British Journal of Cancer

Montgomery, D A; Krupa, K; Cooke, T G

doi: 10.1038/sj.bjc.6603771pmid: 17486134

Regular clinical follow up after breast cancer is a common practice. Evidence from retrospective reviews casts doubt on the efficacy of this practice and the various guidelines for follow up show little concordance. Our aim was to investigate what alternative follow-up methods (including reduced frequency of visits) have been subjected to controlled trial and to establish what evidence exists from controlled trials to advise the guidelines. The study involved systematic review of the literature using MEDLINE, Embase, CancerLit, Web of Sciences and EBM reviews as data sources. Methods included reviewing all randomised controlled trials comparing different follow-up frequencies or comparing an alternative method with clinical follow up after breast cancer. All outcome measures addressed in the trials were analysed. Two trials compared frequency of traditional follow up. Five trials assessed alternative methods. All were of inadequate power or duration to establish ideal frequency of clinic visits or safety of alternative follow-up methods. Alternative follow up had no detrimental effect on satisfaction or outcome. Few trials have been conducted, all of which are underpowered to establish safety of reducing or replacing clinic visits. Alternative methods of follow up are acceptable to patients and may be associated with other benefits. Larger trials are required.

Kerbrat, P; Roché, H; Bonneterre, J; Veyret, C; Lortholary, A; Monnier, A; Fumoleau, P; Fargeot, P; Namer, M; Chollet, P; Goudier, M-J; Audhuy, B; Simon, H; Montcuquet, P; Eymard, J-C; Walter, S; Clavère, P; Guastalla, J-P

doi: 10.1038/sj.bjc.6603773

Pignata, S; Scambia, G; Pisano, C; Breda, E; Di Maio, M; Greggi, S; Ferrandina, G; Lorusso, D; Zagonel, V; Febbraro, A; Riva, N; De Rosa, V; Gallo, C; Perrone, F

doi: 10.1038/sj.bjc.6603787pmid: 17486128

Anthracyclines and platinum derivates are active drugs for advanced endometrial carcinoma (AEC), but new schedules with higher efficacy and better tolerability are needed. A phase II study was conducted to describe activity and tolerability of carboplatin (C)+pegylated liposomal doxorubicin (PLD) in patients with AEC. Patients with chemonaive AEC, PS ⩽2, aged <75 years, with at least one measurable lesion were eligible. Treatment was C (area under curve 5)+PLD (40 mg m−2) on day 1 every 4 weeks, up to six cycles. Forty-two patients were needed in a single-stage design, with at least 13 objective responses to define the treatment active. Forty-two patients were enrolled. Median age was 64 years (31–74). A total of 64% of patients were recurrent while 36% were advanced. Three complete (7%) and 22 partial responses (52%) were observed, for an overall response rate of 59.5% (95% exact CI: 43.3–74.3). One death potentially related to treatment was recorded (death at home for unknown reasons after 6th cycle). Other relevant toxicities (% of patients) were grade 3/4 neutropaenia 33%/14%, febrile neutropaenia 5%, grade 3/4 thrombocytopaenia 17%/5%, grade 3/4 anaemia 31%/2%. Skin toxicity was mild: grade 1 14%, grade 2 10%, grade 3 5%. Hair loss: complete 5%, partial 12%. The combination of carboplatin and PLD shows good activity and favourable toxicity as first-line chemotherapy of patients with AEC, deserving further studies in this setting.

Berghmans, T; Lafitte, J J; Lecomte, J; Alexopoulos, C G; Van Cutsem, O; Giner, V; Efremidis, A; Berchier, M C; Collon, T; Meert, A P; Scherpereel, A; Ninane, V; Leclercq, N; Paesmans, M; Sculier, J P

doi: 10.1038/sj.bjc.6603772pmid: 17473825

Ikeda, M; Okusaka, T; Ito, Y; Ueno, H; Morizane, C; Furuse, J; Ishii, H; Kawashima, M; Kagami, Y; Ikeda, H

doi: 10.1038/sj.bjc.6603788pmid: 17533388

This study investigated the maximum tolerated dose of S-1 based on the frequency of its dose-limiting toxicities (DLT) with concurrent radiotherapy in patients with locally advanced pancreatic cancer. S-1 was administered orally at escalating doses from 50 to 80 mg m−2 b.i.d. on the day of irradiation during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Twenty-one patients (50 three; 60 five; 70 six; 80 mg m−2 seven patients) were enrolled in this trial. At a dose of 70 mg m−2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 haemorrhagic gastritis, whereas no patients at doses other than 70 mg m−2 demonstrated any sign of DLT. Among the 21 enrolled patients, four (19.0%) showed a partial response. The median progression-free survival time and median survival time for the patients overall were 8.9 and 11.0 months, respectively. The recommended dose of S-1 therapy with concurrent radiotherapy is 80 mg m−2 day−1. A multi-institutional phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway.

Nilsson, B; Sjölund, K; Kindblom, L-G; Meis-Kindblom, J M; Bümming, P; Nilsson, O; Andersson, J; Ahlman, H

doi: 10.1038/sj.bjc.6603797pmid: 17533389

Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies.

