Publications (49)515.3 Total impact
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Article: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.
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ABSTRACT: BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6-13·0) compared with 8·8 months (7·7-9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07-1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.The lancet oncology 04/2013; · 14.47 Impact Factor -
Article: Gemcitabine Plus Capecitabine in Unselected Patients With Advanced Pancreatic Cancer.
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ABSTRACT: OBJECTIVES: Gemcitabine in combination with capecitabine (GEMCAP) is a treatment option for patients with advanced pancreatic cancer (APC), but data are lacking concerning outcomes in unselected patients not enrolled to a randomized trial. METHODS: Baseline demographic, clinical, toxicity, tumor response, and survival data were collected for previously untreated patients with APC receiving off-protocol GEMCAP at a single institution between 2005 and 2009. RESULTS: Data from 113 patients were included in the study. The mean age was 65 years; 51% of patients had metastatic disease; and 80% were of World Health Organization performance status 0 or 1. Patients received a mean of 20 weeks of chemotherapy. The objective response rate was 9.7%; the median overall survival was 8.7 months (95% confidence interval, 6.7-10.7), and 34% of patients were alive 1 year after starting treatment. Performance status (0 or 1 vs 2) was a significant prognostic factor (P < 0.0001). Grade 3 or 4 adverse events, excluding nonfebrile neutropenia, were experienced by 37 patients (33%), the commonest being lethargy (8%), hand-foot syndrome (8%), diarrhea (7%), thrombocytopenia (4%), and febrile neutropenia (6%). CONCLUSIONS: Gemcitabine in combination with capecitabine is effective and tolerable in unselected patients with APC, and outcomes are comparable with those of patients receiving GEMCAP in clinical trials.Pancreas 03/2013; · 2.39 Impact Factor -
Article: Primary Follicular Lymphoma of the GI Tract: An Increasingly Recognized Entity.
Journal of Clinical Oncology 11/2012; · 18.37 Impact Factor -
Article: Perioperative Chemotherapy With or Without Bevacizumab in Patients With Metastatic Colorectal Cancer Undergoing Liver Resection.
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ABSTRACT: BACKGROUND: Patients with colorectal cancer (CRC) and liver metastases benefit from perioperative chemotherapy and liver resection. The potential benefit of adding bevacizumab is yet to be defined. The impact of bevacizumab on liver resection complications has been explored in a small number of retrospective studies. METHODS: The records of patients with CRC and liver metastases who underwent liver resection and had received perioperative chemotherapy were reviewed. Complications were reported separately for 2 groups (chemotherapy alone vs chemotherapy and bevacizumab). Survival outcomes (progression-free survival [PFS] and overall survival [OS]) for responders and nonresponders were estimated using the Kaplan-Meier method. RESULTS: Fifty-two patients received chemotherapy alone and 42 patients received chemotherapy and bevacizumab. The median time from the end of systemic treatment to liver resection was 59 days (33-181 days) for the chemotherapy group and 62 days (44-127 days) for the chemotherapy and bevacizumab group. Postoperative complications developed in 54% of the chemotherapy group and in 48% of the chemotherapy and bevacizumab group. Severe complications (grade III-V) occurred in only 13% and 12%, respectively (P = .822). Pathologic complete response (CR) was seen in 11/94 patients. Poor performance status (PS) before starting chemotherapy was associated with higher rates of complications (P = .002), and severe complications led to prolonged hospital admission (P = .001). Patients with pathologic CR had longer OS (P = .0275), but there was no difference in OS between responders and nonresponders (P = .778). CONCLUSION: The addition of bevacizumab to chemotherapy does not increase liver resection complication rates. Pathologic CR is associated with prolonged survival.Clinical Colorectal Cancer 09/2012; · 1.68 Impact Factor -
Article: Peri-operative chemotherapy in the management of resectable colorectal cancer pulmonary metastases.
