ABSTRACT
The understanding of aberrant molecular pathways that result in gastrointestinal stromal tumors (GISTs) and the rapid development of molecular therapies that target these pathways represent one of the great milestones in translational oncology. The story of GIST is unique in that targeted molecular therapy was successfully applied in clinical therapeutics, with dramatic results redefining the management of these traditionally chemotherapy-resistant tumors. We briefly review the molecular biology and clinical presentation of GIST and then discuss the adjuvant and neoadjuvant use of tyrosine kinase inhibitors in early-stage GIST and their use in metastatic disease. Newer therapeutic advances in the rapidly changing field of GIST management are also discussed.
Subject(s)
Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Neoplasms/diagnosis , Gastrointestinal Neoplasms/pathology , Gastrointestinal Stromal Tumors/diagnosis , Humans , Molecular Targeted Therapy , Neoadjuvant Therapy , Neoplasm Metastasis , Prognosis , Protein-Tyrosine Kinases/antagonists & inhibitorsABSTRACT
BACKGROUND: Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is used as monotherapy for chemorefractory metastatic colorectal cancer (mCRC) in patients with wild-type (WT) KRAS tumors. Although skin toxicities are the most common adverse events associated with EGFR inhibitors, the differences in efficacy and safety between pre-emptive and reactive skin treatment according to KRAS tumor status has not been reported. PATIENTS AND METHODS: Eligible patients had mCRC with disease progression or unacceptable toxicity with first-line treatment containing fluoropyrimidine and oxaliplatin-based chemotherapy ± bevacizumab. Patients were randomized 1:1 to pre-emptive or reactive skin treatment (after skin toxicity developed). Patients received either panitumumab 6 mg/kg + FOLFIRI every 2 weeks or panitumumab 9 mg/kg + irinotecan every 3 weeks. Key study endpoints included overall response rate (ORR), overall survival, progression-free survival (PFS), and safety according to KRAS tumor status. RESULTS: Eighty-seven (92%) of 95 enrolled patients had evaluable KRAS tumor status: 49 (56%) patients with WT and 38 (44%) patients with mutant (MT) KRAS tumors, respectively. The ORR was 16% and 8% for patients with WT and MT KRAS tumors, respectively. Median PFS was 5.5 and 3.3 months for patients with WT and MT KRAS tumors, respectively. The most commonly observed adverse events by KRAS tumor status included dermatitis acneiform and pruritus. CONCLUSION: Panitumumab in combination with irinotecan-based chemotherapy has an acceptable toxicity profile in second-line therapy for mCRC. Numerical differences trending in favor of the patients with WT KRAS tumors were observed for most efficacy endpoints.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Mutation/genetics , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Biomarkers, Tumor/genetics , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/mortality , DNA, Neoplasm/genetics , Female , Fluorouracil/administration & dosage , Humans , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Panitumumab , Polymerase Chain Reaction , Premedication , Prognosis , Proto-Oncogene Proteins p21(ras) , Salvage Therapy , Skin Diseases/chemically induced , Skin Diseases/drug therapy , Survival Rate , Young AdultABSTRACT
PURPOSE: Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the United States and Europe for the treatment of refractory metastatic colorectal cancer (mCRC). Skin toxicities are the most common adverse events with EGFR inhibitors. This is the first study designed to examine differences between pre-emptive and reactive skin treatment for specific skin toxicities in patients with mCRC for any EGFR inhibitor. PATIENTS AND METHODS: Patients receiving panitumumab-containing therapy were randomly assigned 1:1 to pre-emptive or reactive treatment (after skin toxicity developed). Pre-emptive treatment included use of skin moisturizers, sunscreen, topical steroid, and doxycycline. The primary end point of the study was the incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period. Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI). RESULTS: Of 95 enrolled patients, 48 received pre-emptive treatment, and 47 received reactive treatment. The incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. Mean DLQI score change from baseline to week 3 was 1.3 points and 4.2 points in the pre-emptive and reactive groups, respectively. CONCLUSION: The pre-emptive skin treatment regimen was well tolerated. The incidence of specific >or= grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the pre-emptive group compared with the reactive group. Patients in the pre-emptive group reported less QOL impairment than patients in the reactive group.
