-
E F Smit,
M A Socinski,
B P Mullaney,
S P Myrand,
G V Scagliotti, P Lorigan,
M Reck,
T Ciuleanu,
J von Pawel,
N A Karaseva,
A Szczesna,
D Ohannesian,
E Powell,
R R Hozak,
S Hong,
S C Guba,
N Thatcher
[show abstract]
[hide abstract]
ABSTRACT: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein.
Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n=395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n=611).
None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P=0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P=0.036).
Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC.
Annals of Oncology 12/2011; 23(7):1723-9. · 6.43 Impact Factor
-
T Eisen,
R Marais,
A Affolter, P Lorigan,
C Robert,
P Corrie,
C Ottensmeier,
C Chevreau,
D Chao,
P D Nathan,
T Jouary,
M Harries,
S Negrier,
E Montegriffo,
T Ahmad,
I Gibbens,
M G James,
U P Strauss,
S Prendergast,
M E Gore
[show abstract]
[hide abstract]
ABSTRACT: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.
In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).
Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.
British Journal of Cancer 07/2011; 105(3):353-9. · 5.04 Impact Factor
-
T Eisen,
R Marais,
A Affolter, P Lorigan,
C Robert,
P Corrie,
C Ottensmeier,
C Chevreau,
D Chao,
P D Nathan,
T Jouary,
M Harries,
S Negrier,
E Montegriffo,
T Ahmad,
I Gibbens,
M G James,
U P Strauss,
S Prendergast,
M E Gore
[show abstract]
[hide abstract]
ABSTRACT: Method: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.
British Journal of Cancer 07/2011; 105(3):353-359. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Accurate radiological staging of small-cell lung cancer (SCLC) is of paramount importance in selection of individual patients with limited stage disease for potentially curative treatment while avoiding toxic treatment in those with distant metastatic disease. [(18)F] flurodeoxy-D-glucose (FDG) positron emission tomography (PET) is an attractive tool for this purpose but there is limited evidence to support its use in the routine staging of SCLC. Whether therapeutic decisions based on FDG-PET imaging should be made remains uncertain. There is only preliminary evidence for use of FDG-PET as a prognostic biomarker, in the assessment of response to treatment and delineation of disease in conformal radiation planning.
Lung cancer (Amsterdam, Netherlands) 04/2011; 73(2):121-6. · 3.14 Impact Factor
-
O A Khan,
M Gore, P Lorigan,
J Stone,
A Greystoke,
W Burke,
J Carmichael,
A J Watson,
G McGown,
M Thorncroft,
G P Margison,
R Califano,
J Larkin,
S Wellman,
M R Middleton
[show abstract]
[hide abstract]
ABSTRACT: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment.
Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells.
The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma.
This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.
British Journal of Cancer 02/2011; 104(5):750-5. · 5.04 Impact Factor
-
Clinical Oncology 09/2010; 22(7):547-9. · 2.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There is a growing awareness that symptoms frequently co-occur in 'symptom clusters' and that understanding these clusters may improve the management of unrelieved symptoms in patients. In-depth longitudinal exploration of lung cancer patients' symptom experiences is used to examine patient symptom experiences and distress across the disease trajectory of lung cancer.
Semi-structured interviews were conducted with patients and their primary caregivers at four time points: at the beginning of treatment and then subsequently at three, six, and twelve months. Interpretative Phenomenological Analysis was employed in the data analysis.
Findings indicate that a cluster of interacting respiratory symptoms play a central role in patients' symptom experiences within the lung cancer population. The interviews also suggest that symptoms such as cough which are under-represented in research within this population may play an important role in patients' symptom experiences.
Longitudinal qualitative investigation offers a valuable method for improving our understanding of patients' experiences of lung cancer and for identifying potential opportunities to improve patient quality of life.