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ABSTRACT: BACKGROUND: Surgery is often advocated in patients with resectable pulmonary metastases from colorectal cancer (CRC). Our study aims to evaluate peri-operative chemotherapy in patients with metastastic CRC undergoing pulmonary metastasectomy. METHODS: Patients treated for CRC who underwent pulmonary metastasectomy by a single surgeon were identified. Outcome measures included survival, peri-operative complications, radiological and histological evidence of chemotherapy-induced lung toxicities. RESULTS: Between 1997 and 2009, 51 eligible patients were identified undergoing a total of 72 pulmonary resections. Thirty-eight patients received peri-operative chemotherapy, of whom 9 received an additional biological agent. Five-year overall survival rate was 72% in the whole cohort - 74% and 68% in those who received peri-operative chemotherapy (CS) and those who underwent surgery alone (S) respectively. Five-year relapse free survival rate was 31% in the whole cohort - 38% and [less than or equal to]18%in CS and S groups respectively. Only 8% had disease progression during neoadjuvant chemotherapy. There were no post-operative deaths. Surgical complications occurred in only 4% of patients who received pre-operative chemotherapy. There was neither radiological nor histological evidence of lung toxicity in resected surgical specimens CONCLUSIONS: Peri-operative chemotherapy can be safely delivered to CRC patients undergoing pulmonary metastasectomy. Survival in this selected group of patients was favourable.BMC Cancer 08/2012; 12(1):326. · 3.01 Impact Factor -
Article: Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C).
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ABSTRACT: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.Journal of Clinical Oncology 04/2012; 30(14):1620-7. · 18.37 Impact Factor -
Article: The authors reply.
Diseases of the Colon & Rectum 03/2012; 55(3):e31-2. · 3.13 Impact Factor -
Article: Preoperative and postoperative chemotherapy for gastric cancer.
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ABSTRACT: Radical surgery offers the only chance of cure for patients with operable gastric cancer; however, outcomes remain generally poor due to a high rate of relapse post gastric surgery. Multimodality therapy using chemotherapy, radiation or a combination of both have been evaluated in different parts of the world to improve outcomes from surgery alone. Perioperative chemotherapy is generally preferred in Europe in contrast to postoperative chemoradiation in the US or adjuvant fluoropyrimidine chemotherapy in East Asia. Regardless of these variations, systemic chemotherapy consistently results in a survival benefit when used in multimodality treatment of operable gastric cancer.Surgical Oncology Clinics of North America 01/2012; 21(1):99-112. · 1.12 Impact Factor -
Article: Timing of surgery following preoperative therapy in rectal cancer: the need for a prospective randomized trial?
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ABSTRACT: In rectal cancer, the standard of care after the completion of radiotherapy is surgery at 6 to 8 weeks. However, there is variation regarding the timing of surgery. This investigation aimed to audit the timing of surgery following radiotherapy and to compare perioperative morbidity and tumor downstaging in patients operated on, before and after the 6- to 8-week window. A retrospective review of rectal cancers treated preoperatively in our cancer network over a 27-month period. The effect of "time till surgery" of 6 to 8 weeks, <6 weeks, and >8 weeks on T downstaging and nodal downstaging was calculated by univariate and multivariate logistic regression analyses. This study was conducted in an oncology tertiary referral center in the Southwest London Cancer Network. Patients receiving preoperative radiotherapy for primary locally advanced rectal cancer undergoing subsequent surgical resection were eligible. The primary outcome measurement was time to surgery following the completion of (chemo) radiotherapy. Thirty-day perioperative morbidity and mortality and tumor and nodal downstaging were examined according to the timing of surgery. This study was limited by its nonrandomized retrospective design and the lack of standardization of preoperative chemotherapy. Thirty-two (34%) patients underwent surgery at 6 to 8 weeks, 45 (47%) at >8 weeks, and 18 (19%) at <6 weeks after radiotherapy. Delay was attributed to scheduling in 87% of cases and to comorbidities in the remainder. T downstaging occurred in 6 (33.3%) patients in the <6 weeks group, in 12 (37.5%) in the 6 to 8 weeks group, and in 28 (62.2%) in >8 weeks group with no significant differences in perioperative morbidity. On multivariate analysis, T downstaging was significantly greater for the >8 weeks group (OR, 3.79; 95% CI: 1.11-12.99; P = .03). More patients were staged ypT0-T2, 19 of 45 (42%) in the >8 weeks group vs other groups, 14 of 50 (28%, P < .05). Following radiotherapy, surgery frequently occurs at >8 weeks and is associated with increased downstaging. The consequences on survival and perioperative morbidity warrant further investigation.Diseases of the Colon & Rectum 10/2011; 54(10):1251-9. · 3.13 Impact Factor -
Article: Nonsurgical management of esophageal adenocarcinoma.
