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More frequently than not, the use of only one anticancer drug is insufficient to obtain recovery or even a long-term clinical response. The rapid appearance of cancer cell resistance (cf. following pages) will result in treatment failure.

The simultaneous use of several drugs can offer an improved therapeutic index based on:

• the use of molecules with different action mechanisms;
  
• occasionally, a genuine synergy between drug families,
  
• furthermore, different toxicities which might allow an increase in dose intensity without proportionate increase in toxicity.

Increasing activity

Such increased activity is easy to demonstrate in vitro or in vivo in animal studies. In a clinical setting, randomised controlled studies are often necessary to objectively demonstrate the superiority of an association to the use of one solitary drug.

For instance, in ovarian carcinoma, it could be established that a higher response rate can be obtained by associating paclitaxel to cisplatin than by treating the patient with cisplatin alone.

New therapeutic associations are proposed based on previous experimental studies:

• Firstly, one drug is tested and proven to be active against a tumour: the drug is chosen because of its experimental in vitro or in vivo results using animals bearing experimental tumours or after systematically conducted Phase II studies.

• Drugs are then associated according to their action mechanisms which are presumed to provoke added or synergetic effect For instance, a topoisomerase inhibitor will be associated with an alkylating (classical association of VP-16 and cisplatin): thus the lesions induced by the alkylating drug (which are more important if it is a double strand alkylating agent) will not be repaired because of topoisomerase impairment. Thus, drug resistance could be avoided or at least delayed.

• Metabolic competitions between two drugs should also be avoided (for instance, there is no point in associating two alkylating agents),

• Similarly, drugs with cross resistance mechanisms (topic dealt with later), either spontaneously or after first-line chemotherapy, should not be combined.

Synchronisation and recruitment

Some cytotoxics (for instance mitotic spindle poison) specifically block the cell cycle of cancer cells (but also of normal cells) at a given time in the cycle. All cells then progress together towards the following cycle in a synchronous manner.

Thus, it should theoretically be possible to act with a second antimitotic phase dependent to which the cells are now more sensitive.

However, in daily practice, this synchronising effect is far less important than when observed in vitro or experimentally. Furthermore, synchronisation also affects healthy cells with an increased risk of excessive bone marrow toxicity.

Non addition of toxic effects

The combination of two drugs is also of interest if their toxicities are not cumulated (or only to a lesser extent):

• For instance we endeavour not to prescribe cytotoxic drugs with the same acute toxicity (for instance two highly emetic drugs or two neurotoxic drugs).
  
• We try to associate only slightly aplastic drugs (such as 5-FU or cisplatin) with more myelotoxic drugs (such as alkylating agents or anthracyclins).
  
• We try to avoid the simultaneous prescription of drugs with elimination metabolisms (thus avoiding two nephrotoxic products or requiring major hydration).
  
• The other drugs administered to the patient and whose combined toxicity might be increased (for instance nephrotoxic antibiotics and simultaneous cisplatin, modification of the metabolism of anticancer drugs by enzymatic inducers such as neuroleptic drugs, addition of ototoxicity of cisplatin and aminoside antibiotics).

Beneficial association

The benefit of polychemotherapy has been demonstrated for almost every type of cancer. Certain very well-known protocols are used on a daily basis.

It can be noted that certain protocols have been elaborated more or less empirically and do not respect all of the 'rules' proposed above.