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1.
Ann Oncol ; 34(2): 200-211, 2023 02.
Article in English | MEDLINE | ID: mdl-36423745

ABSTRACT

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.


Subject(s)
Antineoplastic Agents, Immunological , Circulating Tumor DNA , Neoplasm, Residual , Triple Negative Breast Neoplasms , Humans , Biomarkers, Tumor/blood , Mutation , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Prospective Studies , Triple Negative Breast Neoplasms/blood , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Neoplasm, Residual/blood , Neoplasm, Residual/diagnosis , Neoplasm, Residual/drug therapy , Neoplasm, Residual/genetics , Antineoplastic Agents, Immunological/therapeutic use , Circulating Tumor DNA/blood
2.
Ann Oncol ; 28(8): 1817-1824, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28459938

ABSTRACT

BACKGROUND: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. PATIENTS AND METHODS: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. RESULTS: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. CONCLUSIONS: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. CLINICALTRIALS.GOV NUMBER: NCT01093235.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Breast Neoplasms/drug therapy , Taxoids/therapeutic use , Breast Neoplasms/pathology , Cyclophosphamide/therapeutic use , Docetaxel , Early Diagnosis , Epirubicin/therapeutic use , Female , Fluorouracil/therapeutic use , Genes, erbB-2 , Humans , Middle Aged , Neoadjuvant Therapy , Remission Induction , Survival Analysis
3.
Ann Oncol ; 24(9): 2278-84, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23704196

ABSTRACT

BACKGROUND: Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. PATIENTS AND METHODS: In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS: Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. CONCLUSION: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Inflammatory Breast Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Receptor, ErbB-2/antagonists & inhibitors , Ventricular Function, Left/drug effects , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Cyclophosphamide/therapeutic use , Docetaxel , Epirubicin/therapeutic use , Female , Fluorouracil/therapeutic use , Heart/drug effects , Humans , Inflammatory Breast Neoplasms/surgery , Receptor, ErbB-2/metabolism , Stroke Volume/drug effects , Taxoids/therapeutic use , Trastuzumab
4.
Ann R Coll Surg Engl ; 94(7): 456-62, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23031761

ABSTRACT

Adenocarcinoma of the prostate and rectum are common male pelvic cancers and may present synchronously or metachronously due to their anatomic proximity. The treatment of rectal or prostate cancer (in particular surgery and/or radiotherapy) may alter the presentation, incidence and management should a metachronous tumour develop. This review focuses on the interaction between prostatic and rectal cancer diagnosis and management. We have restricted the scope of this large topic to general considerations, management of rectal cancer after prostate cancer treatment and vice versa, management of synchronous disease and cancer follow-up issues.


Subject(s)
Adenocarcinoma , Neoplasms, Multiple Primary , Neoplasms, Second Primary , Prostatic Neoplasms , Rectal Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/etiology , Adenocarcinoma/therapy , Humans , Male , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/etiology , Prostatic Neoplasms/therapy , Rectal Neoplasms/diagnosis , Rectal Neoplasms/etiology , Rectal Neoplasms/therapy
5.
Br J Cancer ; 105(11): 1788-94, 2011 Nov 22.
Article in English | MEDLINE | ID: mdl-21970877

ABSTRACT

BACKGROUND: Cancer and gross-domestic-product on health expenditure (GDPHE) are critical issues for major developed countries (MDC). Each country's economic input, GDPHE 1980-2005 is contrasted with clinical outputs, cancer mortality rates (CMRs), to compare their efficiency and effectiveness in reducing CMR. METHODS: World Health Organization's CMR data for baseline years (1979-1981) are compared with 2004-2006 by sex and age. The χ(2)-tests are used to determine differences between MDC. Efficiency is analysed by calculating a ratio of average GDPHE to reduced CMR over the period. RESULTS: Inputs: All the countries GDPHE grew substantially. For the United Kingdom this reached 9.3%, which is below the MDC average (10%). Outputs: CMR fell substantially (>20%) in six of the ten countries. The male average (15-74 years) CMR in England and Wales had been third highest but by 2004-2006 was sixth, a 31% reduction, which was significantly greater than seven other countries. Initially England and Wales female average CMR was the highest of all countries and is now the second highest. There were significantly greater reductions for the 55-64 and 65-74 years old than in seven and four countries, respectively. GDPHE reduced CMR ratios--the average GDPHE:reduced CMR ratio of England and Wales was 1:120, greater than all MDC and double that in four countries. CONCLUSION: Comparing GDPHE input with CMR output showed that relatively the NHS achieved more with proportionately less than other MDC.


