J Randolph Hecht

Mayo Clinic - Rochester, Рочестер, Minnesota, United States

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Publications (56)453.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate feasible doses of weekly everolimus and irinotecan given with cetuximab for previously treated metastatic colorectal cancer (mCRC). Adults with mCRC that progressed after 5-fluorouracil or capecitabine-plus-oxaliplatin were treated using a sequential dose escalation scheme. Dosing decisions were based on the probability of experiencing a dose-limiting toxicity (DLT) during the first two 21-day treatment cycles. Patients received everolimus 30 mg/week plus irinotecan 350 mg/m(2) q3w (n=5; dose A1) or everolimus 30 mg/week plus irinotecan 250 mg/m(2) q3w (n=14; dose B1). Among patients evaluable for the maximum tolerated dose, two out of four in A1 and one out of eight in B1 experienced four DLTs. The trial was terminated early based on changes in clinical practice and emerging data on everolimus dosing. The feasible doses of everolimus and irinotecan administered with cetuximab as second-line therapy in mCRC were 30 mg/week and 250 mg/m(2), respectively. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    Anticancer research 03/2015; 35(3):1567-73. · 1.87 Impact Factor
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    ABSTRACT: Second-line treatment with chemotherapy and anti-EGFR or anti-VEGF antibodies improves outcomes in patients with wild-type KRAS metastatic colorectal cancer (mCRC). The choice of biological agent in second-line mCRC remains unclear. This randomized, phase 2 estimation trial compared irinotecan, fluorouracil, and leucovorin (FOLFIRI) in combination with panitumumab or bevacizumab in patients progressing on oxaliplatin-based chemotherapy and bevacizumab.
    Clinical Colorectal Cancer 01/2015; DOI:10.1016/j.clcc.2014.12.009 · 2.91 Impact Factor
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    ABSTRACT: Background Detection of Lynch syndrome has the potential to reduce morbidity and mortality among patients and their family members due to beneficial screening and treatment options. Several institutions have begun to adopt universal rather than risk-stratified screening protocols, but the lack of 100 % compliance rates requires identification of system-level interventions to improve screening practices. Objective We aimed to identify patient, tumor, and system factors associated with lack of screening and identify system-based interventions to improve Lynch syndrome screening. Design and Settings This study is a retrospective analysis of Lynch syndrome screening among colorectal cancer patients undergoing surgery in a single healthcare system. Patients Two hundred and sixty-two patients who underwent surgery for colorectal cancer were studied. Main Outcome Measures Rate of Lynch syndrome screening. Results We identified that 75 % of the total cohort was screened for Lynch syndrome. Of patients under the age of 50, 78 % percent were screened. Lower screening rates were found among patients with complete pathologic tumor response and lower pathologic stage of tumor. Higher screening rates were found at the academic hospital and with colorectal surgeons. In multivariable logistic regression analysis, lower screening rates were associated with community hospital location (OR, 0.22; 95 % CI, 0.08–0.56). Limitations Results may not be generalizable to different hospital settings. Conclusions Several potential system-level interventions were identified to improve screening rates including an emphasis on improved provider communication.
    Journal of Gastrointestinal Surgery 12/2014; 19(3). DOI:10.1007/s11605-014-2687-x · 2.39 Impact Factor
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    ABSTRACT: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.
    Journal of Clinical Oncology 11/2014; 33(1). DOI:10.1200/JCO.2014.56.5887 · 17.88 Impact Factor
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    ABSTRACT: Objectives: Optimal treatment strategies in frail and/or elderly patients with metastatic colorectal cancer have not been well defined. Using data from a prospective, phase II study of elderly patients with metastatic colorectal cancer treated with bevacizumab and capedtabine, we explored the differences in functional measure and quality of life (QoL) between patients with ECOG performance status (PS) 1 and 2. Materials and Methods: Geriatric functional measures included patient reported limitations in ADLs and IADLs, ECOG PS, 3-item recall, hearing acuity, and the "Get up and Go" test. QoL was assessed by means of the FACT-C questionnaire and the EQ-5D questionnaire. The prognostic impact of baseline characteristics on survival was studied using univariate Cox regression analysis. Results: The majority (62%) of the 45 patients had an ECOG PS of 2. The ECOG PS 2 group had more limitations in IADLs, lower baseline QoL, and a lower patient-rated health score. For all participants, QoL significantly improved from baseline to the start of cycle 2 (FACT-C: 99.9 vs. 105.4, p = 0.01) and did not deteriorate when baseline scores were compared to when participants went off study (FACT-C: 99.9 vs. 98.6, p = 0.59). In the Cox-regression analysis, a positive "Get up and Go" test was prognostic for improved survival (HR = 0.31, p = 0.01). Conclusion: There is significant heterogeneity in functional measures and quality of life among elderly patients with metastatic colorectal cancer with ECOG PS 1 and 2. The "Get up and Go" test may be a useful prognostic indicator for survival in this population.
