oncology Group), and EORTC 62024 (conducted by the European Organization for Research and Treatment of Cancer) ( Table 3 ). Data from the ACOSOG Z9001 phase III study, comparing 1 year of adjuvant therapy with imatinib 400 mg daily to placebo in patients after R0 resection of GIST of at least 3 cm in diameter, have shown a significant reduction in the risk of recurrence from 17% to 2% at 1 year (20 months of follow-up; P = .0001, hazard ratio = 0.35). The treatment was well tolerated. However, no significant impact on OS was observed; many patients recurred shortly after adjuvant imatinib cessation and they then received imatinib as a rescue therapy in the metastatic setting. This implies that adjuvant imatinib delays rather than prevents the relapse. Moreover, this trial enrolled many patients with low risk of recurrence according to current criteria. Substantial clinical benefit of adjuvant therapy was most obvious in the group of patients with high risk of relapse according to NCCN-AFIP criteria, with an improvement of 2-year recurrence-free survival (RFS) from 41% to 77% ( P <.0001). This raised interest in the assessment of a more long-term administration of adjuvant imatinib in high risk GIST.
| Trial | Imatinib Dose and Duration | Inclusion Criteria | Efficacy Results | |
|---|---|---|---|---|
| Primary Endpoints | Secondary Endpoints | |||
| ACOSOG Z9001 Randomized, phase III, placebo-controlled | 400 mg daily (n = 359) vs placebo (n = 354) for 1 y |
| 1-y RFS: 98% with imatinib vs 83% placebo (83%) median FU: 19.7 mo HR 0.35, P <.0001 | No significant difference in 1-y OS median FU: 19.7 mo HR 0.66, P = .47 |
| ACOSOG Z9000 One-arm, open-label, phase II | 400 mg daily (n = 107) for 1 y |
| 1-y OS: 99% 2-y OS: 97% 3-y OS: 97% Median FU: 4 y | 1-y RFS: 94% 2-y RFS: 73% 3-y RFS: 61% Median FU: 4 y |
| SSGXVIII/AIO Randomized, open-label, phase III | 400 mg daily for 1 y (n = 200) vs 3 y (n = 200) |
| 5-y RFS: 65.6% after 3 y vs 47.9% after 1 y of imatinib (71.1% vs 52.3% in Intention-to-treat population) Median FU: 54 mo HR 0.46, 95% CI 0.32–0.65; P <.0001 | 5-y OS: 92% after 3 y vs 81.7% after 1 y of imatinib Median 54-mo FU HR 0.45, 95% CI 0.22–0.89; P = .019 |
| EORTC 62024 Two-arms, open-label, randomized, phase III | 400 mg daily vs observation (n = 908) for 2 y |
| 5-y imatinib failure-free survival (IFFS): 84% with imatinib arm vs 84% in control arm HR = 0.80, P = .23 5-y IFFS in high-risk GIST: 89% vs 73%; P = .11 | RFS (at 3 y): 84% after 2 y vs 66% in control arm Median FU: 4.7 y HR 0.45, 95% CI 0.22–0.89; P = .019 OS: no significant difference |
| Kang et al Single-arm, prospective, phase II | 400 mg daily (n = 47) for 2 y |
| 1-y RFS: 97.7% 2-y RFS: 92.7% Median FU: 26.9 mo | — |
| Li et al Open-label, nonrandomized, phase II | 400 mg daily (n = 56) vs no treatment (n = 49) for 3 y |
| RFS with imatinib vs no treatment: 1-y RFS: 100% vs 90% 2-y RFS: 96% vs 57% 3-y RFS: 89% vs 48% Median FU: 45 mo HR 0.188, 95% CI 0.085–0.417; P <.001 | Significantly reduced risk of death with imatinib vs no treatment Median FU: 45 mo HR 0.254, 95% CI 0.070–0.931; P = .025 |
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