Lung cancer (Amsterdam, Netherlands) 05/2010; 71(1):94-102. · 3.14 Impact Factor
-
P Wheatley-Price,
F Blackhall,
S-M Lee,
C Ma,
L Ashcroft,
M Jitlal,
W Qian,
A Hackshaw,
R Rudd,
R Booton,
S Danson, P Lorigan,
N Thatcher,
F A Shepherd
[show abstract]
[hide abstract]
ABSTRACT: Some non-small-cell lung cancer (NSCLC) surgical series have indicated that the positive prognostic effect of female sex is limited to patients with adenocarcinoma. We carried out a retrospective analysis to investigate the role of sex and histology on efficacy, toxicity, and dose delivery after chemotherapy. Patient and methods: Individual patient data were pooled from five randomized, phase III, advanced NSCLC chemotherapy trials. Primary outcomes were response rate, overall survival (OS), toxicity, and dose delivery. A secondary analysis examined survival by sex in histological subgroups.
Of 2349 patients, 34% were women. Women had a higher response rate to chemotherapy (42% versus 40%, P = 0.01) and longer survival than men (median OS 9.6 versus 8.6 months, P = 0.002). The difference in OS remained after adjusting for age, stage, performance status, and histology (hazard ratio 0.83, 95% confidence interval 0.74-0.92, P = 0.0005). Upon further examination, longer survival in women was only seen in patients with adenocarcinoma (test for interaction P = 0.006). There were no differences in hematological toxicity or transfusions. Women experienced more grade 3-4 emesis than men (P < 0.0001) and more dose delays (P = 0.02) or dose reductions (P < 0.0001).
The positive prognostic effect among women is confirmed in patients receiving platinum-based chemotherapy but appears confined to those with adenocarcinoma histology.
Annals of Oncology 03/2010; 21(10):2023-8. · 6.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous studies reported that women survive longer than men, but experience greater toxicity, when treated for small-cell lung cancer (SCLC).
Individual patient data from six randomized phase II/III chemotherapy trials, from the Manchester Lung Group and UK Medical Research Council, were pooled for analysis. End points included overall survival, response rate, toxicity, dose intensity (DI) and transfusion rates.
Of 1707 patients analyzed, 44% were women. At baseline, women had poorer performance status (PS) (57% versus 67% Eastern Cooperative Oncology Group PS 0-1/Karnofsky PS 80-100, P = 0.0004) and more were of normal weight or underweight (57% versus 48%, P = 0.003), but fewer were anemic (25% versus 62%, P < 0.0001). Response rates between women and men were similar (77% versus 76%, P = 0.64). In univariate [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.76-0.96, P = 0.006] and multivariate (HR 0.88, 95% CI 0.79-0.99, P = 0.04) analyses, female sex predicted for longer survival. Women experienced more grade 3/4 emesis (18% versus 9%, P < 0.0001) and grade 3/4 mucositis (13% versus 8%, P = 0.005) than men. There were no differences in DI, infections, transfusions or treatment-related deaths.
Data from >1700 patients in randomized SCLC chemotherapy trials confirm that women survive modestly longer than men but may experience greater toxicity.
Annals of Oncology 09/2009; 21(2):232-7. · 6.43 Impact Factor
-
Annals of Oncology 06/2009; 20(5):801-2. · 6.43 Impact Factor
-
A J Watson,
M R Middleton,
G McGown,
M Thorncroft,
M Ranson,
P Hersey,
G McArthur,
I D Davis,
D Thomson,
J Beith,
A Haydon,
R Kefford, P Lorigan,
P Mortimer,
A Sabharwal,
O Hayward,
G P Margison
[show abstract]
[hide abstract]
ABSTRACT: Patients and methods Results Discussion References Acknowledgements Figures and TablesWe evaluated the pharmacodynamic effects of the O6-methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O6-methylguanine (O6-meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O6-meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O6-meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O6-meG in PBMC DNA during treatment.Keywords: O6-methylguanine-DNA methyltransferase, lomeguatrib, temozolomide, melanoma
British Journal of Cancer 04/2009; 100(8):1250-1256. · 5.04 Impact Factor
-
Clinical Oncology 12/2008; 21(1):78. · 2.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and <or=2 adverse prognostic factors. Patients were randomised to receive six cycles of either ACE (doxorubicin 50 mg/m(2) i.v., cyclophosphamide 1 g/m(2) i.v. and etoposide 120 mg/m(2) i.v. on day 1, then etoposide 240 mg/m(2) orally for 2 days) or PE (cisplatin 80 mg/m(2) and etoposide 120 mg/m(2) i.v. on day 1, then etoposide 240 mg/m(2) orally for 2 days) given for every 3 weeks. For patients where cisplatin was not suitable, carboplatin (AUC6) was substituted. A total of 280 patients were included (139 ACE, 141 PE). The response rates were 72% for ACE and 77% for PE. One-year survival rates were 34 and 38% (P=0.497), respectively and 2-year survival was the same (12%) for both arms. For LD patients, the median survival was 10.9 months for ACE and 12.6 months for PE (P=0.51); for ED patients median survival was 8.3 months and 7.5 months, respectively. More grades 3 and 4 neutropenia (90 vs 57%, P<0.005) and grades 3 and 4 infections (73 vs 29%, P<0.005) occurred with ACE, resulting in more days of hospitalisation and greater i.v. antibiotic use. ACE was associated with a higher risk of neutropenic sepsis than PE and with a trend towards worse outcome in patients with LD, and should not be studied further in this group of patients.
