Doxorubicin‐based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma

Abstract

Background

Considerable controversy exists as to whether any benefit of doxorubicin‐based combination chemotherapy outweighs increased toxic effects, inconvenience, and additional costs, compared to single‐agent doxorubicin. There is substantial variation in clinical practice in the treatment of patients with locally advanced and metastatic soft tissue sarcoma (STS).

Objectives

To determine:- 1) the effect, if any on response rate or survival, by using doxorubicin‐based combination chemotherapy compared with single‐agent doxorubicin for the treatment of patients with incurable locally advanced or metastatic STS- 2)if combination chemotherapy is associated with increased adverse effects compared with single‐agent doxorubicin in this setting.

Search methods

We searched CENTRAL (Cochrane Library, issue 4, 2002), MEDLINE (1966 to October 2002), CANCER LIT (1975 to October 2002), reference lists, the Physician Data Query (PDQ) clinical trials database, and the American Society of Clinical Oncology (ASCO) Annual Meeting Proceedings (1995 to 2002).

Selection criteria

Randomized controlled trials (RCTs) comparing single‐agent doxorubicin with doxorubicin‐based combination chemotherapy in adults with locally advanced or metastatic STS requiring palliative chemotherapy. Abstracts and full reports published in English were eligible.

Data collection and analysis

Data were abstracted and assessed by two reviewers. Response and survival data were pooled. Data on adverse effects was tabulated.

Main results

Data on 2281 participants from eight RCTs were available from reports of single‐agent doxorubicin versus doxorubicin‐based combination chemotherapy. Meta‐analysis using the fixed effect model detected a higher tumour response rate with combination chemotherapy compared with single‐agent chemotherapy (odds ratio [OR= 1.29; 95% confidence interval [CI], 1.03 to 1.60; p = 0.03), but the OR from a pooled analysis using the random effects model and the same data did not achieve statistical significance (OR= 1.26; 95% CI, 0.96 to 1.67; p = 0.10). No significant difference between the two regimens was detected in the pooled one‐year mortality rate (OR = 0.87; 95% CI, 0.73 to 1.05; p=0.14) or two‐year mortality rate (OR = 0.84; 95% CI, 0.67 to 1.06; p=0.13) (N=2097). Although reporting of adverse effects was limited and inconsistent among trials (making pooling of data for this outcome impossible), adverse effects such as nausea/vomiting and hematologic toxic effects were consistently reported as being worse with combination chemotherapy across the eight eligible studies.

Authors' conclusions

Compared to single‐agent doxorubicin, the combination chemotherapy regimens evaluated, given in conventional doses, produced only marginal increases in response rates, at the expense of increased toxic effects and with no improvements in overall survival.

Author(s)

Vivien Bramwell, Dale Anderson, Manya Charette,  

Abstract

Plain language summary

Additional chemotherapy with doxorubicin marginally improves tumour response but increases side effects with no improvement in survival

Doxorubicin is commonly used as palliative chemotherapy for patients with advanced or metastatic soft tissue sarcoma (cancer of muscle/tendon/fat/blood vessel). This review was conducted to find out if combining doxorubicin with other drugs is more effective than doxorubicin alone. Eight studies were considered together, which showed if combination chemotherapy is given: (1) tumour shrinkage was marginally better than in patients treated with doxorubicin alone; (2) survival was no different; and (3) side effects were worse than for patients treated with doxorubicin alone

Author(s)

Vivien Bramwell, Dale Anderson, Manya Charette,  

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Combinations of the known active drugs used at conventional doses can produce marginal increases in response rate in advanced metastatic soft tissue sarcoma, at the expense of increased adverse effects, but do not significantly increase survival rates. Thus, the results of this review favour the use of single‐agent doxorubicin for palliative treatment of advanced/metastatic soft tissue sarcoma.

Implications for research 

Future randomized clinical trials should compare new regimens, whose activity has been established in single‐arm studies, with single agent doxorubicin. Future trials should include quality of life as an outcome measure.

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