Subject(s)
Developed Countries , Health Expenditures , Neoplasms/economics , Neoplasms/mortality , Adolescent , Adult , Aged , England/epidemiology , Female , Humans , Male , Middle Aged , Wales/epidemiology , World Health Organization , Young Adult
6.
Ann Oncol ; 22(9): 2042-2048, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21285134

ABSTRACT

BACKGROUND: Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection. PATIENTS AND METHODS: Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR). RESULTS: Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen. CONCLUSION: Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability.


Subject(s)
Adenocarcinoma/secondary , Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/surgery , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Capecitabine , Chemotherapy, Adjuvant , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/surgery , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Perioperative Care/methods , Risk Factors
7.
J Med Econ ; 13(1): 162-7, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20136578

ABSTRACT

AIMS: To describe renal function monitoring practice in patients with metastatic bone disease (MBD) treated with IV zoledronic acid (ZA) and oral ibandronic acid (IA), the management pathways and NHS hospital resources used. METHODS: Medical records of 189 patients; IA (91), ZA (98) with primary breast cancer and MBD were reviewed, and data collected on renal monitoring and hospital visits during bisphosphonate therapy. Time and motion review of resources to administer the bisphosphonates was also conducted. RESULTS: Only 30% of patients given ZA and no patient given IA had baseline creatinine clearance (CrCl) recorded. Calculated baseline CrCl suggested impaired renal function in 33% ZA and 29% IA patients. Dose reductions were not made correctly in 29 ZA and 2 IA patients whose monitoring suggested it. ZA patients made more clinic and day care attendances than IA-treated patients, at twice the cost. Staff activity and patient time per visit was higher with ZA than IA. CONCLUSION: Although limited by retrospective design, these results demonstrate that in many patients, CrCl is not calculated before or during treatment with bisphosphonates. Renal function deteriorated in many patients during therapy. In view of these effects, practice should be reviewed to ensure appropriate dosing.


Subject(s)
Bone Density Conservation Agents/adverse effects , Bone Neoplasms/drug therapy , Diphosphonates/adverse effects , Imidazoles/adverse effects , Kidney/drug effects , Administration, Oral , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/economics , Bone Neoplasms/secondary , Breast Neoplasms/drug therapy , Breast Neoplasms/economics , Breast Neoplasms/pathology , Diphosphonates/administration & dosage , Diphosphonates/therapeutic use , Female , Health Care Costs , Health Resources/economics , Health Resources/statistics & numerical data , Humans , Ibandronic Acid , Imidazoles/administration & dosage , Imidazoles/therapeutic use , Infusions, Intravenous , Kidney/physiology , Kidney Function Tests , Middle Aged , Renal Insufficiency/chemically induced , State Medicine , Zoledronic Acid
8.
Ann Oncol ; 21(8): 1623-1629, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20093351

ABSTRACT

BACKGROUND: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. METHODS: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). RESULTS: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. CONCLUSIONS: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Cyclophosphamide/administration & dosage , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Survival Analysis
9.
Ann Oncol ; 20(5): 885-91, 2009 May.
Article in English | MEDLINE | ID: mdl-19164454