British Journal of Cancer 09/2008; 99(3):442-7. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Radiotherapy has an established role in the management of limited-disease small-cell lung cancer. However, essential questions related to the optimisation of thoracic radiotherapy remain unanswered including (i) optimal total dose, (ii) fractionation, (iii) timing and sequencing of radiation, (iv) volume of irradiation, and (v) concurrent chemotherapy combinations. The role of thoracic radiotherapy for extensive-disease small-cell lung cancer is more poorly understood but evidence suggests radiotherapy may have an important role in this setting. This review highlights the need for well-designed multi-national trials aimed at the optimisation and standardisation of radiotherapy for SCLC.
Lung Cancer 09/2008; 63(3):307-14. · 3.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of the study was to assess levels of chemotherapy-induced nausea and vomiting (CINV) in routine practice.
The study was an observational prospective evaluation using patient self-reports. One hundred and two patients with cancer in a single cancer centre in UK receiving their first chemotherapy treatment participated in the study and were followed up over four cycles, providing a total of 272 assessments of nausea and vomiting. Data was collected with the use of the MASCC Antiemesis Tool (MAT), which is an eight-item short clinical scale assessing acute and delayed nausea and vomiting after chemotherapy.
Results indicated that acute vomiting was experienced by 15.7% of the patients in cycle 1 and delayed vomiting by 14.7%, while acute nausea was present in 37.3% of the patients and delayed nausea in 47.1%, increasing over the subsequent cycles. Moderately emetogenic and highly emetogenic chemotherapy had the highest incidence of CINV, whereas patients receiving highly emetogenic chemotherapy showed significant levels of delayed nausea. Acute symptoms were more easily controlled than delayed symptoms.
The data suggest that, while vomiting is well controlled, nausea remains a significant problem in practice, and optimal management of CINV is yet to be achieved. Understanding more clearly the biological basis of nausea will assist in managing this complex symptom more effectively in practice.
Supportive Care Cancer 03/2008; 16(2):201-8. · 2.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: At present, there are no standard therapies for the adjuvant treatment of malignant melanoma. Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death. Given this, it is important that novel therapies are investigated in the adjuvant melanoma setting. Since angiogenesis is essential for primary tumour growth and the development of metastasis, anti-angiogenic agents are attractive potential therapeutic candidates for clinical trials in the adjuvant setting. Therefore, we initiated a phase II trial in resected high-risk cutaneous melanoma, assessing the efficacy of bevacizumab versus observation.In the interim safety data analysis, we demonstrate that bevacizumab is a safe therapy in the adjuvant melanoma setting with no apparent increase in the surgical complication rate after either primary tumour resection and/or loco-regional lymphadenectomy.
ecancermedicalscience 01/2008; 2:108.
