European Journal of Cancer: Highlights of Issue 38:06

CONTINUOUS---------------
PULSED------------------------------CELL DEATH

Can drug scheduling and recovery phases improve efficacy in the treatment of CML?

This is the question raised in this issue by Liu and colleagues who study the effects of drug scheduling and recovery phases on the activity of etoposide in BCR-ABL-positive chronic myeloid leukaemia (CML) cells (K562 and KU812 cells). Interestingly, they found that a continuous schedule (5 days incubation with etoposide) induced a G2/M arrest, without any substantial increase in the sub-G1 content or decrease in viability. In contrast, an intermittent schedule (for example, 3 days of drug exposure followed by 3 days in drug-free medium) resulted in a marked increase in the sub-G1 content following the removal of the drug. Furthermore, an increase in p21 levels and a decrease in cdk1 levels were observed during the arrest in G2/M and upon release of the cells into drug-free medium the p21 levels gradually returned to control levels suggesting that these changes may be linked with the arrest. Where multiple recovery phases were examined, the increase in the sub G1 content was even more pronounced. Thus, rather than acting as a “stop” signal as observed following continuous treatment, the authors concluded that “a pulsed schedule may be more active than a single prolonged exposure” and “that the possibility that the efficacy of other cytotoxic agents could be improved through a similar approach is exciting and warrants further investigation”.

A similar risk for women participating in spontaneous and invited screening in the Netherlands.

The age at which to screen women for cervical cancer and the screening interval are still a matter of debate in a number of European countries (see EJC Special Issue (2000) 36:17 and the Editorial by Professor Miller (2002) 38:03 p 321 - 326). Spontaneous screening, especially at younger ages, is thought to be inefficient for many reasons such as the lack of cover and decreased screening intervals. An excessive use of smears will thus result in an increase in costs and negative side-effects with a relatively small effect (if any) on incidence and mortality. As discussed by Bos and colleagues in this issue, women who undergo spontaneous screening could be at a higher risk than women participating in the screening programme. The authors investigated this issue using data taken from the national pathological database in the Netherlands, from which all primary smears taken in 1994 were retrieved. They showed that the detection rate of severe dysplasia or worse, after adjusting for age and screening history, was the same for women who had a spontaneous smear as for those who had a smear within the screening programme (Odds Ratio 0.97, 95% Confidence Interval 0.84-1.14). Thus, the authors suggest that doctors who take preventive smears should follow the currently recommended guidelines of the screening programme.

No consensus in the guidelines for systemic adjuvant therapy for breast cancer.

In this issue, Baum and Ravdin provide an interesting discussion with regard to the evidence-based guidelines that are being derived to aid in determining the use of systemic adjuvant therapy for early breast cancer. Three sets of guidelines are compared and contrasted (the National Cancer Institute (NCI), the National Comprehensive Cancer Network (NCCN) and St. Gallen Guidelines) and the lack of consensus between these guidelines is clearly demonstrated in examples provided by the authors. Baum and Ravdin suggest that this is due to the lack of “quantitive underpinnnings” and the different underlying assumptions. They examine in their paper alternate methods that may be used for decision-making such as the Quality adjusted Time Without Symptoms or Treatment (Q-TwiST) method, the use of “Decision Boards” and computer programs from which some estimates of the magnitude of benefit may be derived.

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