Adjuvant Therapy
Year published | Study name or reporting institution | Type of study | Eligibility criteria and cohort numbers | Major findings | Impact on practice | |
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Primary endpoints | Secondary endpoints | |||||
2013 | ACOSOG Z9000 | Single-arm, multicenter, phase II | Adjuvant imatinib (400 mg/day) for 1 year Cohort (n = 106): Patients who underwent complete gross tumor removal, with high-risk tumor defined as ≥ 10 cm, intraperitoneal tumor rupture, or up to four peritoneal implants | 1-year OS: 99% 3-year OS: 97% 5-year OS: 83% | 1-year RFS: 96% 3-year RFS: 60% 5-year RFS: 40% 83% completed 1 year of adjuvant imatinib Tumor mutation status associated with RFS | 1. Adjuvant imatinib was well tolerated and safe in the adjuvant setting 2. Confirmed impact of tumor mutation on the efficacy of adjuvant imatinib and RFS |
2009, 2014 | ACOSOG Z9001 | Randomized, placebo-controlled, phase III | Adjuvant imatinib (400 mg/day) for 1 year Cohort (imatinib n = 359, placebo n = 354): Patients who underwent complete gross resection of GIST ≥ 3 cm | Imatinib 1-year RFS: 98% Placebo 1-year RFS: 83% | 1. Adjuvant imatinib was well tolerated and safe in the adjuvant setting 2. Adjuvant imatinib was associated with improved RFS compared with placebo 3. US FDA approval of imatinib for postoperative treatment of adult patients after resection of KIT-positive GIST | |
2012, 2014, 2016, 2017, 2020 | SSG XVIII AIO | Randomized, open-label, phase III | Adjuvant imatinib (400 mg/day) for 1 vs. 3 years Cohort (1 year of adjuvant imatinib, n = 200; 3 years of adjuvant imatinib, n = 200): Patients who underwent complete gross resection of GIST with tumor diameter > 10 cm, mitotic count > 10/50 HPFs, tumor diameter > 5 cm and mitotic count > 5/50 HPFs, or tumor rupture before or at the time of surgical resection | 1 year of adjuvant imatinib 5-year RFS: 52.3% 10-year RFS: 42% 3 years of adjuvant imatinib 5-year RFS: 71.1% 10-year RFS: 53% | 1 year of adjuvant imatinib 5-year OS: 85.3% 10-year OS: 65% 3 years of adjuvant imatinib 5-year OS: 91.9% 10-year OS: 79% | 1. Established new standard of adjuvant imatinib therapy for 3 years for patients following complete resection of high-risk GISTs 2. Few patients developed recurrence while receiving adjuvant imatinib, suggesting that adjuvant therapy does not increase the risk of secondary resistance and that recurrence that develops after cessation of adjuvant imatinib may respond to rechallenge with imatinib |
2015 | EORTC 62024 | Randomized, open-label, phase III | Adjuvant imatinib (400 mg/day) for 2 years vs. observation Cohort (imatinib n = 417, observation n = 454): Patients who underwent complete gross resection of high-risk GIST (tumor > 10 cm, mitotic count > 10/50 HPFs, or tumor > 5 cm and mitotic rate > 5/50 HPFs), or intermediate-risk GIST (tumor ≤ 5 cm and mitotic rate 6/50 to 10/50 HPFs or tumor size > 5 cm to 10 cm and mitotic rate ≤ 5/50 HPFs) | 2 years of adjuvant imatinib 5-year IFFS: 87% 5-year IFFS, high-risk: 89% Observation 5-year IFFS: 84% 5-year IFFS, high-risk: 73% | 2 years of adjuvant imatinib 3-year RFS: 84% 5-year RFS: 69% 5-year OS: 100% Observation 3-year RFS: 66% 5-year RFS: 63% 5-year OS: 99% | 1. Supports use of adjuvant imatinib following complete resection of intermediate- and high-risk GISTs 2. Few patients developed recurrence while receiving adjuvant imatinib, suggesting that adjuvant therapy does not increase the risk of secondary resistance and that recurrence that develops after cessation of adjuvant imatinib may respond to rechallenge with imatinib |
