Combined Modality Treatment

Rationale

This section is based on Chapter 18 from the 4th edition of Basic Clinical Radiobiology (Gregoire V and Baumann M)

There are several reasons to consider delivering chemotherapy with radiation:

Spatial Co-operation

Spatial co-operation refers to using chemotherapy and radiotherapy to target different anatomical sites. This can either be:

  • Radiotherapy treating the main bulk of tumour with chemotherapy to treat widespread disease
    • For example, this is the goal of adjuvant chemotherapy in breast cancer, with radiation and surgery acting as local treatment.
  • Chemotherapy treating the main bulk of tumour, with radiotherapy reserved for sanctuary sites.
    • Example: Treatment of the central nervous system in patients with leukaemia following chemotherapy ablation of the tumour cells in the rest of the body
  • A combination of the above
    • In small cell lung cancer, radiotherapy may be used to treat the bulky intrathoracic disease in combination with chemotherapy. Chemotherapy is used to kill microscopic disease. Radiotherapy is then used for prophylactic cranial irradiation, as the brain is a sentry site for small cell lung cancer.

When a combination of chemotherapy and radiotherapy is used for spatial co-operation, treatment is often given separately to avoid the increased toxicity seen with concurrent treatments.

Independent Cell Kill

In some situations, the toxicity of single agent therapy is too high. It is sometimes possible to use a smaller dose of two modalities to accomplish the same clinical benefit, while minimising toxicity.

  • For example, in Hodgkin's Disease, the use of radiotherapy or chemotherapy alone is often associated with unacceptable late effects. By combining the two treatments, the risk of late effects is reduced.

If the action of the two agents is additive but not supra-additive, they should be separated in time to prevent combination of their toxicity.

Synergy

Some chemotherapy agents enhance the effect of radiation.

  • Cisplatin causes interstrand and intrastrand crosslinks, interfering with double strand break repair and enhancing the effect of radiotherapy because of this
  • 5-fluorouracil and gemcitabine impair normal repair mechanisms by reducing the availability of normal nucleotides. This prevents cells from repairing DNA damage induced by radiation
  • Agents which are active in S-phase (generally the most radioresistant phase) may kill the cells that are relatively invulnerable to radiation
  • Bleomycin is an antibiotic based molecule that binds to DNA and causes single strand breaks. It is strongly synergistic with radiation, particularly in the lung where the threshold dose for pulmonary fibrosis falls significantly if these two drugs are administered concurrently.

These agents must be given with radiation in order to see synergy; if they are given before (neo-adjuvantly or induction) or after (adjuvant) then minimal synergy is seen. Care must be taken to avoid excessive normal tissue side effects (see hazards of combined modality treatment)

Mechanisms for Synergy

Inhibition of DNA repair

Some chemotherapy agents may impair DNA repair, either by reducing the availability of nucleosides (nucleoside analogues) or by causing structual damage near the DNA break (cisplatin).

Enhancement of DNA damage

Some compounds may be incorporated into DNA and enhance the effect of radiation. These are not in common use.

Cell cycle synchronisation

Chemotherapeutic agents that act in a certain part of the cell cycle may cause the remaining cells to be at a sensitive phase some point in the future. As this can not be predicted with current technology, this mechanism of synergy is not available.

Apoptosis

By increasing the likelihood that a cell may undergo apoptosis (more commonly seen in normal cells following radiation) chemical agents may be able to increase the cell kill of malignant cells. Targets for these agents would be inhibitors of BCL2 or promoters of BAX or the BH3-only family.

Reoxygenation

It is thought that chemotherapeutic agents may cause increased oxygenation of tumours, allowing radiotherapy to have an increased effect in the normally hypoxic parts of the tumour mass. This is not used clinically in the present day.

Inhibition of cell proliferation

By prevent cells from repopulating between fractions, chemotherapy may be able to reduce the cell survival that occurs due to the interfraction interval. This effect is proposed for numerous chemotherapeutic agents. It may also be useful to counter the accelerated repopulation seen in some squamous cell carcinomas (H&N, cervix).

Sequencing

Radiotherapy and chemotherapy can be delivered in three possible ways:

  • Chemotherapy followed by radiotherapy (eg. induction chemotherapy, radiotherpy to sanctuary sites after radical chemotherapy)
  • Concurrent chemoradiotherapy
  • Radiotherapy followed by chemotherapy (eg. adjuvant chemotherapy)

The choice depends on the type of tumour and the goals of each treatment.

  • The treatment most likely to influence overall outcome is generally delivered first
    • For example, in small cell cancer of the lung, chemotherapy is the most important treatment in overall disease control. Therefore it is started first while radiotherapy is held back for several cycles.
    • Another example would be adjuvant chemotherapy following treatment for glioblastoma multiforme. Evidence suggests that radiotherapy is an important early treatment whereas tamsulosin is more effective in the long term setting.
    • In breast carcinoma requiring chemotherapy, radiotherapy is usually delayed until after the chemotherapy has finished. The rationale for this method is that the surgery has provided some local control, and that distant disease is usually more of a long term problem. Radiotherapy to the breast can wait until distant disease has been dealth with.
  • Induction of accelerated repopulation must be avoided
    • Induction chemotherapy studies have generally been disappointing, possibly due to chemotherapy initiating the accelerated repopulation response.

Consequences

See Hazards of Combined Modality Treatment