    Journal of Geriatric Oncology 07/2014; 5(4). DOI:10.1016/j.jgo.2014.05.002 · 1.15 Impact Factor
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    ABSTRACT: To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevavcizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS. Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety. Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevavcizumab arms, respectively (HR, 0.62; 95% CI, 0.44 to 0.89; P = .009). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevavcizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms. PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti-epidermal growth factor receptor therapy.
    Journal of Clinical Oncology 03/2014; 32(21). DOI:10.1200/JCO.2013.53.2473 · 17.88 Impact Factor
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    ABSTRACT: Objectives Optimal treatment strategies in frail and/or elderly patients with metastatic colorectal cancer have not been well defined. Using data from a prospective, phase II study of elderly patients with metastatic colorectal cancer treated with bevacizumab and capecitabine, we explored the differences in functional measure and quality of life (QoL) between patients with ECOG performance status (PS) 1 and 2. Materials and Methods Geriatric functional measures included patient reported limitations in ADLs and IADLs, ECOG PS, 3-item recall, hearing acuity, and the “Get up and Go” test. QoL was assessed by means of the FACT-C questionnaire and the EQ-5D questionnaire. The prognostic impact of baseline characteristics on survival was studied using univariate Cox regression analysis. Results The majority (62%) of the 45 patients had an ECOG PS of 2. The ECOG PS 2 group had more limitations in IADLs, lower baseline QoL, and a lower patient-rated health score. For all participants, QoL significantly improved from baseline to the start of cycle 2 (FACT-C: 99.9 vs. 105.4, p = 0.01) and did not deteriorate when baseline scores were compared to when participants went off study (FACT-C: 99.9 vs. 98.6, p = 0.59). In the Cox-regression analysis, a positive “Get up and Go” test was prognostic for improved survival (HR = 0.31, p = 0.01). Conclusion There is significant heterogeneity in functional measures and quality of life among elderly patients with metastatic colorectal cancer with ECOG PS 1 and 2. The “Get up and Go” test may be a useful prognostic indicator for survival in this population.
    Journal of Geriatric Oncology 01/2014; · 1.12 Impact Factor
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    ABSTRACT: Objectives This study aims to determine the efficacy and tolerability of capecitabine (CAP) plus bevacizumab (BEV) as treatment for frontline metastatic colorectal cancer (mCRC) in frail and/or elderly patients. Materials and Methods This was an open label, multi-site, single arm, phase II study in frontline mCRC. In this study, patients (pts) who were frail (ECOG 2) or older patients with ECOG 1 performance status (PS) received CAP (1000 mg/m2 bid, 14 days of every 21 days) plus BEV (7.5 mg/kg iv once every 21 days). The primary objective was progression free survival (PFS). Secondary objectives were overall response rate (ORR) and toxicity. Results In terms of patients: 50 were enrolled; 5 withdrew consent prior to treatment; 45 were treated, and 41 were evaluable. The mean age was 75.9 (range 54–93) and 62% had an ECOG 2 PS. The median PFS was 6.87 months (95% CI, 5.1–11.5 months) and median overall survival was 12.7 months (95% CI, 6.9–12.7 months). The most common grades 3–4 toxicities were: diarrhea (17.8%), fatigue (13.3%), hand–foot syndrome (13.3%), dehydration (8.9%), hypertension (6.7%) and vomiting (6.7%). Conclusions The results of this trial support the use of CAP plus BEV as first-line treatment for frail/elderly patients with metastatic CRC. The ORR (40%) is comparable to pooled data in elderly on fluorouracil (5-FU) + BEV. The median PFS (7.2 months) in this study is slightly lower than that seen with 5-FU + BEV but this study had a high percentage of ECOG PS 2 patients. Side effects were manageable with no new safety signals.