2018 | PERSIST-5 | Single-arm, prospective, phase II | Adjuvant imatinib (400 mg/day) for 5 years or until progression or intolerance Cohort (n = 91): Primary GIST at any site ≥ 2 cm with ≥ 5 mitoses/50 HPFs or non-gastric primary GIST ≥ 5 cm | 5-year RFS: 90% No patient with imatinib-sensitive mutation recurred while receiving imatinib therapy | 5-year OS: 95% | 5 years of adjuvant therapy appeared safe and effective at controlling the recurrence rate |
ACOSOG Z9000
Purpose and Study Design
Results
Implications for Practice
ACOSOG Z9001
Purpose and Study Design
Results
Scandinavian/German SSG XVIII/AIO
Purpose and Study Design
Results
Implications for Practice
EORTC 6202413
Purpose and Study Design
Results
Implications for Practice
Persist-514
Purpose and Study Design
Results
Implications for Practice
Neoadjuvant Treatment
Year published | Study name or reporting institution | Type of study | Eligibility criteria and cohort numbers | Major findings | Year published | ||
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Primary endpoints | Secondary endpoints | Impact on practice | |||||
2008, 2012 | RTOG 0132/ACRIN 6665 | Multi-institution, non-randomized, phase II | Neoadjuvant imatinib (600 mg/day) for 8–12 weeks followed by resection in patients with SD/PR and adjuvant imatinib for 2 years Cohort A (n = 31): Primary GIST ≥ 5 cm Cohort B (n = 22): Potentially resectable metastatic/recurrent GIST ≥ 2 cm | Cohort A 2-year OS: 93.5% 2-year DSS: 93.5% 5-year OS: 76.9% 5-year DSS: 76.9% Cohort B 2-year OS: 90.9% 2-year DSS: 100% 5-year OS: 68.2% 5-year DSS: 77.3% | Cohort A 2-year PFS: 83.9% 5-year PFS: 56.7% Cohort B 2-year PFS: 77.3% 5-year PFS: 29.8% | Grade 3: 34% Grade 4: 21% Grade 5: 2% | 1. First prospective study of preoperative imatinib in GISTs 2. Preoperative imatinib therapy for 8–12 weeks was shown to be safe and well tolerated 3. Long-term follow-up showed a significant drop in PFS and OS after 2 years when adjuvant imatinib was discontinued |
2009 | MD Anderson Cancer Center | Single-institution, randomized, phase II | Neoadjuvant imatinib (600 mg/day) for 3 (n = 7), 5 (n = 6), or 7 (n = 6) days followed by resection and adjuvant imatinib for 2 years Cohort: Primary GIST ≥ 1 cm (n = 19) | 1-year DFS: 94% 2-year DFS: 87% | 1. Preoperative imatinib therapy was shown to be safe and well tolerated 2. Radiographic response to imatinib can be observed within the first week of therapy by 18FDG-PET and dCT, as well as histologically | ||
2013 | EORTC STBSG | Collaborative retrospective series of pooled databases from 10 centers | Neoadjuvant imatinib (400 mg/day) for a median of 40 weeks (range 6–190) Cohort: Locally advanced, non-metastatic GIST (n = 161) | 5-year OS: 87% 5-year DSS: 95% | 5-year DFS: 65% | 1. Higher observed partial response rate compared with RTOG 0132/ACRIN 6665, likely related to the longer median duration of preoperative imatinib treatment, supporting recommendations to continue neoadjuvant therapy until maximal response was achieved prior to surgical resection |
RTOG 0132/ACRIN 666517,18
Purpose and Study Design
Results
Implications for Practice
MD Anderson, McAuliffe et al.19
Purpose and Study Design
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EORTC STBSG20
Purpose and Study Design
Results
Implications for Practice
Combination of Targeted Therapy and Metastasectomy
Authors, year published | Number of cases, clinical indications | Key results |
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Raut et al.25 | N = 69 patients who underwent surgery for advanced GISTs while receiving TKI therapy Group I (n = 23): surgery at stable disease Group II (n = 32): surgery at limited progression Group III (n = 14): surgery at generalized progression | Group I: 1-year PFS 80%, 1-year OS 95% Group II: 1-year PFS 33%, 1-year OS 86% Group III: 1-year PFS 0%, 1-year OS 0% |
