British Journal of Cancer

Nathan, P; Chao, D; Brock, C; Savage, P; Harries, M; Gore, M; Eisen, T

doi: 10.1038/sj.bjc.6603025pmid: 16508632

Vascular endothelial growth factor (VEGF) is overexpressed in around 80% of patients with clear cell carcinoma of the kidney owing to the inactivation of von Hippel Lindau gene activity. VEGF stimulates angiogenesis and acts as an autocrine growth factor. A number of different agents are now available which target VEGF and its signalling pathways. A significant body of evidence has accumulated demonstrating that antagonism of VEGF and its downstream pathways is clinically useful in a significant proportion of patients with metastatic clear cell carcinoma of the kidney. Enough data is now available to recommend that patients with metastatic clear cell carcinoma of the kidney should at some point during the course of their disease be offered entry into a clinical trial enabling exposure to a targeted inhibitor of VEGF or its signalling pathways. Assuming early clinical trial data is substantiated by ongoing registration studies, efforts should be made to minimise the time taken between licensing and general availability of these active agents.

Kelesidis, I; Kelesidis, T; Mantzoros, C S

doi: 10.1038/sj.bjc.6603051pmid: 16570048

Recent studies have demonstrated that obesity is a significant risk factor for the development of several malignancies, but the mechanisms underlying this relationship remain to be fully elucidated. Adiponectin, an adipocyte secreted endogenous insulin sensitizer, appears to play an important role not only in glucose and lipid metabolism but also in the development and progression of several obesity-related malignancies. In this review, we present recent findings on the association of adiponectin with several malignancies as well as recent data on underlying molecular mechanisms that provide novel insights into the association between obesity and cancer risk. We also identify important research questions that remain unanswered.

de Jonge, M E; Huitema, A D R; Beijnen, J H; Rodenhuis, S

doi: 10.1038/sj.bjc.6603097pmid: 16622453

We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m−2 day−1), thiotepa (80 or 120 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) (CTC) for 4 consecutive days. The area under the plasma concentration–time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P=0.003) but not of phosphoramide mustard (P=0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity.

Ackers, C; Rustin, G J S

doi: 10.1038/sj.bjc.6603087pmid: 16622461

As part of surveillance protocols for stage I germ cell tumours, many centres routinely measure human chorionic gonadotrophin (HCG), alpha feto-protein (AFP) as well as lactate dehydrogenase (LDH). In conjunction with regular imaging and clinical examination, does routine measurement of LDH add anything to our relapse/pick up rate? Records of 494 patients at Mount Vernon Hospital who relapsed on surveillance between 1985 and 2005 were examined. Of the 494 patients who relapsed, 125 had raised LDH at the time of relapse. 112 of these had a concurrent rise in either AFP, HCG or both, 11 had their disease detected on CT before the rise in LDH, one had a clinically palpable para-aortic mass and the final patient complained of back pain and his retroperitoneal disease was thus discovered on imaging. Routine measurement of LDH in patients on surveillance for stage I germ cell tumours does not add to the early detection of relapse.

Pacilio, C; Morabito, A; Nuzzo, F; Gravina, A; Labonia, V; Landi, G; Rossi, E; De Maio, E; Di Maio, M; D'aiuto, G; Botti, G; Normanno, N; Chiodini, P; Gallo, C; Perrone, F; de Matteis, A

doi: 10.1038/sj.bjc.6603096pmid: 16622454

Kümmel, S; Krocker, J; Kohls, A; Breitbach, G-P; Morack, G; Budner, M; Blohmer, J-U; Elling, D

doi: 10.1038/sj.bjc.6603085pmid: 16622463

We evaluated the survival benefit, safety, feasibility, and tolerability of dose-dense (DD) adjuvant chemotherapy with epirubicin and paclitaxel for women with node-positive primary breast cancer. Randomised patients (n=216) received DD or conventional-schedule (CS) chemotherapy. Dose-dense regimen patients (n=108) received epirubicin 90 mg m−2 plus paclitaxel 175 mg m−2 in four 14-day cycles, then cyclophosphamide 600 mg m−2, methotrexate 40 mg m−2, and fluorouracil 600 mg m−2 (CMF 600/40/600) in three 14-day cycles, plus filgrastim 5 μg kg day−1 as growth support in every cycle. Conventional-schedule regimen patients (n=108) received epirubicin 90 mg m−2 plus cyclophosphamide 600 mg m−2 in four 21-day cycles, then CMF 600/40/600 in three 21-day cycles, plus filgrastim if required. After a median follow-up of 38.4 months, 71 patients (33%) relapsed or died: DD, 33 patients (15 deaths); CS, 38 patients (22 deaths). Dose dense showed a trend for improved disease-free survival (DFS) and overall survival (OS). Four-year rates of DFS and OS were 64 and 85% for DD, and 58 and 75% for CS. All seven cycles were administered to 208 patients (96%). Rates of cycle delay, discontinuation, dose reduction, and adverse events were similar in both groups. Dose-dense sequential chemotherapy with epirubicin/paclitaxel then CMF, supported by filgrastim, is safe and improves survival for patients with node-positive breast cancer.

