MIAMI BEACH—It has been just over a decade since Larry Norton, MD, was honored with the David A. Karnofsky award by the American Society of Clinical Oncology, given “in recognition of innovative clinical research and developments that have changed the way oncologists think about the general practice of oncology.” At the time it was called “sweet vindication” for Norton, now Deputy Physician-in-Chief for Breast Cancer Programs and Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center (MSKCC), for his then radical concept of applying mathematics to cancer biology.
Dose-dense administration of cytotoxic chemotherapy to optimize adjuvant chemotherapy is a practical application of the concept championed by Norton.
Clifford A. Hudis, MD, Chief of the Breast Medicine Service at MSKCC, a speaker here at the Miami Breast Cancer Conference, said the practice of dose-dense chemotherapy is alive and well. In fact, he emphasized that it appears to provide a better baseline platform for the addition of targeted therapies than standard treatment scheduling.
Dose-dense scheduling of chemotherapy refers to the use of optimal standard doses administered more frequently, often with the aid of growth-factor support. The simplest idea about dose-dense therapy is that more frequent or dense dosing will decrease the time for tumor growth; it will allow for ever more treatment of ever smaller volumes of residual tumor; and it results in greater overall cell-kill.
Delving into the history of dose-dense scheduling, Hudis said the practice-changing trial was CALGB 9741 (JCO 2003;10:1431-1439). Hudis, who was an investigator on this trial, said this was key in the acceptance of dose-dense chemotherapy because it was positive, and well controlled.
The trial compared concurrent AC (doxorubicin-cyclophosphamide) versus sequential A then C, and in both cases paclitaxel was given as a single agent. Using a two-by-two factorial design, the other comparison was every-three-week therapy versus every-two-week, thus requiring colony stimulating factor support.
“What made this a test of dose density was that every single patient got the exact same total dose, the exact same number of doses of each drug, and the exact same dose sizes. So the variable was schedule or sequential versus concurrent dosing.”
This study was positive when first reported, he said, and it remains that way through a 10-year follow-up, showing that every-two-week dosing is superior to every-three-week, and that was true for overall survival as well.
“This was a trial that fundamentally made dose-dense therapy a standard option,” Hudis said. Six years later, a clinical trial of dose-dense AC plus targeted therapy with trastuzumab (JCO 2009;36:6117-6123) brought a pleasant surprise concerning cardiac toxicity with the dose-dense schedule—a rate of approximately two percent—in line, he said, with what would be expected with doxorubicin.
“Notwithstanding everybody's a priori bias that it must be more toxic, these data suggest that it is not more dangerous in terms of cardiac toxicity.”
Subsequent trials at MSKCC have highlighted a secondary benefit of the dose-dense platform: that alternative or additional targeted therapies such as trastuzumab or lapatinib can be added.
Six Cycles Not Superior to Four
Hudis described a more recent study, CALGB 40101 (JCO 2012;33:4071-4076), also a two-by-two factorial design, that asked two questions:
- “First, in low-risk breast cancer, using every two-week scheduling and filgrastim support, do we need the anthracycline-cyclophosphamide combination, or would single-agent paclitaxel do the job in these low-risk patients?” and
- “Secondly, would six cycles of therapy be better than four?”
The answer was that there was no difference whatsoever in progression-free survival or overall survival between six cycles and four.
Similarly, single-agent paclitaxel was not non-inferior.
“I'm sorry for the double-negative, but from a statistical design point of view, that's the way this study was set up,” Hudis said. “The practical take-home message is, don't use single-agent paclitaxel in the adjuvant setting, it really doesn't do the job. You need AC here.”
Hudis said he was not arguing the need for combination therapy, though: “What I'm arguing is that for low-risk breast cancer in the adjuvant setting, you do need more than one chemotherapy drug for chemo-sensitive tumors.”
Even shorter intervals have been tried in pilot studies. The MSKCC 03-092 trial (Clin Cancer Res 2007;13:223-227) looked at 10- or 11-day intervals, using epirubicin and cyclophosphamide followed by paclitaxel, with filgrastim support (not pegylated). This approach was feasible, Hudis said.
Then, clinicians in the Memorial network tested the CMF regimen (cyclophosphamide-methotrexate-fluorouracil) in a dose-dense schedule. That trial, MSKCC pilot study 07-0133, “made IV-CMF into a more dose-dense regimen for convenience, if nothing else,” he said.
“Indeed, we were able to deliver this at 14 days, and then we could even deliver it at 10- or 11-day intervals, all of which was possible” (Clin Breast Cancer 2010;6:440-444).
‘Remains a Standard’
Hudis said that fundamentally, the test of time for dose-dense therapy is that it remains a standard in the administration of chemotherapy: “It's clearly important at the extremes—if you don't give your chemotherapy at a frequent enough interval, you lose efficacy.
“And it is also less or equally toxic—not more toxic—than standard scheduling. That's one of the long-standing myths about dose-dense scheduling that is hard to overcome.
“You clearly need to use supportive care and growth factors to do [dose-dense scheduling],” Hudis concluded, “But then this allows you to deliver more effective chemo.”