ABSTRACT

BACKGROUND: It is unclear if differential chemotherapy effects exist on overall survival (OS), response rate (RR) and toxicity depending on primary tumour origin [oesophageal versus oesophago-gastric junction (OGJ) versus gastric adenocarcinoma]. PATIENTS AND METHODS: A total of 2110 patients were enrolled in four randomised controlled trials (RCTs) assessing fluoropyrimidine +/- platinum-based chemotherapy. This analysis used individual patient data and restricted to patients with adenocarcinoma who received one or more dose of chemotherapy. Gastric origin was the control in comparisons of tumour origin. RESULTS: Of the 2110 patients randomised, 1775 (84%) patients had adenocarcinoma with oesophageal (n = 485), OGJ (n = 457) and gastric (n = 833) origins. The median OS was 9.5 months in oesophageal, 9.3 months in OGJ and 8.7 months in gastric cancer (P = 0.68). RR was 44.1% in oesophageal, 41.1% in OGJ and 35.6% in gastric cancers (P = 0.11 and 0.27, respectively, compared with gastric cancer on multivariate analysis). Toxicity composite end point occurred in 46%, 47% and 45% in oesophageal, OGJ and gastric cancers, respectively (P = 0.85 and 0.62 compared with gastric). CONCLUSIONS: In our large multicentre RCT dataset, no significant differences were demonstrated on multivariate analyses in OS, RR and toxic effects among patients with advanced oesophageal, OGJ and gastric adenocarcinoma. Future RCTs should not exclude oesophageal adenocarcinoma.


Subject(s)
Adenocarcinoma/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Stomach Neoplasms/pathology , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Australia , Capecitabine , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/mortality , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multicenter Studies as Topic , Proportional Hazards Models , Randomized Controlled Trials as Topic , Risk Assessment , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Time Factors , Treatment Outcome , United Kingdom , Young Adult
10.
Article in English | MEDLINE | ID: mdl-22275969

ABSTRACT

BACKGROUND: The successful treatment of cancer is a major health and political issue for England and Wales and the major developed countries (MDCs). All malignancy deaths by age and sex are analysed to determine how successful the MDCs were in reducing cancer mortality between the end points of 1979-81 and 2000-2, and whether there was any association between each nations 'gross domestic product expenditure on health' (GDPEH) and the reduction in their cancer deaths. METHOD: Incidence of cancer in England and Wales was examined for 1979-80 to 2003-4 to highlight the extent of the problem. The cancer mortality rates for England and Wales were compared with each MDC by age and sex, using 'WHO all malignancies mortality rates' for the periods of 1979-81 and 2000-2, and tests of significance were made. The GDPEH for each MDC was examined for 1980-2002, and Spearman rank-order correlations calculated to explore any association between declining cancer deaths and the GDPEH of each MDC. RESULTS: Men's All Age malignancy incidence in England and Wales rose 48% and women's 51%, with notable rises for females aged 15-34 and 55-74 years.Every MDC increased its GDPEH substantially; it rose to 9.3% in the United Kingdom, but the United Kingdom still remains eighth of the ten MDCs and below the MDC average (9.85%).The average number of cancer related deaths for men in England and Wales (15-74 years) was third highest in 1979-81, but fell to eighth by 2000-2. This decline was significantly greater than in seven other MDCs. Average female death rates in England and Wales were highest both in 1979-81 and in 2000-2, but declined significantly more than most MDCs in every age band from 35 to 74 years.There was a significant correlation between reduced deaths and the level of GDPEH of each nation.Male death rates declined significantly more than that of female in each MDC, with the exception of Japan and Spain. CONCLUSIONS: The rising incidence in cancer-related deaths poses a problem for every MDC, and the poorer women's results should be a matter of concern for most MDCs. The reduction in cancer deaths reflects well on frontline services, and the significant association between reduced cancer mortality and increased GDPEH is encouraging, but still a challenge for governments, especially if the incidence continues to rise.

11.
Colorectal Dis ; 10(4): 386-9, 2008 May.
Article in English | MEDLINE | ID: mdl-17608754

ABSTRACT

OBJECTIVE: The aim of this retrospective study was to assess the significance of incidental focal colonic lesions on fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) scans in patients undergoing staging for noncolorectal cancer. METHOD: Of the 110 patients in our PET/CT database, 10 were found to have abnormally high uptake of tracer in their large bowel. RESULTS: Seven patients who underwent further endoscopic evaluation of these abnormalities had intermediate to high-risk adenomatous polyps. CONCLUSION: Benign colonic polyps produce high-intensity focal FDG uptake in large bowel. Endoscopic evaluation is recommended before curative resectional surgery of the presenting cancer where appropriate.