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ABSTRACT: The benefit of induction chemotherapy (IC) before chemoradiotherapy (CRT) for inoperable esophageal adenocarcinoma has not been established. To clarify toxicities and outcomes of combined modality treatment, we performed a retrospective review. Sixty-eight consecutive patients were identified. Fifty-one patients had CRT, 17 had radiotherapy (RT). Fifty-eight received IC before RT. IC consisted of 4 cycles of platinum and fluoropyrimidines followed by CRT 54 Gy with concurrent infusional 5-fluorouracil (5-FU) or capecitabine. Response to IC was assessed at 3 months and response to CRT at 3 months. Time to progression (TTP) and overall survival (OS) are reported. Fifty-four patients were men and 14 were women, with median age 72 years (range, 42-87 years). There were 29 stage II, 33 stage III, 4 stage IVa, and 2 stage IVb tumors. The response 3 months after completion of treatment was 39.6%. No grade 4 toxicity was reported, but 10/58 patients had grade 3 toxicity from IC. The median TTP and OS from RT for the entire cohort was 12 months (95% confidence interval [CI], 7-18) and 16 months (95% CI, 5-27), respectively. The 1- and 2-year survival rates from diagnosis were 73% and 47%, respectively. There was no statistically significant difference in TTP or OS in patients who responded to IC compared with those who did not (median TTP 11 vs. 12 months, respectively; P = .8; median OS 15 vs. 14 months, respectively; P = .8). The outcome in patients with adenocarcinoma of the esophagus after CRT is comparable to unselected surgical series. Response to IC is not always an indicator of eventual outcome.Clinical Colorectal Cancer 09/2011; 10(3):165-70. · 1.68 Impact Factor -
Article: Neoadjuvant chemotherapy alone for early-stage rectal cancer: an evolving paradigm?
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ABSTRACT: Current management of early-stage rectal cancer comprises combinations of surgery, radiotherapy, and chemotherapy, with the presence or absence of several validated high-risk features determining which treatment modalities will be used and the order of administration. In high-risk individuals, most centers have adopted neoadjuvant combined chemotherapy and radiotherapy followed by surgery as the initial approach. However, long-term toxicity, limited survival gains, and high rates of distant failure have called this approach into question, with early data suggesting that neoadjuvant chemotherapy alone may be feasible in selected patient groups. This review discusses the current data and feasibility of managing early stage rectal cancer with neoadjuvant chemotherapy before surgical resection.Seminars in radiation oncology 07/2011; 21(3):196-202. · 4.32 Impact Factor -
Article: Targeting the human EGFR family in esophagogastric cancer.
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ABSTRACT: Esophagogastric cancer represents a significant global health problem, with most patients presenting with advanced-stage disease and consequently with a poor prognosis. Chemotherapy improves survival compared with supportive care alone, and combination chemotherapy regimens are more effective than monotherapy. Overexpression of EGFR and possibly HER2 confer a poor prognosis, providing potentially important therapeutic targets for selected patients. Inhibition of HER2 with the monoclonal antibody trastuzumab in patients with HER2 overexpression, HER2 gene amplification, or both, is effective and has been the standard of care for HER2-positive breast cancer for almost a decade. In patients with advanced-stage gastric or esophagogastric-junction adenocarcinomas, the addition of trastuzumab to a cisplatin plus fluoropyrimidine doublet was reported to improve response rate, progression-free survival and overall survival, with the greatest benefit reported in the subgroup of patients with the highest expression of HER2. Cetuximab and panitumumab, two monoclonal antibodies against EGFR, and the dual EGFR and HER2 tyrosine kinase inhibitor lapatinib are currently undergoing phase III evaluation in esophagogastric cancer. We discuss the preclinical rationale for targeting human EGFRs and recent clinical reports of these targeted agents in esophagogastric cancer.Nature Reviews Clinical Oncology 04/2011; 8(8):492-503. · 11.96 Impact Factor -
Article: Patupilone in cancer treatment.
