[Show abstract][Hide abstract] ABSTRACT: A strong association between smoking and SCLC is noted whereas the dose–response relationships are less clear. We demonstrate that cumulative smoking of the first 50 pack-years is associated with a sharper increase in SCLC risk. Moreover, although the relationship between smoking and COPD or COPD and SCLC is well-established, no study has investigated the causal pathway among smoking, COPD, and SCLC. Here we reveal the risks of smoking behaviors on SCLC which are partially mediated (up to 7.6%) through COPD. The findings warrant further experimental study to elucidate the mechanisms in this causal pathway.
[Show abstract][Hide abstract] ABSTRACT: Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal-related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer.
[Show abstract][Hide abstract] ABSTRACT: Aim
Switch maintenance is an effective strategy in advanced NSCLC treatment. Pz is an orally active, multi-targeted tyrosine kinase inhibitor (TKI), potentially effective in lung cancer. EORTC 08092 evaluated Pz given as maintenance following standard first line platinum-based chemotherapy (CT) in pts with advanced NSCLC.
Pts with non-progressive disease after 4-6 cycles of CT were randomized to receive either Pz 800 mg/day or matched placebo until progression or unacceptable toxicity. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and safety. Assuming 80% power and 5% 2-side type I error and taking into account an Interim Analysis (IA) for futility based on PFS, 587 pts had to be randomized in order to improve median overall survival (OS) from 9.7 to 12.7 months.
After 102 pts were randomized to Pz (n = 50) or P (n = 52), the trial was prematurely stopped due to an early IA. Median age was 64 years in both arms. Baseline characteristics for Pz and P arms (%): male/female: 57/43 and 55/45; squamous/non-squamous-cell: 78/22 and 82/18; ECOG PS 0/1/2: 21/75/4 and 36/64/0; Prior Chemotherapy Response CR-PR/SD: 27/73 and 32/68; current/former/never smoker/NA: 8/67/19/6 and 22/52/22/4. OS was not significantly different, median 17.4 months(m) for Pz vs. 12.3 m for P (adjusted HR was 0.72 [95% CI 0.40-1.28]; p = 0.257). Median PFS was 4.3 m vs. 3.2 m (HR 0.67, [95% CI 0.43,1.03]), p = 0.068. PFS rates at 4 months were 56% and 45% respectively. Pz was well tolerated: the majority of treatment-related adverse events (AEs) were grade 1/2. Reported grade 3/4 AEs (% Pz vs. P) were neutropenia (8% vs. 0%), hypertension (38% vs. 8%) and elevated SGPT (6% vs. 0%). Only 22% of pts receiving Pz withdrew due to a treatment-related AE.
Switch maintenance with Pazopanib following platinum-based chemotherapy in pts with advanced NSCLC was well tolerated. This study was stopped for futility following an IA due to lack of efficacy judging by a stringent criteria for PFS.
[Show abstract][Hide abstract] ABSTRACT: Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p=0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p=0.07) and inflammatory vascular lesions (p=0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p=0.001, p=0.001, p<0.001 and p<0.001 respectively). Notch1 also correlated with Tie2 expression (p=0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK.
[Show abstract][Hide abstract] ABSTRACT: Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets.
Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays.
Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p = 0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p = 0.07) and inflammatory vascular lesions (p = 0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p = 0.001, p = 0.001, p < 0.001 and p < 0.001 respectively). Notch1 also correlated with Tie2 expression (p = 0.004).
In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK.
Experimental and Molecular Pathology 01/2014; · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma.
Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening.
Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %).
Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.
Supportive Care in Cancer 10/2013; 22(3). DOI:10.1007/s00520-013-2022-1 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma.
Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC.
Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA.
In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1823-1829. DOI:10.1097/JTO.0b013e31826aec2b · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. METHODS: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. FINDINGS: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups. INTERPRETATION: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. FUNDING: Cancer Research UK, Roche.
The Lancet Oncology 10/2012; 13(11). DOI:10.1016/S1470-2045(12)70412-6 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
We conducted a retrospective study, pooling data from two clinical trials in high risk soft tissue sarcoma (STS) patients, with the objective of comparing two different age groups: 15-29 years (adolescents and young adults (AYA) population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population.
Patients selected for analysis were treated in two randomised trials of adjuvant chemotherapy in STS (European Organisation for Research and Treatment of Cancer (EORTC) 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n=161, median FU 9.46 years; patients ≥ 30 years: n=632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumour size and localisation (limb versus other), absence or presence of local recurrence and treatment (control arm versus adjuvant chemotherapy).
