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  • Review Article
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Repopulation of cancer cells during therapy: an important cause of treatment failure

Nature Reviews Cancer volume 5, pages 516–525 (2005)Cite this article

Key Points

  • The repopulation of surviving tumour cells during treatment with radiation and chemotherapy is an important cause of treatment failure.

  • The rate of repopulation often increases with time during treatment with either radiotherapy or chemotherapy.

  • Mechanisms that underlie tumour repopulation are poorly understood, but might involve the proliferation of tumour cells that are distant from blood vessels and that were destined to die in the absence of cancer treatment.

  • Prolongation of a course of fractionated radiotherapy requires a substantial increase in total dose, to counter the effects of accelerated repopulation.

  • Accelerated repopulation during successive courses of chemotherapy can lead to an initial response followed by tumour regrowth in the absence of any change in the intrinsic sensitivity of the tumour cells.

  • Accelerated radiotherapy and dose-dense chemotherapy (with support from growth factors) represent promising strategies for reducing the effects of repopulation by shortening the overall treatment time.

  • The use of molecular-targeted cytostatic agents during radiotherapy, or between courses of chemotherapy, is a promising strategy to inhibit repopulation and thereby to improve therapeutic outcome.

Abstract

Radiotherapy and chemotherapy are given in multiple doses, which are spaced out to allow the recovery of normal tissues between treatments. However, surviving cancer cells also proliferate during the intervals between treatments and this process of repopulation is an important cause of treatment failure. Strategies developed to overcome repopulation have improved clinical outcomes, and now new strategies to inhibit repopulation are emerging in parallel with advances in the understanding of underlying biological mechanisms.

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Figure 1: Survival curves and processes that influence response to radiotherapy.
Figure 2: The relationship between total dose of radiation to control 50% of oropharyngeal cancers and duration of fractionated radiotherapy.
Figure 3: Models for repopulation.
Figure 4: Model curves that illustrate the potential effects of repopulation on the total number of cells present in a tumour at different times during chemotherapy, relative to the start of treatment.

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Authors and Affiliations

  1. Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto, 610 University Avenue, Toronto, M5G 2M9, ON, Canada

    John J. Kim

  2. Department of Medical Oncology, Princess Margaret Hospital and University of Toronto, 610 University Avenue, Toronto, M5G 2M9, ON, Canada

    Ian F. Tannock

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  1. John J. Kim
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DATABASES

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breast cancer

cervical cancer

head and neck cancer

non-Hodgkin's lymphoma

non-small cell lung cancer

oesophageal cancer

oropharyngeal cancer

ovarian cancer

laryngeal Cancer

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FURTHER INFORMATION

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Radiation Therapy Oncology Group

Glossary

FRACTIONATED RADIOTHERAPY

Radiotherapy that is delivered in several discrete dose fractions. Conventional fractionation is usually delivered once daily on weekdays using a dose per fraction of either 1.8 or 2.0 Gray. In accelerated fractionation, treatment is delivered over a shorter total time as a strategy to overcome repopulation.

CLONOGENIC CELL

A tumour cell that has the ability to proliferate and produce a substantial number of progeny. Clonogenic cells are usually assayed by allowing them to form colonies. Clonogenic cells are likely to represent tumour stem cells that have the ability to regenerate the tumour and lead to death of the host.

HYPOXIC CELLS

The imperfect vasculature in solid tumours leads to the presence of tumour cells that exist in a microenvironment where the oxygen concentration is very low. Such hypoxic tumour cells are 2–3 fold less sensitive to radiation than well-oxygenated cells.

50% TUMOUR CONTROL DOSE

The dose of radiation that will lead to local control of 50% of tumours. When delivered under hypoxic conditions (to eliminate variable radio-sensitivity of tumour cells due to varying levels of oxygen), a change in the TCD50 can be used to estimate the change in the number of clonogenic tumour cells that are present.

GOMPERTZ EQUATION

An equation that has been used to fit tumour growth curves. The equation is V = V0exp(a(1–exp(–bt))) where V is tumour volume, t is time and a, b and V0 are constants. The equation describes a decreasing rate of tumour growth with increasing time, as is commonly observed.

TUMOUR SPHEROIDS

Spherical aggregates of tumour cells that can be grown in tissue culture. Spheroids retain many properties of solid tumours, including tight junctions between epithelial cells, the generation of an extracellular matrix, and gradients of nutrient concentration and proliferative rate from the outer to inner layers.

PROLIFERATIVE INDEX

The proportion of cells in a population that are identified by a marker of cell proliferation such as Ki67, or by the uptake of bromodeoxyuridine (BrdU).

CYTOSTATIC AGENT

An agent for which the principle effect is to stop cells from proliferating, rather than directly causing their death.

INTENSITY-MODULATED RADIATION THERAPY

A form of 3-dimensional conformal radiotherapy. In this advanced radiotherapy technique, multiple radiation beams of varying intensity are used to 'shape' the radiation dose to encompass specified target volumes, while limiting the dose to normal tissues.

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Kim, J., Tannock, I. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 5, 516–525 (2005). https://doi.org/10.1038/nrc1650

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