Elsevier

The Lancet Oncology

Volume 1, Issue 2, October 2000, Pages 86-93
The Lancet Oncology

Review
Repopulation of tumour cells between cycles of chemotherapy: a neglected factor

https://doi.org/10.1016/S1470-2045(00)00019-XGet rights and content

Summary

Repopulation of clonogenic tumour cells during fractionated radiation treatment is recognised as an important factor affecting local control. Given the longer intervals between cycles and longer total duration of treatment, the impact of repopulation is likely to be greater following chemotherapy. Limited data from experimental models suggest that, after chemotherapy, there is a ‘lag period’, followed by variable but rapid rates of repopulation of tumour cells, possibly accelerating between cycles. Modelling of these properties indicates that after the initial response, accelerated repopulation between cycles can lead to tumour regrowth without any change in the drug sensitivity of the tumour cells. The importance of repopulation may be comparable with that of intrinsic or acquired cellular resistance in determining the effective resistance of tumours to chemotherapy. Biological agents with rapid onset and short duration of action, which can selectively inhibit tumour-cell repopulation, administered between cycles of chemotherapy, might improve the therapeutic index.

Section snippets

Repopulation in normal tissues

The role of repopulation in normal tissues after a cytotoxic insult varies according to the turnover rate of the cell population. Slowly proliferating tissues do not show significant increases in proliferation, as assessed by the mitotic or labelling index, in the first few weeks following irradiation or administration of a cytotoxic drug.1, 2, 3 Conversely, in tissues with a high turnover rate, such as the bone marrow and intestinal mucosa, the overall mitotic rate increases greatly after

Repopulation and radiation therapy

There is extensive experimental and clinical evidence to support the concept of repopulation of clonogenic tumour cells during a course of fractionated radiation therapy. Rates of repopulation have been estimated for various transplanted tumours in laboratory animals by estimating the number of surviving clonogenic tumour cells as a function of time, after single or fractionated doses of radiation. Methods used include colony-forming assays and measurements of TCD50, where TCD50 is the

Repopulation and chemotherapy

The intervals between doses of cytotoxic chemotherapy are necessarily longer than the usual daily intervals between radiation dose fractions, because of the need to allow recovery (repopulation) of normal tissues such as the bone marrow and intestinal mucosa. Most drugs are present in cytotoxic concentrations for only a few hours after administration, and although lower concentrations that inhibit cell proliferation may be present for longer, these times are still likely to be shorter than the

Models of repopulation between cycles of chemotherapy

The simplest model for repopulation between cycles of chemotherapy assumes that a constant proportion of cells is killed with each cycle and that the rate of repopulation between treatments is constant.37 As shown in Figure 3, the overall ‘response’ to treatment will then depend on the ratio between the cell kill induced by each treatment and the rate of repopulation. If repopulation is rapid, the number of viable cells may increase, despite the cells being ‘sensitive’ to the chemotherapy. If

Possible methods for inhibiting repopulation after chemotherapy

Although we have few data on repopulation after chemotherapy, there is good reason to expect that repopulation will have a major effect on clinical outcome, and that approaches which inhibit its effect might positively alter that outcome. After chemotherapy, the pattern of repopulation is likely to be more complex than that after radiotherapy, for several reasons. First, most drugs are cytostatic as well as cytotoxic, and proliferation is likely to be inhibited for some time after treatment,

Discussion

Our inability to cure most cancers in their advanced stages, or to prevent the recurrence of many of them when detected early, is a reflection of the fundamental resistance of most solid tumours to chemotherapy. For a few malignant diseases, including testicular cancer, Hodgkin's disease, and other lymphomas, even advanced bulky disease is often curable when treated with combined chemotherapy. These tumours are very sensitive to chemotherapy and most do not express clinically relevant

Search strategy and selection criteria

Published data for this review were identified by searches of PUBMED and MEDLINE, and from references in relevant articles. All relevant English-language articles relating to the search terms: ‘chemotherapy’ and ‘repopulation’, ‘proliferation’ or ‘tumour kinetics’ have been included. Selected papers only were used to outline the experimental and clinical data in the radiation literature, which was not the main focus of this paper.

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