-
Clinical Oncology 12/2006; 18(9):722-3. · 2.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To determine the efficacy and tolerability of SPI-77 (sterically stabilised liposomal cisplatin) at three dose levels in patients with advanced non-small-cell lung cancer (NSCLC). Patients had Stage IIIB or IV NSCLC and were chemo-naïve, and Eastern Oncology Cooperative Group 0-2. The first cohort received SPI-77 at 100 mg m-2, the second 200 mg m-2 and the final cohort 260 mg m-2. Patients had also pharmacokinetics and analysis of leucocyte platinum (Pt)-DNA adducts performed. Twenty-six patients were treated, with 22 patients being evaluable for response. Only one response occurred at the 200 mg m-2 dose level for an overall response rate of 4.5% (7.1% at >or=200 mg m-2). No significant toxicity was noted including nephrotoxicity or ototoxicity aside from two patients with Grade 3 nausea. No routine antiemetics or hydration was used. The pharmacokinetic profile of SPI-77 was typical for a liposomally formulated drug, and the AUC appeared to be proportional to the dose of SPI-77. Plasma Pt levels and leucocyte DNA adduct levels did not appear to rise with successive doses. SPI-77 demonstrates only modest activity in patients with NSCLC.
British Journal of Cancer 10/2006; 95(7):822-8. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This is a dose-finding study of fixed dose gemcitabine and escalating doses of ifosfamide, in chemo naïve patients with advanced non-small cell lung cancer. The purpose of the study was to determine the optimal dosage and the maximal tolerated dose (MTD) of a specified schedule of gemcitabine and ifosfamide. Patients received gemcitabine 1250 mg/m2 and ifosfamide between 1.6 and 2.2 g/m2, intravenously, on days 1 and 8, repeated every 3 weeks for a maximum of four cycles. RESULTS: Sixteen patients entered the study. Three patients were entered at the first dose level of ifosfamide (1.6 g/m2) and none experienced any dose limiting (DLT) toxicity. In dose level 2 (1.8 g/m2), two patients had grade IV haematological toxicities, but they reached 21 days without any other dose limiting toxicity (DLT). Three further patients entered at this level but they were withdrawn due to disease progression. The sixth patient entered without any DLT. Three patients entered dose level 3 (2.0 g/m2), without any grade IV toxicity. The first patient entered into dose level 4 (2.2 g/m2), had progressive disease within 21 days and was withdrawn and another three were entered and had no DLT during the first 21 days. Four (33%) of the patients had stable disease and 67% had progressive disease. CONCLUSION: The MTD of the ifosfamide gemcitabine combination was not reached in the present study, as no DLT was observed. This combination at the dose levels of this protocol has little or no activity in patients with advanced NSCLC.
Lung Cancer 09/2006; 53(2):165-70. · 3.43 Impact Factor
-
R Booton, P Lorigan,
H Anderson,
S Baka,
L Ashcroft,
M Nicolson,
M O'Brien,
D Dunlop,
K O'Byrne,
V Laurence,
M Snee,
G Dark,
N Thatcher
[show abstract]
[hide abstract]
ABSTRACT: Phase III studies suggest that non-small-cell lung cancer (NSCLC) patients treated with cisplatin-docetaxel may have higher response rates and better survival compared with other platinum-based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC or MVP in patients with advanced NSCLC.
Patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy were randomised to receive four cycles of either DCb (docetaxel 75 mg/m(2), carboplatin AUC 6), or MIC/MVP (mitomycin 6 mg/m(2), ifosfamide 3 g/m(2) and cisplatin 50 mg/m(2) or mitomycin 6 mg/m(2), vinblastine 6 mg/m(2) and cisplatin 50 mg/m(2), respectively), 3 weekly. The primary end point was survival, secondary end points included response rates, toxicity and quality of life.
The median follow-up was 17.4 months. Overall response rate was 32% for both arms (partial response = 31%, complete response = 1%); 32% of MIC/MVP and 26% of DCb patients had stable disease. One-year survival was 39% and 35% for DCb and MIC/MVP, respectively. Two-year survival was 13% with both arms. Grade 3/4 neutropenia (74% versus 43%, P < 0.005), infection (18% versus 9%, P = 0.01) and mucositis (5% versus 1%, P = 0.02) were more common with DCb than MIC/MVP. The MIC/MVP arm had significant worsening in overall EORTC score and global health status whereas the DCb arm showed no significant change.
The combination of DCb had similar efficacy to MIC/MVP but quality of life was better maintained.
Annals of Oncology 07/2006; 17(7):1111-9. · 6.43 Impact Factor