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ABSTRACT: Since the introduction of taxane-based chemotherapy for advanced solid tumors in the 1990s, the median overall survival of patients with metastatic breast cancer increased from 2 years to almost 5 years. Similarly, the 5-year overall survival for ovarian cancer has increased from 30% to more than 40%. Patupilone is a novel cytotoxic compound, with similar microtubule-binding and apoptotic properties of taxanes and is active in taxane-resistant cell lines. Over 1200 patients have been treated with patupilone in Phase I - III clinical trials and a wealth of knowledge has accumulated about this compound. This review discusses current pharmacology and data from clinical trials with patupilone from the last seven years. We present a comprehensive summary of data from Phase II and III trials, as well as an overview of currently accruing trials. Although patupilone has not demonstrated superiority over pegylated liposomal doxorubicin in a large Phase III trial in relapsed or refractory ovarian cancer, its evaluation is continuing in a range of other malignancies, especially in primary or secondary tumors of the CNS.Expert Opinion on Investigational Drugs 01/2011; 20(1):107-17. · 5.27 Impact Factor -
Article: Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer.
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ABSTRACT: Systemic chemotherapy improves survival in oesophagogastric cancer however no standard second-line regimen exists due to a paucity of randomised data. Docetaxel combined with irinotecan (DI) provides a suitable option due to the lack of cross-reactivity with first-line therapeutics and a tolerable toxicity profile. We retrospectively reviewed a cohort of patients with advanced oesophagogastric cancer in two institutions treated with the combination of docetaxel 35 mg/m(2) plus irinotecan 60 mg/m(2) day 1 and day 8 every 21 days, following progression with first-line platinum-based therapy. Between January 2000 and September 2009, 41 eligible patients were identified. Median age was 58 years, male:female 25:16, adenocarcinoma:squamous cell carcinoma 37:4, oesophageal:oesophagogastric junction:gastric 7:10:24. Locally advanced:metastatic disease 6:35. Previous radical surgery:radiotherapy:both 6:4:7. 27/41 had progressed within 90 days of receiving platinum-based therapy. Median number of chemotherapy cycles: 3 (range 1-12). Eight patients required dose reductions due to DI toxicity. 10/28 evaluable patients had a response, median progression-free survival (PFS) was 11 weeks (95% confidence intervals (CI): 9-13 weeks) with median overall survival 24 weeks (95%CI: 12-35 weeks). No significant prognostic factors were identified. Weekly docetaxel combined with irinotecan has acceptable safety and modest efficacy in the second-line treatment of advanced oesophagogastric cancer. Further prospective evaluation of this regimen is warranted.European journal of cancer (Oxford, England: 1990) 01/2011; 47(8):1146-51. · 4.12 Impact Factor -
Article: Trastuzumab for gastric cancer treatment.
The Lancet 11/2010; 376(9754):1736; author reply 1736-7. · 38.28 Impact Factor -
Article: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial.
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ABSTRACT: Epirubicin, oxaliplatin, and capecitabine (EOC) is a standard treatment in advanced esophagogastric cancer. Panitumumab (P) is a fully human, immunoglobulin G2 monoclonal antibody targeting epidermal growth factor receptor. Randomized Trial of EOC +/- Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer (REAL-3) will evaluate whether the addition of P to EOC improves survival in patients with advanced esophagogastric adenocarcinoma and undifferentiated carcinoma. The original design of REAL-3 added P 9 mg/kg to the standard dose of EOC (dose level [DL] + 1). Due to toxicity, a dose de-escalation was made to EOC + P DL-1 (epirubicin 50 mg/m(2), oxaliplatin130 mg/m(2), capecitabine 1,000 mg/m(2)/d + P 9 mg/kg every 3 weeks). After additional toxicity was observed, the study was amended to include two additional EOC + P dose levels. Using a 3 + 3 design, dose-limiting toxicities (DLTs) were assessed weekly during cycle 1. Patients were randomly assigned 1:1 to EOC +/- P. Between July 2008 and October 2009, 29 patients were randomly selected for standard-dose EOC (n = 13) or EOC + P (n = 16). Five patients were treated at DL + 1, with grade 3 diarrhea in four of five patients by cycle 4. At DL-1, one patient had grade 3 diarrhea and grade 5 infection. Three patients were treated at DL-3, and then six were treated at DL-2, without DLTs. The recommended dose for EOC + P is epirubicin 50 mg/m(2), oxaliplatin 100 mg/m(2), capecitabine 1,000 mg/m(2)/d, and P 9 mg/kg every 3 weeks. This dose has been selected for the ongoing phase II/III REAL-3 study.Journal of Clinical Oncology 09/2010; 28(25):3945-50. · 18.37 Impact Factor -
Article: Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial.