Malcles, M-H; Wang, H-W; Koumi, A; Tsai, Y-H; Yu, M; Godfrey, A; Boshoff, C

doi: 10.1038/sj.bjc.6603768pmid: 17505517

Survivin is an oncogenic protein involved in cell division and acts as an anti-apoptotic factor. It is highly expressed in most cancers and is associated with chemotherapy resistance, increased tumour recurrence, and shorter patient survival. This makes anti-survivin therapy an attractive cancer treatment strategy. These functions are mediated by several survivin spliced variants, whose expression may correlate with cancer progression. One of the spliced variants, survivin-ΔEx3, is known to inhibit apoptosis, through undefined mechanisms. Here, we characterised these mechanisms upon TNFα−mediated apoptosis, and showed that survivin-ΔEx3 acts as an adaptor, allowing the formation of a complex between Bcl-2 and activated caspase-3. The Bcl-2/survivin-ΔEx3 complex, but not survivin-ΔEx3 itself, inhibits the activity of caspase-3. Bcl-2 is therefore linked to the postmitochondrial apoptotic machinery by survivin-ΔEx3. Thus, survivin-ΔEx3 plays a key role in the inhibition of caspase-3 activity, and in the control of the mitochondrial checkpoint of apoptosis. This study suggests that targeting survivin-ΔEx3, rather than survivin alone, could be relevant for treating human cancers.

Rephaeli, A; Waks-Yona, S; Nudelman, A; Tarasenko, I; Tarasenko, N; Phillips, D R; Cutts, S M; Kessler-Icekson, G

doi: 10.1038/sj.bjc.6603781pmid: 17473824

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (ΔΨm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.

Armstrong, J L; Taylor, G A; Thomas, H D; Boddy, A V; Redfern, C P F; Veal, G J

doi: 10.1038/sj.bjc.6603779pmid: 17486130

Isomerisation to all-trans-retinoic acid (ATRA) is widely accepted as the key mechanism underlying the favourable clinical properties of 13-cis-retinoic acid (13cisRA). As intracellular metabolism of ATRA by CYP26 may result in clinical resistance to 13cisRA, an increase in efficacy may be achieved through modulation of this metabolic pathway. We have evaluated the effect of the CYP26 inhibitor R116010 on retinoid metabolism in neuroblastoma cell lines and a xenograft model. In neuroblastoma cells, which showed a high level of CYP26 induction in response to ATRA, R116010 selectively inhibited ATRA metabolism. In addition, siRNA-mediated knockdown of CYP26 selectively increased ATRA levels and the expression of retinoid-responsive marker genes was potentiated by R116010. Treatment of mice bearing SH-SY5Y xenografts with 13cisRA (100 mg kg−1) revealed substantial levels (16%) of intratumoral ATRA after 6 h, despite plasma ATRA levels representing only 1% total retinoids under these conditions. Co-administration of R116010 with 13cisRA in this mouse model resulted in significant increases in plasma ATRA and 13cisRA concentrations. Furthermore, R116010 induced significant decreases in levels of 4-oxo metabolites in hepatic tissue after co-administration with either ATRA or 13cisRA. These data suggest considerable potential for CYP26 inhibitors in the future treatment of neuroblastoma with 13cisRA.

Borel, M; Degoul, F; Communal, Y; Mounetou, E; Bouchon, B; C-Gaudreault, R; Madelmont, J C; Miot-Noirault, E

doi: 10.1038/sj.bjc.6603778pmid: 17486131

The antitumoral profile of the microtubule disrupter N-(4-iodophenyl)-N′-(2-chloroethyl)urea (ICEU) was characterised in vitro and in vivo using the CT-26 colon carcinoma cell line, on the basis of the drug uptake by the cells, the modifications of cell cycle, and β-tubulin and lipid membrane profiles. N-(4-iodophenyl)-N′-(2-chloroethyl)urea exhibited a rapid and dose-dependent uptake by CT-26 cells suggesting its passive diffusion through the membranes. Intraperitoneally injected ICEU biodistributed into the grafted CT-26 tumour, resulting thus in a significant tumour growth inhibition (TGI). N-(4-iodophenyl)-N′-(2-chloroethyl)urea was also observed to accumulate within colon tissue. Tumour growth inhibition was associated with a slight increase in the number of G2 tetraploid tumour cells in vivo, whereas G2 blockage was more obvious in vitro. The phenotype of β-tubulin alkylation that was clearly demonstrated in vitro was undetectable in vivo. Nuclear magnetic resonance analysis showed that cells blocked in G2 phase underwent apoptosis, as confirmed by an increase in the methylene group resonance of mobile lipids, parallel to sub-G1 accumulation of the cells. In vivo, a decrease of the signals of both the phospholipid precursors and the products of membrane degradation occurred concomitantly with TGI. This multi-analysis established, at least partly, the ICEU activity profile, in vitro and in vivo, providing additional data in favour of ICEU as a tubulin-interacting drug accumulating within the intestinal tract. This may provide a starting point for researches for future efficacious tubulin-interacting drugs for the treatment of colorectal cancers.