Daniel Pink

One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor A Randomized Trial

CONTEXT Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo. OBJECTIVE To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery. DESIGN, SETTING, AND PATIENTS Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria. INTERVENTION Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery. MAIN OUTCOME MEASURES The primary end point was RFS; the secondary end points included overall survival and treatment safety. RESULTS Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence. CONCLUSION Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00116935.

Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate

Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor α (PDGFRα) gene. Both PDGFRα and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Diffusion‐weighted magnetic resonance imaging allows monitoring of anticancer treatment effects in patients with soft‐tissue sarcomas

To determine if diffusion‐weighted imaging (DWI) can be used as a surrogate marker of tumor response to anticancer therapy in patients with soft‐tissue sarcomas.

A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.

Purpose: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. Experimental Design: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. Results: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. Conclusions: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation. (Clin Cancer Res 2009;15(18):5910–6)

Docetaxel and Continuous-Infusion Fluorouracil Versus Epirubicin, Cisplatin, and Fluorouracil for Advanced Gastric Adenocarcinoma: A Randomized Phase II Study

PURPOSE A combination of docetaxel and fluorouracil (DF) was evaluated in an outpatient setting and compared with epirubicin, cisplatin, and fluorouracil (ECF), which served as an internal control arm to avoid selection bias. PATIENTS AND METHODS Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks). RESULTS Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively. CONCLUSION DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin.

Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial

PURPOSE Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial. PATIENTS AND METHODS Eligible patients had macroscopically completely excised, KIT-positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival. RESULTS A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio [HR], 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024). Similar numbers of cardiac events and second cancers were recorded in the groups. CONCLUSION Three years of adjuvant imatinib therapy results in longer survival than 1 year of imatinib. High 5-year survival rates are achievable in patient populations with high-risk GIST.

Survival and prognostic factors in chondrosarcoma: Results in 115 patients with long-term follow-up

Background and purpose There have been few long-term studies on the outcome of chondrosarcoma and the findings regarding prognostic factors are controversial. We examined a homogeneous group of patients with primary central chondrosarcoma of bone who were treated according to a uniform surgical protocol at our institution, in order to determine the factors that influence survival and identify potential improvements to our therapeutic algorithm. Patients and methods We performed a retrospective analysis of 115 patients with primary central chondrosarcoma of bone who presented with localized disease and who had a minimum follow-up of 5 years after diagnosis. 68 tumors were localized in the extremities and 47 in the axial skeleton or pelvis. 59 patients had a high-grade (II and III) and 56 a low-grade (I) tumor. 94 patients underwent surgical resection with adequate (wide or radical) margins, while 21 patients had inadequate (marginal or intralesional) margins. Results Tumor grade and localization were found to be statistically significant independent predictors of disease-related deaths in multivariate analysis. The quality of surgical margins did not influence survival. The AJCC staging system was able to predict prognosis in patients with chondrosarcoma of the extremities, but not in those with tumors of the axial skeleton and pelvis. Long-term survival after secondary metastatic disease was only observed when metastases were resected with wide margins. Patients with metastases who received further treatment with conventional chemotherapy, radiotherapy, and/or further surgery had significantly better survival compared to those who received best supportive care. Interpretation The outcome in patients with primary central chondrosarcoma of bone who present with localized disease is mostly affected by tumor-related parameters.

Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib.

Little is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib.

An open label, non-comparative phase II study of topotecan as salvage treatment for patients with soft tissue sarcoma.

Background: The number of effective cytotoxic agents for the treatment of patients with metastatic soft tissue sarcoma (STS) is limited, especially when patients have failed anthracyline-based chemotherapy. Patients and methods: Between 1999 and 2000 a total of 16 patients with histologically proven STS progressing during or after first-line anthracycline-based chemotherapy were entered into this open-label, noncomparative study. Topotecan was administered as a 30-min infusion at a dosage of 1.5 mg/m2 on five consecutive days every 3 weeks. All patients had received an anthracycline- or ifosfamide-based first-line chemotherapy. Results: None of the 16 included patients achieved an objective response to topotecan. Six patients achieved stable disease (38%), lasting for at least 6 weeks in four patients (25%) and for less than 6 weeks in two patients (13%). Ten patients (62%) had progressive disease. The median time to progression was 79 days calculated from the start of topotecan therapy (range, 28–230). The treatment was well tolerated; however, both anemia and thrombopenia grade III/IV occurred in 25% of the patients as well as severe neutropenia in 69% of the patients. Nonhematologic toxicities grade III/IV such as diarrhea and severe bleeding occurred only in one patient each (6%). Discussion: Topotecan is well tolerated in anthracycline-resistant patients with metastatic STS, but no objective response has been observed in this trial.

Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib : An exploratory analysis of a randomized clinical trial

Importance Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor &agr; (PDGFRA) mutations. Objective To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib. Design, Setting, and Participants This exploratory study is based on the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) multicenter clinical trial. Between February 4, 2004, and September 29, 2008, 400 patients who had undergone surgery for GISTs with a high risk of recurrence were randomized to receive adjuvant imatinib for 1 or 3 years. Of the 397 patients who provided consent, 341 (85.9%) had centrally confirmed, localized GISTs with mutation analysis for KIT and PDGFRA performed centrally using conventional sequencing. During a median follow-up of 88 months (completed December 31, 2013), 142 patients had GIST recurrence. Data of the evaluable population were analyzed February 4, 2004, through December 31, 2013. Main Outcomes and Measures The main outcome was RFS. Mutations were grouped by the gene and exon. KIT exon 11 mutations were further grouped as deletion or insertion-deletion mutations, substitution mutations, insertion or duplication mutations, and mutations that involved codons 557 and/or 558. Results Of the 341 patients (175 men and 166 women; median age at study entry, 62 years) in the 1-year group and 60 years in the 3-year group), 274 (80.4%) had GISTs with a KIT mutation, 43 (12.6%) had GISTs that harbored a PDGFRA mutation, and 24 (7.0%) had GISTs that were wild type for these genes. PDGFRA mutations and KIT exon 11 insertion or duplication mutations were associated with favorable RFS, whereas KIT exon 9 mutations were associated with unfavorable outcome. Patients with KIT exon 11 deletion or insertion-deletion mutation had better RFS when allocated to the 3-year group compared with the 1-year group (5-year RFS, 71.0% vs 41.3%; P < .001), whereas no significant benefit from the 3-year treatment was found in the other mutational subgroups examined. KIT exon 11 deletion mutations, deletions that involved codons 557 and/or 558, and deletions that led to pTrp557_Lys558del were associated with poor RFS in the 1-year group but not in the 3-year group. Similarly, in the subset with KIT exon 11 deletion mutations, higher-than-the-median mitotic counts were associated with unfavorable RFS in the 1-year group but not in the 3-year group. Conclusions and Relevance Patients with KIT exon 11 deletion mutations benefit most from the longer duration of adjuvant imatinib. The duration of adjuvant imatinib modifies the risk of GIST recurrence associated with some KIT mutations, including deletions that affect exon 11 codons 557 and/or 558. Trial Registration clinicaltrials.gov Identifier: NCT00116935