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    • Artesunate has a very high probability

    2018-10-23

    Artesunate has a very high probability (0.97, calculated with an informative prior in Bayesian analysis, Fig. 2b) of effect on Ki67 staining of tumour cells. This is consistent with a high probability of artesunate effect on Ki67 staining of fibroblasts (0.84; Table 2). Ki67 is a marker of tumour cell proliferation whose upregulation is associated with a poorer prognosis in colorectal cancer. Other markers of tumour biology were also affected by artesunate, although with lower probabilities (for example, 0.79 probability for increased CD31 expression). In one case (Fig. 4b) there was a ~75% fall in circulating CEA levels after 2weeks of artesunate treatment alone. The recurrence-free survival probability was also higher after artesunate compared with placebo (at 3years 0.89 compared with 0.5; Fig. 3) although confidence intervals for these estimates overlap (HR 0.16, p=0.091, Supplementary Table 1) because of the small numbers of patients and therefore events included in this study. Till this analysis, there have been no deaths in artesunate recipients (despite some patients having relatively poor prognosis), and 3 deaths in placebo recipients. Two patients who were at the lower weight limit for inclusion in this study (50kg, giving an effective dose of 4mg/kg of artesunate/day) developed leucopenia (Fig. 4). In one case this reversed shortly after stopping artesunate, whereas in the other G-CSF may have hastened recovery. Bone-marrow examination suggested a toxic effect of artesunate. These findings are consistent with the recent observations in malaria of a dose-dependent neutropenia with artesunate (>4mg/kg) (Bethell et al., 2010), although bone marrow examinations have not been carried out before. We instituted mid-treatment monitoring for neutropenia after observations on malaria but did not note this complication in other patients. Artesunate associated leucopenia may be dose-dependent in cancer patients as it arn-509 is in malaria, and although delayed haemolysis has been observed after artemisinin use (Rolling et al., 2014, 2012) it was not a complication in our patients. In future studies, it may be safer to restrict daily dose of artesunate to <4mg/kg and to monitor for haematological complications. A recent publication on an artesunate dose-finding study in metastatic breast cancer disease suggests that 200mg once a day can be tolerated for up to 3weeks (Ericsson et al., 2014). Liver recurrence was commonest in our patients, followed by peritoneal and ovarian sites, suggesting that seeding is mainly haematogenous and trans-peritoneal. As patients had clear circumferential and longitudinal margins at surgery, and detectable metastases were not identified at randomisation, it is likely that micrometastases spread through vascular invasion (VI) caused recurrence. Previous experience suggests that VI predicts decreased survival in CRC (Ganapathi et al., 2011; Liang et al., 2007; Talbot et al., 1980; Betge et al., 2012). Patients with cryptic dissemination of CRC may benefit from systemic neo-adjuvant therapy and artesunate may be particularly suitable because it does not usually delay surgery. It also reduces liver metastases in an animal model (Li et al., 2007). These observations provide critical information for the design of further studies. In assessing its neo-adjuvant properties, we have also examined artesunate\'s mechanisms of action in human CRC. Artesunate does not restore apoptosis in tumour cells in our study, but rather decreases the expression of a Ki67. Ki67 is also an important marker of prognosis in CRC unlike CD31, which is increased in expression. These findings are consistent with uncontrolled observations made in cervical cancer (Jansen et al., 2011), where decreased Ki67 staining was also observed, although decreased CD31 staining of blood vessels in that study contrasts with our observations. Detailed laboratory observations on anti-cancer mechanisms of artesunate such as on proliferation (Efferth et al., 2007, 2003; Yeung et al., 2013) and expression of tumour cell markers (Konkimalla et al., 2009; Efferth et al., 2004; Konkimalla and Efferth, 2010) (including for angiogenesis) can now be interpreted in light of in vivo observations. Larger clinical studies with artesunate that aim to provide well tolerated and convenient anticancer regimens should be implemented, and may provide an intervention where none is currently available, as well as synergistic benefits with current regimens.