Subject(s)
Adenoma, Villous/diagnosis , Adenomatous Polyps/diagnostic imaging , Colorectal Neoplasms/diagnostic imaging , Incidental Findings , Positron-Emission Tomography , Aged , Aged, 80 and over , Female , Fluorodeoxyglucose F18 , Gastrointestinal Neoplasms/pathology , Head and Neck Neoplasms/pathology , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging/methods , Retrospective Studies , Tomography, X-Ray Computed
12.
Ann Oncol ; 18(4): 730-7, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17237473

ABSTRACT

BACKGROUND: To establish the recommended dose level (RDL) and to evaluate the efficacy and safety of gefitinib plus irinotecan in patients with advanced fluoropyrimidine-refractory colorectal cancer (CRC). PATIENTS AND METHODS: Patients with advanced CRC progressing on or within 12 weeks of fluoropyrimidine-based chemotherapy, irinotecan naive and performance status of two or less were recruited. During dose-finding phase, dose-limiting toxicity (DLT) was encountered at dose level 1, therefore subsequent dose de-escalation and pharmacokinetic (PK) studies were carried out. The RDL was then expanded in a multicentre setting to further evaluate safety and efficacy. RESULTS: From June 2002 to February 2005, 39 patients were treated in total with 27 at the RDL. The RDL was established at irinotecan 225 mg/m(2) every 3 weeks and gefitinib 250 mg daily. The DLTs were neutropenia and diarrhoea. For the patients treated at RDL, the objective tumour response rate was 11.1% (95% confidence interval 2.4% to 29.2%) and median survival was 9.3 months. PK studies indicated that the addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib (P < 0.05), but gefitinib did not alter the PK profiles of irinotecan or SN-38. Grade 3-4 toxic effects in all patients included diarrhoea (35.9%), lethargy (15.4%), neutropenia (15.4%), febrile neutropenia (10.3%) and skin rash (7.7%). CONCLUSIONS: Irinotecan and gefitinib at this dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Quinazolines/administration & dosage , Adult , Aged , Area Under Curve , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Colorectal Neoplasms/mortality , ErbB Receptors/genetics , Female , Gefitinib , Humans , Irinotecan , Male , Middle Aged , Mutation , Quinazolines/adverse effects
13.
Br J Cancer ; 94(8): 1107-15, 2006 Apr 24.
Article in English | MEDLINE | ID: mdl-16622436

ABSTRACT

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand- foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs.


Subject(s)
Antineoplastic Agents/therapeutic use , Fluorouracil/therapeutic use , Pancreatic Neoplasms/drug therapy , Receptor, Cholecystokinin B/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Disease Progression , Dose-Response Relationship, Drug , Double-Blind Method , Female , Fluorouracil/adverse effects , Follow-Up Studies , Humans , Infusions, Intravenous , Male , Middle Aged , Pilot Projects , Placebos , Predictive Value of Tests , Single-Blind Method , Survival Rate , Time Factors , Treatment Outcome
14.
Eur J Cancer ; 42(7): 827-34, 2006 May.
Article in English | MEDLINE | ID: mdl-16466913

ABSTRACT

The aim of this study was to determine the benefits of chemotherapy for oesophago-gastric cancer (OGC) in patients 70 years and above (> or =70) in comparison to younger patients. 1080 patients were enrolled into three randomised controlled trials assessing fluorouracil-based combination chemotherapy. Patients received either a platinum-containing regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil)+/-mitomycin C (MMC), or FAMTX. Of the 1080 patients randomised, 257 (23.8%) were aged > or =70 years. There were no significant differences in the incidence of grades 3/4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free and overall survival were not significantly different. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, not age. Patients > or =70 years with OGC obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumour regression and survival, without increased toxicities.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Male , Randomized Controlled Trials as Topic , Treatment Outcome
15.
Ann Oncol ; 16(9): 1435-41, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15946977

