New targeted therapies for cancer present a significantly lower risk of severe side-effects to patients in early-phase trials than traditional chemotherapy options, a UK study suggests.

An analysis of 36 Phase I clinical trials by researchers at The Institute of Cancer Research in London and The Royal Marsden NHS Foundation Trust found the overall risk of patients experiencing a life-threatening side-effect was around seven times lower for targeted drugs than for traditional cytotoxic agents.

The study, ‘Defining the risk of toxicity in phase I oncology trials of novel molecularly targeted agents: a single centre experience’, was published in the August edition of Annals of Oncology.

Recent studies have shown that patient response rates in Phase I trials of new-generation targeted drugs are around two times higher than for old-style therapies, the researchers pointed out. Until now, though, the relative risk to patients of side-effects in early-stage trials of targeted therapies has been unclear.

Retrospective analysis

The study involved a retrospective analysis of data from 687 patients treated at the Drug Development Unit of The Institute of Cancer Research and The Royal Marsden between January 2005 and December 2009. The patients had a range of cancer types, the most common being gastrointestinal, gynaecological and sarcomas.

The overall risk to patients in the study of a Grade 4, life-threatening side-effect was 1.9%, compared with a 14% risk identified in an analysis of trials from 1991 to 2002, the researchers reported.

The risk of a Grade 3, severe, side-effect in the ICR-Royal Marsden study was 14.1%, compared with 10-36% in two previous analyses of Phase I trials with cytotoxic agents.

The toxicities most seen with targeted drugs were gastrointestinal, such as loss of appetite, diarrhoea and vomiting, as well as fatigue. With cytotoxic drugs, side-effects are generally haematological or cardiovascular in nature, the researchers noted.

Patients in the study were more likely to experience side-effects if they were given a higher dose of the drug than was later found to be optimal, or if they were sicker when they joined the trial.

Trial design

The findings should help to guide researchers in selecting patients for trials and improving trial design, the study authors said.

“The theory behind targeted drugs is that they should affect only cancer cells that have a specific fault and spare healthy cells, which we hoped would lead to higher rates of efficacy and lower rates of side-effects,” commented senior author Dr Rhoda Molife, senior investigator in Phase I clinical trials at the Drug Development Unit of The Institute of Cancer Research and The Royal Marsden.