    Journal of Geriatric Oncology 10/2013; 4(4):302–309. DOI:10.1016/j.jgo.2013.05.001 · 1.12 Impact Factor
  • Annals of Oncology 06/2013; 24(suppl 4):iv17-iv17. DOI:10.1093/annonc/mdt201.15 · 6.58 Impact Factor
  • ASCO; 01/2013
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    ABSTRACT: BACKGROUND: Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. METHODS: Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 1; leucovorin 200 mg/m(2) plus fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m(2) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2) twice daily on days 1-15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4-8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918. FINDINGS: Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab-FOLFOX4, and 952 to receive bevacizumab-XELOX. After a median follow-up of 48 months (range 0-66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab-FOLFOX4 group, and 253 (27%) in the bevacizumab-XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98-1·39; p=0·07), and for bevacizumab-XELOX versus FOLFOX4 was 1·07 (0·90-1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·27 (1·03-1·57; p=0·02), and for bevacizumab-XELOX versus FOLFOX4 was 1·15 (0·93-1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3-5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab-XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab-FOLFOX4: 297 [26%]; bevacizumab-XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab-FOLFOX4, and five receiving bevacizumab-XELOX. INTERPRETATION: Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer. FUNDING: Genentech, Roche, and Chugai.
    The Lancet Oncology 11/2012; DOI:10.1016/S1470-2045(12)70509-0 · 25.12 Impact Factor
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    ABSTRACT: Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
    Nature 06/2012; 486(7404):537-40. DOI:10.1038/nature11219 · 42.35 Impact Factor
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    ABSTRACT: TNFeradeBiologic (AdGVEGR.TNF.11D) is a replication-deficient adenoviral vector that expresses tumor necrosis factor-α (TNF-α) under the control of the Egr-1 promoter, which is inducible by chemotherapy and radiation. This study was conducted to determine the maximal tolerated dose of TNFeradeBiologic with standard chemoradiotherapy and preliminary activity and safety of the combination in the treatment of locally advanced pancreatic cancer (LAPC). TNFeradeBiologic was injected into locally advanced pancreatic carcinomas by using EUS or percutaneous administration once a week for 5 weeks together with 50.4 Gy radiation and 5-fluorouracil (5-FU) 200 mg/m(2) daily over 5.5 weeks. Dose levels from 4 × 10(9) to 1 × 10(12) particle units (PU) were studied. Multicentered, academic institutions. Fifty patients with LAPC were treated. Doses of TNFerade Biologic were administered to patients. Toleration of TNFerade Biologic was measured through toxicity and tumor response, by using the criteria of the Response Evaluation Criteria in Solid Tumors and the World Health Organization, and was reviewed by a central radiology facility. Overall survival and progression-free survival were also measured. Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3 patients at the 1 × 10(12) PU dose, making 4 × 10(11) PU the maximum tolerated dose. One complete response, 3 partial responses, and 12 patients with stable disease were noted. Seven patients eventually went to surgery, 6 had clear margins, and 3 survived >24 months. This is a Phase 1/2 non-randomized study. Intratumoral delivery of TNFerade Biologic by EUS with fine-needle viral injection or percutaneously, combined with chemoradiation, shows promise in the treatment of LAPC. There appeared to be better clinical outcome at the maximal tolerated dose than at lower doses. The dose of 4 ×10(11) PU TNFerade Biologic was generally well tolerated, with encouraging indications of activity, and will be tested in the randomized phase of this study. Delivery of TNFerade Biologic did not interfere with subsequent surgical resection.
