1. Goodwin, Peter M.

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AMSTERDAM, Netherlands-A meta-analysis of the MIG1 and GIM2 phase III studies has confirmed the superiority of dose-dense chemotherapy as compared to standard interval regimens in premenopausal patients with breast cancer at higher risk of relapse without increasing the risk of developing treatment-induced amenorrhea in findings reported at the 10th European Breast Cancer Conference (Abstract 5).

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"Dose-dense adjuvant chemotherapy in premenopausal patients with breast cancer is associated with significantly improved overall survival," said lead author Matteo Lambertini, MD, a Resident in Medical Oncology at IRCCS AOU San Martino-IST Hospital and the National Institute for Cancer Research, Genoa, Italy.


And he told OT that the results confirm its use should be implemented in Europe, as it is in the U.S. "We think that dose-dense chemotherapy should be considered the preferred treatment option in this specific subgroup of premenopausal patients-especially because premenopausal patients are known to develop more aggressive subtypes of breast cancer and are more sensitive to chemotherapy," he said.


In addition, Lambertini explained that subgroup analyses indicate that dose-dense chemotherapy also benefits other women in the overall population with high-risk disease irrespective of their age.

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"We believe that high-risk patients-those with node positive disease or with high-risk node negative disease-should be considered [for] the use of dose-dense chemotherapy," he said, adding this was particularly true for young patients.


Large Data Set

A total of 1,549 patients were included in the pooled analysis: 528 out of 1,214 from the MIG1 study and 1,021 out of 2,091 from the GIM2 study. Median age was 44.1 years.


In the MIG1 study patients with node-positive or high-risk node-negative breast cancer were randomized to receive six cycles of fluorouracil, epirubicin, and cyclophosphamide every two weeks (dose dense) or every three weeks (standard intensity).


The GIM2 study randomized patients with node-positive early breast cancer to receive four cycles of dose-dense or standard interval epirubicin plus cyclophosphamide-with or without fluorouracil -followed by four cycles of dose-dense or standard interval paclitaxel.


Treatment-induced amenorrhea was defined as the absence of menses after three months beyond the end of chemotherapy in the MIG1 study and 12 months after in the GIM2 study.


The pooled data on pre-menopausal patients showed a significant improvement in 10-year overall survival-increased by nearly a third (29%): a hazard ratio of 0.71.


Lambertini reported a larger benefit for hormone receptor-negative breast cancer-an improvement in 10-year overall survival of 35 percent compared with an improvement of 22 percent in those with hormone receptor negative tumours: hazard ratios of 0.565 and 0.78, respectively.


There were no significant changes in rates of treatment-induced amenorrhea between the dose-dense and standard-interval treatments. And amenorrhea did not affect survival. The study found no significant differences in overall survival between patients who developed treatment-induced amenorrhea and those who did not.


Lambertini told OT that they conducted the investigation because the most recent St. Gallen consensus meeting recommended no standard treatment for early premenopausal breast cancer in young women of reproductive age. "Treatment-induced amenorrhea is a negative quality-of-life issue so we wanted to look at the efficacy of dose-dense chemotherapy in this specific subgroup of patients and to evaluate the impact of dose-dense chemotherapy on the risk of developing amenorrhea-one of the worst side effects for a young patient with breast cancer," he said.


When he was asked whether the data are changing practice, he said yes, especially because it will be very difficult to conduct other phases III studies to look at the same question.


Fatima Cardoso, MD, Director of the Breast Unit at the Champalimaud Clinical Centre, Lisbon, Portugal, and Chair of EBCC-10, agreed. "This meta-analysis has the potential to change and improve the treatment of breast cancer in premenopausal patients without increasing their risks of treatment-induced amenorrhea, as well as showing a survival benefit," she said.


Emiel J.T. Rutgers, MD, PhD, Surgical Oncologist and Department Head at the Netherlands Cancer Institute in Amsterdam, thought international practice needed to embrace dose-dense therapy. "To me, it should be taken into the standard of care in young women with high-risk breast cancer," he told OT. He said there is now sufficient data to validate the use of dose-dense therapy, that it takes less time to give and is very manageable.


"We use it in our institute," Rutgers added. And he was convinced the option of using it should be discussed with women who are candidates for adjuvant systemic treatment because of the higher risk they face of distant disease later on.


In an interview for OT, Karen Gelmon, MD, Professor of Medicine at the University of British Columbia and Medical Oncologist at the BC Cancer Agency, Vancouver, said she was pleased to see the present convergence of European and North American practice on this issue-more than 10 years since investigators from Memorial Sloan Kettering Cancer Center found that dose-dense treatment was more efficacious and not as toxic as giving it every three weeks.


"These studies really do show that dose dense is better and is not toxic and is probably the way that we should be doing it internationally," she said.


Gelmon added that the cost implications are minimal. "It's the same number of chemotherapies-just given more frequently, she said, and many patients already get cytokine support."


But she was impressed by the potential psychological and practical advantages for patients. "For the woman, getting her adjuvant therapy dose sooner may give cost benefits. It may mean that she can get back to work or start feeling better sooner," Gelmon said, noting that she had been a firm believer in dose-dense chemotherapy for a long time. "I'm very pleased to see further data that supports that."


Peter M. Goodwin is a contributing writer.