Patients' characteristics were globally similar with two exceptions, histological subtype (p=0.0043) and tumour size (p<.0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29%), whereas leiomyosarcoma (18%), malignant fibrous histiocytoma (MFH, presently being termed undifferentiated pleomorphic sarcoma (UPS), 16%) and liposarcoma (15%) were more frequent in patients ≥ 30 years. For OS, independent favourable prognostic factors were low grade and small tumour size for both groups; radical resection and MFH or liposarcoma subtype were favourable factors for patients ≥ 30 years only. For RFS, favourable prognostic factors were small tumour size and low grade for both groups; tumour location in the extremities was a favourable factor for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favourable factors for patients ≥ 30y ears only.
Significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications for the treatment of STS patients in different age groups, as well as the design of future clinical trials.
European journal of cancer (Oxford, England: 1990) 09/2012; 49(2). DOI:10.1016/j.ejca.2012.08.007 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown. We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas.
In this multicentre randomised trial, patients with macroscopically resected, Trojani grade II-III soft-tissue sarcomas at any site, no metastases, performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery. Patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy (control group). Randomisation was done with a minimisation technique, stratified by hospital, site of primary tumour, tumour size, planned radiotherapy, and isolated limb perfusion therapy. Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2), ifosfamide 5 g/m(2), and lenograstim every 3 weeks. Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent. The primary endpoint was overall survival and analyses were done by intention to treat. The final results are presented. This trial is registered with ClinicalTrials.gov, NCT00002641.
Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68-1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67-1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8-73·0) in the chemotherapy group and 67·8% (60·3-74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded.
Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival. Future studies should focus on patients with larger, grade III, and extremity sarcomas.
The Lancet Oncology 09/2012; 13(10):1045-1054. DOI:10.1016/S1470-2045(12)70346-7 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
This multicenter, open-label, phase II study was carried out to compare the efficacy and safety of cilengitide (EMD 121974), a selective inhibitor of the cell-surface integrins αVβ3 and αVβ5, with that of docetaxel in patients with advanced non-small-cell lung cancer (NSCLC).
Patients (n = 140) with advanced NSCLC who had failed first-line chemotherapy were randomized to cilengitide 240, 400, or 600 mg/m(2) twice weekly, or docetaxel 75 mg/m(2) once every 3 weeks for eight cycles. Non-progressing patients could continue cilengitide for up to 1 year. The primary endpoint was progression-free survival (PFS). No statistical tests were performed since the study was exploratory in nature and the number of patients enrolled was relatively small.
Median PFS was 54, 63, 63, and 67 days for cilengitide 240, 400, and 600 mg/m(2), and docetaxel 75 mg/m(2), respectively. One-year survival rates were 13 %, 13 %, 29 %, and 27 %, respectively. The response rate (partial response only) with docetaxel was 15 %. No responses were reported in any cilengitide arm. The most frequent grade 3/4 treatment-related adverse events in the docetaxel group were leukopenia and neutropenia (experienced by 13 % of patients). Hematologic toxicity of this severity did not occur in cilengitide-treated patients.
With the highest dose of cilengitide (600 mg/m(2)), median PFS and 1-year survival were similar to those in patients treated with docetaxel 75 mg/m(2) and there were fewer grade 3/4 treatment-related adverse events.
Investigational New Drugs 07/2012; 31(1). DOI:10.1007/s10637-012-9842-6 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals.
Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR) = 1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR = 1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR = 1.44, 95% CI: 1.07, 1.93), after adjustment.
The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group.
European journal of cancer (Oxford, England: 1990) 03/2012; 48(13):1957-68. DOI:10.1016/j.ejca.2012.01.038 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acquired chemoresistance is a major obstacle in successful treatment of small cell lung cancer (SCLC). DNA damage responses can potentially contribute to resistance by halting the cell cycle following exposure to therapeutic agents, thereby facilitating repair of drug-induced lesions and protecting tumour cells from death. The Chk1 protein kinase is a key regulator in this response. We analysed the status of cell cycle checkpoint proteins and the effects of the Chk1 inhibitor Gö6976 on cisplatin toxicity in SCLC cell lines. IC50s for cisplatin were determined using the MTT assay in six SCLC cell lines. Effects on cell cycle distribution and apoptosis were determined by flow cytometry and caspase 3 activation in the presence or absence of the Chk1 inhibitor Gö6976. The activation of checkpoint proteins was determined by Western blotting. Cell lines were divided into chemosensitive and chemoresistant groups on the basis of our results. While checkpoint responses were detected in these cell lines through Western blotting, some of these responses were delayed or weaker than those seen in other cell types in response to DNA damage and replication stress. Gö6976 significantly (p<0.05) enhanced the levels of apoptosis seen in response to a clinically relevant dose of cisplatin (<6 µM) and decreased drug-induced G2 arrest in chemosensitive cells. Our data suggest a role for Chk1 in chemoresistance of SCLC cells and a potential approach to improve initial response of SCLC to cisplatin therapy.
International Journal of Oncology 09/2011; 40(1):194-202. DOI:10.3892/ijo.2011.1187 · 3.03 Impact Factor