    Gastrointestinal endoscopy 02/2012; 75(2):332-8. DOI:10.1016/j.gie.2011.10.007 · 4.90 Impact Factor
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    ABSTRACT: There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ. This study evaluates the efficacy and safety of mFOLFOX6 and erlotinib in patients with metastatic or advanced Eso/GEJ cancers. Patients with previously untreated advanced or metastatic Eso/GEJ adenocarcinoma are treated with oxaliplatin 85 mg m(-2), 5-FU 400 mg m(-2), LV 400 mg m(-2) on day 1, 5-FU 2400 mg m(-2) over 48 h and erlotinib 150 mg PO daily. Treatment was repeated every 14 days. The primary objective was response rate (RR), secondary objectives include toxicity, progression-free survival (PFS), overall survival (OS) and to correlate clinical outcome with expression patterns and molecular alterations in the epidermal growth factor receptor-dependent pathways. A total of 33 patients were treated and evaluable: there were two complete responses, 15 partial responses for an objective RR of 51.5% (95% CI, 34.5-68.6%). Median PFS was 5.5 months (95% CI, 3.1-7.5 months) and median OS was 11.0 months (95% CI, 8.0-17.4 months). The most common grade 3-4 toxicities were: diarrhoea (24%), nausea/vomiting (11%), skin rash (8%) and peripheral neuropathy (8%). The frequency of alterations was KRAS mutations (8%), EGFR mutations (0%) and HER2 amplification (19%). In patients with Eso/GEJ adenocarcinoma, mFOLFOX6 and erlotinib is active, has an acceptable toxicity profile and FOLFOX ± erlotinib could be considered for further development.
    British Journal of Cancer 08/2011; 105(6):760-5. DOI:10.1038/bjc.2011.280 · 5.08 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors. Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Stratification factors included WHO performance status (PS; 0 v 1 to 2) and lactate dehydrogenase ([LDH] ≤ 1.5× the upper limit of normal [ULN] v > 1.5 × ULN). Treatment was given until disease progression or unacceptable toxicity. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, tolerability, and pharmacokinetics of PTK/ZK. No statistically significant differences were seen between the treatment groups for the overall comparison of OS. With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months (hazard ratio [HR], 1.00; 95% CI, 0.87 to 1.16; P = .957). Median PFS was longer with PTK/ZK than with placebo (5.6 and 4.2 months, respectively; HR, 0.83; 95% CI, 0.71 to 0.96; P = .013). An exploratory, post hoc analysis demonstrated improved PFS in patients with high LDH, regardless of WHO PS (HR, 0.63; 95% CI, 0.48 to 0.83; P < .001). PTK/ZK in combination with FOLFOX4 did not improve OS of patients with pretreated mCRC but did improve PFS. The effect of PTK/ZK was more pronounced in patients with high LDH at baseline.
    Journal of Clinical Oncology 04/2011; 29(15):2004-10. DOI:10.1200/JCO.2010.29.5436 · 17.88 Impact Factor
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    ABSTRACT: PTK787/ZK 222584 (PTK/ZK; vatalanib), an orally active, multitargeted angiogenesis inhibitor, has shown tolerability and promising activity in early-phase studies, which led to a phase III trial in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Patients (N = 1,168) with previously untreated metastatic colorectal cancer were randomly assigned 1:1 to receive FOLFOX4 plus PTK/ZK or placebo (ClinicalTrials.gov identifier: NCT00056459). Stratification factors included WHO performance status (0 v 1 or 2) and serum lactate dehydrogenase (LDH; ≤ v > 1.5× the upper limit of normal). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR). PFS, OS, and ORR were not statistically improved with PTK/ZK (P > .05). Median PFS by central review was 7.7 months with PTK/ZK versus 7.6 months with placebo (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .118); median OS was 21.4 months with PTK/ZK versus 20.5 months with placebo (HR, 1.08; 95% CI, 0.94 to 1.24; P = .260). In an exploratory post hoc analysis of PFS in patients (n = 158 per arm) with high serum LDH, a potential marker of hypoxia, PFS was longer with PTK/ZK versus placebo (7.7 v 5.8 months, respectively; HR, 0.67; 95% CI, 0.49 to 0.91; P = .009). Although the efficacy objectives of this study were not met, a subgroup of patients who may potentially benefit from small-molecule vascular endothelial growth factor receptor inhibitor therapy has been identified and further research is warranted.