Rutkowski et al.42 | N = 141 patients who underwent surgery for initially inoperable and/or metastatic GISTs after receiving imatinib therapy Group I (n = 24): resection of residual disease after complete/partial response or lack of further response Group II (n = 8): surgery as salvage therapy for progression after initially successful imatinib therapy | Median follow-up 12 months Group I: Four recurrences of 5 patients who did not resume imatinib postoperatively, 1 recurrence of 19 patients who resumed imatinib postoperatively Group II: 5/8 patients progressed |
Gronchi et al.39 | N = 159 patients with advanced/metastatic GISTs treated initially with imatinib Group I (n = 27): surgery at response Group II (n = 8): surgery at progression | Group I: 1-year PFS 96%, 1-year OS 100%; 2-year PFS 69% Group II: 1-year PFS 0%, 1-year OS 60% |
DeMatteo et al.38 | N = 40 patients with metastatic GISTs treated with TKI therapy Group I (n = 20): surgery at response Group II (n = 13): surgery at focal progression Group III (n = 7): surgery at multifocal progression | Median follow-up 15 months Group I: 2-year PFS 61%, 2-year OS 100% Group II: 2-year PFS 24%, 2-year OS 36%, median TTP 12 months Group III: 1-year OS 36%, median TTP 3 months |
Mussi et al.37 | N = 80 patients with metastatic GISTs treated with TKI therapy Group I (n = 49): surgery at best response Group II (n = 31): surgery at focal progression | Morbidity in 13 patients Group I: 2-year PFS 64.4%, median PFS not reached, 5-year DSS 82.9%, median DSS not reached Group II: 2-year PFS 9.7%, median PFS 8 months, 5-year DSS 67.6%, median DSS not reached |
Raut et al.36 | N = 50 patients with metastatic imatinib-resistant GISTs undergoing surgery following sunitinib therapy Group I (n = 10): responsive disease Group II (n = 22): limited progression Group III (n = 18): generalized progression | Complication rate 54%, 48% R2 resection Median follow-up 15.2 months Median PFS and OS after surgery 5.8 and 16.4 months, respectively Median PFS and OS after the start of sunitinib 15.6 and 26 months, respectively Differences in PFS and OS between groups were not significant |
Tielen et al.35 | N = 55 patients with advanced/metastatic GISTs treated with TKI therapy Group I (n = 35): responders Group II (n = 20): nonresponders | Group I: 48% recurrence/progression, median PFS and OS not reached, 5-year OS 78% Group II: 85% recurrence/progression, median PFS 4 months, median OS 25 months, 3-year OS 26% |
Bauer et al.26 | N = 239 patients with GISTs undergoing surgery for metastatic GISTs Group I (n = 177): complete gross resection (R0/R1) Group II (n = 62): incomplete gross resection (R2) | Group I: median OS 8.7 years, median OS was not reached when surgery was performed at remission, median TTP was not reached Group II: median OS 5.3 years, median OS 5.1 years when surgery was performed at remission, median TTP 1.9 years when surgery was performed at response Groups I and II: no difference in median PFS in patients progressing at the time of surgery |
Du et al.34 | N = 41 of 210 planned patients with recurrent/metastatic GISTs treated with TKI therapy Arm A (n = 19): surgery Arm B (n = 22): imatinib alone | Group I: 2-year PFS 88.4%, median OS not reached Group II: 2-year PFS 57.7%, median OS 49 months |
Fairweather et al.33 | 400 operations performed in 323 patients with metastatic GISTs treated with TKI therapy Group 1 (n = 64): surgery at response Group 2 (n = 100): surgery at stable disease Group 3 (n = 132): surgery at limited progression Group 4 (n = 104): surgery at generalized progression | In patients receiving imatinib before surgery, radiographic response was predictive of PFS and OS from the time of surgery Group 1: PFS 36 months, OS not reached Group 2: PFS 30 months, OS 144 months Group 3: PFS 11 months, OS 105 months Group 4: PFS 6 months, OS 66 months |