MILAN – A systematic review of 11 trials involving 2,269 women supports the common American practice of prolonging first-line chemotherapy in metastatic breast cancer until disease progression.
Dr. Alessandra Gennari
Longer chemotherapy duration was associated with a 36% reduction in the risk of progression (hazard ratio, 0.64; P less than .001,) and a 9% reduction in the risk of death (HR, 0.91; P = .04), lead author Dr. Alessandra Gennari reported at the annual congress of the European Society for Medical Oncology.
In subgroup analyses, the effect of longer chemotherapy was independent of time of randomization (either before or after induction chemotherapy), trial design (same vs. different maintenance), duration of chemotherapy in the control arm (fewer than six cycles vs. six or more cycles), and concomitant endocrine therapy (yes or no).
“In a pragmatic way, these results support the clinical approach of prolonging first-line chemotherapy in the absence of significant toxicity and disease progression,” said Dr. Gennari of the Galliera Hospital in Genoa, Italy.
Despite many years of research, the optimal length of first-line chemotherapy is still a matter of debate among clinical oncologists. Although many American clinicians administer first-line chemotherapy in metastatic breast disease until progression, chemotherapy in Europe is often given for a predetermined number of cycles, with duration dictated by treatment response, tolerability, and physician preference, Dr. Gennari explained during a press briefing at the meeting.
The National Comprehensive Cancer Network guidelines for metastatic breast cancer also state that “due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.”
“The first question that all patients with metastatic disease ask is not ‘How [long] will I live?’ but ‘How many cycles of chemotherapy will I receive?’?” she told reporters. “It should be clear that today the best answer is ‘As long as you can, because this means you will remain free of disease and possibly live longer.’?”
The meta-analysis included 11 trials conducted between 1987 and 2010, of which 10 were published in peer-reviewed journals.
Invited discussant Dr. Miguel Martin said the meta-analysis features trials with very different designs and strategies, and he questioned whether the standard arms would be considered standard today since, for example, six used different anthracycline combinations and three used only three to four cycles of chemotherapy. He also suggested there could be a potential literature bias since many negative trials are rejected or never submitted for publication, and that trial registration at Web sites such as clinicaltrials.gov started only in 1997.
“Even considering all the mentioned caveats, this Italian study provides support for the administration of chemotherapy until disease progression,” said Dr. Martin of the Hospital General Universitario Gregorio Marañón in Madrid.
Assuming that the median overall survival of metastatic breast cancer after first-line chemotherapy is 24 months, he said that longer chemotherapy is associated with an absolute improvement in median progression-free survival of around 3 months and an absolute increase in overall survival of around 2 months.
“Do more prolonged side effects justify a gain of 3 months of progression-free survival and 2 months for overall survival? I guess that most patients would accept that in exchange for more toxicity,” Dr. Martin said.
Dr. Gennari said that several open questions remain, including what the optimal maintenance chemotherapy is and whether oncologists should maintain patients on the same drugs or give planned sequences using different single agents. Also unclear is the role for prolonged low-dose maintenance therapy and what the optimal association of chemotherapy is with targeted agents such as anti-HER2 and antiangiogenesis therapies.
The Italian Association for Cancer Research supported the trial. Dr. Gennari and her colleagues disclosed no conflicts of interest. Dr. Martin disclosed no conflicts.