ABSTRACT

BACKGROUND: Vinorelbine is active and well tolerated against advanced breast cancer but there are no published efficacy studies in early breast cancer. We have therefore carried out a randomised phase III neoadjuvant trial in operable breast cancer. PATIENTS AND METHODS: Patients with > or =3 cm operable breast carcinoma were randomised to receive either vinorelbine 25 mg/m(2) on days 1 and 8 and epirubicin 60 mg/m(2) on day 1, 3 weekly for six cycles (VE) or doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) i.v. on day 1, 3 weekly for six cycles (AC), prior to standard local therapy, and adjuvant endocrine therapy as appropriate. RESULTS: A total of 451 patients were randomised. Results for AC and VE, respectively, were: overall clinical response 73% and 74%, complete clinical remission 20% and 24%, pathological complete remission 12% and 12%, mastectomy rate 52% and 55%. None of these differences were significant. Dose reduction was required in 8% for AC and 20% for VE (P <0.001) (GSCF support not used). Significantly more grade 3/4 toxicity for nausea, vomiting and alopecia (despite scalp cooling) was seen for AC compared with VE but significantly less grade 3/4 thrombophlebitis and neuropathy. CONCLUSIONS: Neoadjuvant VE is as effective as AC in early breast cancer and was better tolerated except for thrombophlebitis and neuropathy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Epirubicin/administration & dosage , Female , Humans , Mastectomy , Middle Aged , Remission Induction , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine
16.
Br J Cancer ; 92(11): 1976-83, 2005 Jun 06.
Article in English | MEDLINE | ID: mdl-15928658

ABSTRACT

The purpose of the study was to establish the optimal dose of capecitabine (X) to be used within a multicentre, randomised study evaluating the potential roles of oxaliplatin (O) and X in chemonaive patients (pts) with advanced oesophagogastric cancer. Two by two design was used, and pts were randomised to one of four regimens and stratified for extent of disease, performance status (PS) and centre. The treatment regimens are epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX. Doses: E 50 mg m(-2), C 60 mg m(-2) and O 130 mg m(-2) i.v. 3 weekly; F 200 mg m(-2) day(-1) i.v. and X 500 mg m(-2) b.i.d.(-1) (escalated to 625 mg m(-2) b.i.d.(-1) after results of first interim analysis) p.o., continuously. First interim analysis was performed when 80 pts had been randomised. Dose-limiting fluoropyrimidine toxicities were stomatitis, palmar plantar erythema (PPE) and diarrhoea; 5.1% of X-treated pts experienced grade 3/4 toxicity. Protocol planned dose escalation of X to 625 mg m(-2) b.i.d.(-1) was instituted and a second interim analysis has been performed; results are presented in this paper. A total of 204 pts were randomised at the time of the protocol planned 2nd interim analysis. Grade 3/4 fluoropyrimidine-related toxicity was seen in 13.7% pts receiving F, 8.4% pts receiving X 500 mg m(-2) b.i.d.(-1) and 14.7% pts receiving X 625 mg m(-2) b.i.d.(-1). Combined complete and partial response rates were ECF 31% (95% CI 18.7-46.3), EOF 39% (95% CI 25.9-53.1), ECX 35% (95% CI 21.4-50.3), EOX 48% (95% CI 33.3-62.8). Grade 3/4 fluoropyrimidine toxicity affected 14.7% of pts treated with X 625 mg m(-2) b.i.d.(-1), which is similar to that observed with F, confirming this to be the optimal dose. The replacement of C by O and F by X does not appear to impair efficacy. The trial continues to total accrual of 1000 pts.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Esophageal Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Dose-Response Relationship, Drug , Epirubicin/administration & dosage , Esophageal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Injections, Intravenous , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Stomach Neoplasms/pathology , Treatment Outcome
17.
Ann Oncol ; 16(4): 549-57, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15695501