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ABSTRACT: Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051. 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. UK National Health Service, Sanofi-Aventis.The lancet oncology 03/2010; 11(3):241-8. · 14.47 Impact Factor -
Article: Upper gastrointestinal malignancies: a new era in clinical colorectal cancer.
Clinical Colorectal Cancer 10/2009; 8(4):185-9. · 1.68 Impact Factor -
Article: Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer.
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ABSTRACT: This study evaluated safety and efficacy of chemotherapy (gemcitabine plus capecitabine) plus bevacizumab/erlotinib in advanced pancreatic cancer because dual epidermal growth factor receptor/vascular endothelial growth factor blockade has a rational biologic basis in this malignancy. Patients with untreated, unresectable, locally advanced or metastatic pancreatic carcinoma were enrolled onto one of the following four sequential dose levels (DLs) of escalating capecitabine doses (days 1 to 21): DL1, 910 mg/m(2); DL2, 1,160 mg/m(2); DL3, 1,400 mg/m(2); or DL4, 1,660 mg/m(2). Doses of coadministered gemcitabine (1,000 mg/m(2) on days 1, 8, and 15), bevacizumab (5 mg/kg on days 1 and 15), and erlotinib (100 mg/d) every 28 days (up to six cycles) were fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed in cycle 1. Results Twenty assessable patients were enrolled (DL1, n = 8; DL2, n = 3; DL3, n = 6; and DL4, n = 3); 97 cycles were administered. Median age was 63 years (range, 33 to 77 years), and male-to-female ratio was 10:10. Performance status was 0 and 1 in two and 17 patients, respectively; and nine and 11 patients had locally advanced and metastatic disease, respectively. DLT occurred in one patient at DL1 (grade 3 epistaxis) and two patients at DL4 (grade 3 diarrhea and grade 3 skin rash > 7 days). Common grade 3 and 4 toxicities (10% to 20%) were diarrhea, hand-foot syndrome, stomatitis, and skin rash. Grade 3 lethargy and grade 3 or 4 neutropenia occurred in 40% and 45% of patients, respectively. No GI perforation, grade 3 GI hemorrhage/hypertension, or pneumonitis occurred. Ten partial responses were observed. Median overall and progression-survival times (all patients) were 12.5 and 9.0 months, respectively. The maximum-tolerated dose of capecitabine was 1,660 mg/m(2). The recommended capecitabine dose in this cytotoxic doublet/biologic doublet regimen is 1,440 mg/m(2); this regimen is under evaluation in an ongoing phase II study.Journal of Clinical Oncology 10/2009; 27(33):5499-505. · 18.37 Impact Factor -
Article: Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer.
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ABSTRACT: Both gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP). Patients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status <or= 2 were recruited. Patients were randomly assigned to GEM or GEM-CAP. The primary outcome measure was survival. Meta-analysis of published studies was also conducted. Between May 2002 and January 2005, 533 patients were randomly assigned to GEM (n = 266) and GEM-CAP (n = 267) arms. GEM-CAP significantly improved objective response rate (19.1% v 12.4%; P = .034) and progression-free survival (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .004) and was associated with a trend toward improved OS (HR, 0.86; 95% CI, 0.72 to 1.02; P = .08) compared with GEM alone. This trend for OS benefit for GEM-CAP was consistent across different prognostic subgroups according to baseline stratification factors (stage and performance status) and remained after adjusting for these stratification factors (P = .077). Moreover, the meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of GEM-CAP (HR, 0.86; 95% CI, 0.75 to 0.98; P = .02) with no intertrial heterogeneity. On the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.Journal of Clinical Oncology 10/2009; 27(33):5513-8. · 18.37 Impact Factor
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2001–2013
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Royal Marsden Hospital
London, ENG, United Kingdom
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