Lehto, U-S; Ojanen, M; Dyba, T; Aromaa, A; Kellokumpu-Lehtinen, P

doi: 10.1038/sj.bjc.6603091pmid: 16670704

Despite the large number of studies on the impact of psychosocial factors on breast cancer progression, there is no certainty about the contributing factors or processes involved. We investigated the relative impacts of socioeconomic, psychological, and psychosocial factors on survival in breast cancer. A consecutive sample of 102 patients (participation 82%) under 72 years of age with locoregional breast cancer completed validated questionnaires on coping with cancer, emotional expression (anger), perceived available support, noncancer life stresses, and quality of life 3−4 months after diagnosis. Survival times were measured from the date of diagnosis to the date of relapse and further to the date of death or date of last follow-up. Cumulative Cox regression analyses were carried out. After controlling for biological prognostic factors, age, and baseline treatment, longer survival was predicted by a long education and a minimising-related coping, while shorter survival was predicted by emotional defensiveness (antiemotionality), behavioural-escape coping, and a high level of perceived support. A shorter event-free time was also predicted by unemployment and depressive symptoms. Cancer survival is affected by a complex combination of psychosocial factors, among which minimising predicts a favourable prognosis and anger nonexpression and escape behaviour an unfavourable prognosis. Higher socioeconomic status is associated with longer survival. High scores in well-being scales may reflect emotional nonexpression.

Gray, N M; Sharp, L; Cotton, S C; Masson, L F; Little, J; Walker, L G; Avis, M; Philips, Z; Russell, I; Whynes, D; Cruickshank, M; Woolley, C M

doi: 10.1038/sj.bjc.6603086pmid: 16622462

Receipt of an abnormal cervical smear result often generates fear and confusion and can have a negative impact on a woman's well-being. Most previous studies have focussed on high-grade abnormal smears. This study describes the psychological and psychosocial effects, on women, of having received a low-grade abnormal smear result. Over 3500 women recruited to TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) participated in this study. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS) at recruitment. Socio-demographic and lifestyle factors, locus of control and factors associated with the psychosocial impact of the abnormal smear result were also assessed. Women reported anxiety levels consistent with those found in previous studies of women with high-grade smear results. Women at highest risk of anxiety were younger, had children, were current smokers, or had the highest levels of physical activity. Interventions that focus particularly on women's understanding of smear results and pre-cancer, and/or directly address their fears about cancer, treatment and fertility might provide the greatest opportunity to reduce the adverse psychosocial impact of receiving a low-grade abnormal cervical smear result.

Tibaldi, C; Prochilo, T; Russo, F; Pennucci, M C; Del Freo, A; Innocenti, F; Fabbri, A; Falcone, A; Conte, P F; Baldini, E

doi: 10.1038/sj.bjc.6603074pmid: 16622468

The aim of this study was to evaluate feasibility and toxicity of escalating doses of epirubicin and paclitaxel plus fixed dose of etoposide and to define the activity of the triplet in extensive disease small-cell lung cancer. Thirteen patients entered the phase I study: the maximum tolerated doses were epirubicin (EpiDX) 90 mg m−2 and paclitaxel (P) 175 mg m−2 with febrile neutropenia as dose-limiting toxicity. The recommended schedule for this regimen for the phase II study was EpiDX 75 mg m−2, P 175 mg m−2, etoposide (E) 100 mg m−2 intravenous (fixed dose) days 1–3 with courses repeated every 21 days. The prophylactic use of colony-stimulating factors (CSFs) was not allowed. Twenty patients entered the phase II trial: median age was 61 years (range 50–70), median Eastern Cooperative Oncology Group performance status 0 (0–2); nine patients had visceral disease and 17 had more than two metastatic sites. A total of 100 courses were administered with a median of 5 (range 1–6) per patients. Main toxicity (NCI-CTC) was myelosuppression: neutropenia grades 3 and 4 in 16 and 35% of the courses, respectively. Seven episodes of febrile neutropenia were documented and one patient required hospital admission. Nonhaematological toxicity was moderate. Seven out of 19 evaluable patients achieved a complete response (37%), nine patients (47.3%) a partial response with an overall response rate of 84.2% ((95% confidence interval=60.4–96.6)). In this poor prognostic population of patients the triplet epirubicin/paclitaxel/etoposide showed high antitumour activity with mild nonhaematological side effects. The use of CSFs should be able to improve the haematological profile.

Kinoshita, A; Fukuda, M; Soda, H; Nagashima, S; Fukuda, M; Takatani, H; Kuba, M; Nakamura, Y; Tsurutani, J; Kohno, S; Oka, M

doi: 10.1038/sj.bjc.6603079pmid: 16622467

To determine the efficacy and toxicity of irinotecan combined with carboplatin, we conducted a phase II trial. Eligibility criteria were: chemotherapy-naïve, small-cell lung cancer (SCLC), good performance status (PS: 0–2), age⩽75 years, and adequate organ function. The patients' characteristics were: male/female=56/5; PS 0/1/2=19/38/4; median age (range)=68 years(51–75 years); limited disease (LD)/extensive disease (ED)=27/34. The patients received irinotecan (50 mg m−2) on days 1, 8, and 15, and carboplatin (AUC 5, Chatelut formula) on day 1 every 4 weeks. In total, 61 patients were eligible and all were evaluated. In all, 31 patients were treated with four or more courses of chemotherapy. Of the patients, 17 showed a complete response (CR), 34 showed a partial response (PR), nine had stable disease (SD), and one had progressive disease (PD). The overall response rate was 84% (95% confidence interval (CI), 72–91%; LD 89%, ED 79%) and the CR rate was 28% (95%CI, 17–41%; LD 37%, ED 21%). The median time to tumour progression was 6.1 (LD 6.4, ED 5.4) months. The medial survival time was 15.0 (LD 20.0, ED 9.7) months, and the 2-year and 5-year survival rates were 31.1% (LD 48.1%, ED 17.7%) and 9.5% (LD 11.1%, ED 5.9%), respectively. Grade 3 or 4 leucopenia, neutropenia, thrombocytopenia, anaemia, and diarrhoea occurred in 33, 74, 41, 39, and 13% of cases, respectively. In conclusion, the combination of irinotecan and carboplatin is an active and well-tolerated regimen in cases of SCLC.