ABSTRACT

BACKGROUND: We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of protracted venous infusion (PVI) 5-fluorouracil (5-FU) against the standard bolus monthly regimen of 5-FU/leucovorin (LV) given for 6 months as adjuvant treatment in colorectal cancer (CRC). PATIENTS AND METHODS: Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m(2) intravenously (i.v.) and LV 20 mg/m(2) i.v. bolus days 1-5 every 28 days for 6 months] or to PVI 5-FU (300 mg/m(2)/day for 12 weeks). RESULTS: Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.62-1.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.61-1.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU. CONCLUSIONS: There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Fluorouracil/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Colorectal Neoplasms/surgery , Drug Administration Schedule , Female , Fluorouracil/adverse effects , Gastrointestinal Diseases/chemically induced , Humans , Infusions, Intravenous , Injections, Intravenous , Leucovorin/administration & dosage , Leucovorin/adverse effects , Male , Middle Aged , Survival Analysis , Time Factors
18.
Ann Oncol ; 15(5): 751-8, 2004 May.
Article in English | MEDLINE | ID: mdl-15111342

ABSTRACT

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Infusions, Intravenous , Injections, Intravenous , Middle Aged , Neoadjuvant Therapy , Survival Analysis , Treatment Outcome
19.
Br J Cancer ; 88(12): 1859-65, 2003 Jun 16.
Article in English | MEDLINE | ID: mdl-12799627

ABSTRACT

We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of 5-fluorouracil (5-FU) delivered by protracted intravenous infusion (PVI 5-FU) against the standard bolus regimen of 5-FU and folinic acid (5-FU/FA) given for 6 months as adjuvant treatment in colorectal cancer. A total of 716 patients with curatively resected Dukes' B or C colorectal cancer were randomised to 5-FU/FA (5-FU 425 mg m(-2) i.v. and FA 20 mg m(-2) i.v. bolus days 1-5 every 28 days for 6 months) or to PVI 5-FU alone (300 mg m(-2) day for 12 weeks). With a median follow-up of 19.8 months, 133 relapses and 77 deaths have been observed. Overall survival did not differ significantly (log rank P=0.764) between patients receiving 5-FU/FA and PVI 5-FU (3-year survival 83.2 vs 87.9%, respectively). Patients in the 5-FU/FA group had significantly worse relapse-free survival (RFS, log rank P=0.023) compared to those receiving PVI 5-FU (3-year RFS, 68.6 vs 80%, respectively). Grades 3-4 neutropenia, diarrhoea, stomatitis and severe alopecia were significantly less (P<0.0001) and global quality of life scores significantly better (P&<0.001) for patients in the PVI 5-FU treatment arm. In conclusion, infused 5-FU given over 12 weeks resulted in similar survival to bolus 5-FU and FA over a 6 month period, but with significantly less toxicity.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/administration & dosage , Colorectal Neoplasms/drug therapy , Fluorouracil/administration & dosage , Leucovorin/administration & dosage , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Drug Administration Schedule , Female , Fluorouracil/adverse effects , Humans , Infusions, Intravenous , Leucovorin/adverse effects , Male , Middle Aged , Neoplasm Recurrence, Local , Quality of Life
20.
Eur J Cancer ; 39(8): 1121-8, 2003 May.
Article in English | MEDLINE | ID: mdl-12736112

ABSTRACT

No standard regimen has been identified for patients with a carcinoma of unknown primary (CUP). This study compared protracted venous infusion 5-fluorouracil (PVI 5-FU) with or without mitomycin C (MMC) in patients with CUP in a multicentre, prospectively randomised study. 88 patients were randomised to PVI 5-FU (300 mg/m(2)/day for a maximum of 24 weeks) +/-MMC (7 mg/m(2) 6 weekly for four courses). The overall response rate was 11.6% for PVI 5-FU alone compared with 20.0% for PVI 5-FU plus MMC (P=0.29). Median failure-free survival (FFS) was 4.1 months for PVI 5-FU and 3.6 months for PVI 5-FU plus MMC (P=0.78) with an equivalent overall survival (OS) (6.6 versus 4.7 months, P=0.60). Symptomatic benefit was observed in most patients in each arm. PVI 5-FU is a well tolerated outpatient treatment regimen for patients with CUP, although the addition of MMC provides little extra benefit. PVI 5-FU may be a potential reference regimen in randomised trials with newer chemotherapy agents in patients with CUP.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Unknown Primary/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Infusions, Intravenous , Male , Middle Aged , Mitomycin/administration & dosage , Mitomycin/adverse effects , Quality of Life , Regression Analysis , Treatment Outcome
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