The most commonly measured efficacy endpoints in chemotherapy trials are tumour response
rate, progression-free survival and overall survival. Of these, the most critical is overall survival.
The evidence that chemotherapy improves overall survival in advanced breast cancer is indirect but compelling. However, significant benefits seen in overall survival for one chemotherapy
regimen over another are relatively small in clinical trials. Superiority for these endpoints of one
regimen over another will also influence treatment decisions, particularly where disease is rapidly
progressing and a quick response is necessary.
Both quality of life and treatment toxicity are important factors to be considered. While toxicity
is generally well-recorded in clinical trials, quality of life is less frequently measured and the
reported analyses of quality of life data are often superficial.
A review4 of 63 trials, including over 21,000 women, identified eight trials that reported a statistically significant overall survival benefit ranging from 3-7 months (see Table 1).
Table 1. Chemotherapy trials in advanced breast cancer with an overall survival benefit (p less than 0.05)
|Trial||Arm A||Arm B||Number of patients (n)||OS Arm A (months)||OS Arm B (months)||p-value|
|Jassem 200132||Doxorubicin/ paclitaxel||FAC||267||23.3||18.3||0.01|
|Albain 200822||Paclitaxel/ gemcitabine||Paclitaxel||529||18.5||15.8||0.02|
|Bontenbal 200533||Docetaxel/ doxorubicin||FAC||216||22.6||16.2||0.02|
|Stockler 200720||Intermittent or continuous capecitabine||CMF||325||22.0||18.0||0.02|
|Icli 200535||Oral etoposide/ cisplatin||Paclitaxel||201||14.0||9.5||0.04|
Notes: OS = overall survival; FAC = 5-fluorouracil/doxorubicin/cyclophosphamide; CMF = cyclophosphamide/methotrexate/5-fluorouracil
A Cochrane meta-analysis5 found that combination chemotherapy improved tumour response rates, time to progression and overall survival, but was associated with higher rates of toxicity, compared with single-agent chemotherapy. However, very few such trials specifically compared a combination regimen with the sequential use of the component agents. In two trials10,11 that did so, differences in time to progression (after both drugs) and overall survival were not seen, suggesting that the sequential use of single agents is safe and effective in the absence of rapidly progressive disease.
Older trials36,37 have shown that lower-than-standard doses or very short durations of chemotherapy may be associated with reduced overall survival compared to standard doses. A Cochrane review38 showed that very high dose chemotherapy did not improve overall survival and a 2008 meta-analysis12 found that extending chemotherapy beyond the standard duration (18-24 weeks) had little effect on overall survival. Thus optimal overall survival is achieved when standard doses and durations of conventional drug regimens are used.
In trials published between 2000 and 2007, 22 trials4 reported statistically significant differences in progression-free survival, and 19 trials4 reported significant differences in response rate.Considered together, these trials4 showed improved progression-free survival or response rates for combinations compared with single agents, anthracyclines compared with non-anthracycline regimens, and taxanes compared with non-taxane regimens.
How best to incorporate targeted therapies into chemotherapy regimens is the subject of ongoing trials. Trials25-27, 39 testing the addition of lapatinib or bevacizumab have demonstrated some clinical benefits, but not differences in overall survival. A trial26, 27 in women with HER2-positive breast cancer that had progressed after trastuzumab, showed that the addition of lapatinib to capecitabine improved response rate and time to progression, but not overall survival, compared with capecitabine alone.
Only a third of the 63 trials4 identified in the 2000-2007 review mentioned formal quality of life measurements in the abstract. While toxicity is sometimes used as a surrogate for quality of life, two important older trials36, 37 showed that toxicity and quality of life are not always closely linked. These trials36, 37 showed that strategies to limit toxicity (by lowering either the dose or duration of chemotherapy) led to decreased quality of life.
Table 2. Common chemotherapy drugs and their side effects
Please see Statements of evidence for further evidence on adverse effects of chemotherapy drugs.
|Class/agent||Characteristic side effects of common chemotherapy drugs|
Bladder irritation, fatigue, hair loss, lowered blood counts,
Cardiac toxicity, fatigue, lowered blood counts, mouth ulcers, nausea/vomiting
Diarrhoea, fatigue, hand-foot syndrome, nausea, stomatitis
Allergic reactions paclitaxel, fatigue, hair loss, lowered blood counts, muscle aches, neurological damage
|Vinorelbine1||Fatigue, injection site pain, hair loss (moderate), lowered blood counts, neuropathy|
|Bevacizumab39||Cerebrovascular ischemia, fatigue, headache, hypertension, infection, sensory neuropathy, proteinuria|
|Lapatinib26||Diarrhoea, dyspepsia, fatigue, hand-foot syndrome, nausea/vomiting, rash|
|Trastuzumab3||Anaemia, cardiac dysfunction, infection, leukopenia, neutropenia|