    Journal of Clinical Oncology 04/2011; 29(15):1997-2003. DOI:10.1200/JCO.2010.29.4496 · 17.88 Impact Factor
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    ABSTRACT: Adding irinotecan and/or oxaliplatin to every-2-week 5-fluorouracil (5-FU)/leucovorin (LV) prolongs survival in patients with colorectal cancer (CRC) but increases neutropenia frequency. Pegfilgrastim is indicated to decrease infection as manifested by febrile neutropenia (FN) in patients receiving chemotherapy at > 14-day intervals. This randomized, placebo-controlled phase II study examined pegfilgrastim efficacy and safety in patients with CRC receiving every-2-week chemotherapy. Patients with CRC were randomized 1:1 to pegfilgrastim 6 mg or placebo administered per-cycle on day 4. Randomization was stratified by chemotherapy regimen (patients received every-2-week FOLFOX4 [5-FU/LV/oxaliplatin], FOLFIRI [5-FU/LV/irinotecan], or FOIL [5-FU/LV/oxaliplatin/irinotecan] at physician discretion). The primary endpoint was incidence of grade 3/4 neutropenia. Secondary endpoints included incidence of grade 3/4 FN and adverse events. After 4 cycles of study treatment, progression-free survival (PFS) and overall survival (OS) were followed for <or= 2 years in long-term follow-up. Of 241 eligible patients analyzed, 118 were in the placebo and 123 in the pegfilgrastim group. In the treatment period, the odds ratio for grade 3/4 neutropenia for pegfilgrastim versus placebo was 0.19 (95% CI, 0.10-0.37; P < .001); grade 3/4 FN incidence was also significantly lower in pegfilgrastim-treated patients (2%) compared with placebo-treated patients (8%; P = .04). Pegfilgrastim was well tolerated, with leukocyte counts remaining stable during cycles 2-4. In long-term follow-up, both treatment groups had similar PFS and OS. Pegfilgrastim was well tolerated in patients with CRC receiving every-2-week chemotherapy and significantly reduced neutropenia and FN compared with placebo, though FN was uncommon in both treatment groups. Results suggest that pegfilgrastim administration is feasible in CRC patients receiving every-2-week chemotherapy.
    Clinical Colorectal Cancer 04/2010; 9(2):95-101. DOI:10.3816/CCC.2010.n.013 · 2.91 Impact Factor
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    ABSTRACT: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is approved as monotherapy for the treatment of metastatic colorectal cancer. We evaluated the association of tumor EGFR expression levels with outcomes in patients with chemorefractory metastatic colorectal cancer. Two phase II, multicenter, single-arm, open-label studies enrolled chemorefractory patients with tumors expressing low/negative (1-9%/<1%; Low/Negative EGFR study) or high (> or =10%; High EGFR study) levels of EGFR. Patients received panitumumab 6 mg/kg every two weeks until disease progression or intolerance. End points included objective response rate (per response evaluation criteria in solid tumors), progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses by tumor KRAS status were carried out. A total of 203 patients (Low/Negative EGFR) and 185 patients (High EGFR) enrolled in the studies. The overall response rate was 5.7% [95% confidence interval (95% CI), 2.6-10.5] in patients with low/negative EGFR and 4.2% (95% CI, 1.6-9.0) in patients with high EGFR; the response rate at week 16 was 4% in both studies (all partial responses). Median PFS times were 8.1 weeks (95% CI, 7.1-12.6), 8.1 weeks (95% CI, 7.4-11.1), and 7.3 weeks (95% CI, 7.1-7.6) in patients with negative, low, and high levels of EGFR expression, respectively. PFS and OS were longer in patients with wild-type KRAS than those with mutant KRAS. As expected, most adverse events were skin related. These studies confirm previous reports that tumor EGFR expression levels are not associated with efficacy with an anti-EGFR antibody and that anti-EGFR antibody therapy should be limited to those patients whose tumors express wild-type KRAS.
    Clinical Cancer Research 03/2010; 16(7):2205-13. DOI:10.1158/1078-0432.CCR-09-2017 · 8.19 Impact Factor
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    ABSTRACT: HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. Lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts. EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells, the combination of trastuzumab and lapatinib was evaluated using the median effects principal. The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models. Lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.
    Clinical Cancer Research 02/2010; 16(5):1509-19. DOI:10.1158/1078-0432.CCR-09-1112 · 8.19 Impact Factor
  • Journal of Surgical Oncology 04/2009; 99(5):273-4. DOI:10.1002/jso.21231 · 2.84 Impact Factor

Publication Stats

3k Citations
453.62 Total Impact Points

Institutions

  • 2014
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 1999–2014
    • University of California, Los Angeles
      • • Division of Hematology and Medical Oncology
      • • Department of Medicine
      • • Jonsson Comprehensive Cancer Center
      • • Department of Pathology and Laboratory Medicine
      Los Angeles, California, United States
  • 2007
    • Hospital Universitari Germans Trias i Pujol
      Badalona, Catalonia, Spain
  • 2006–2007
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1997–2004
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2003
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States