G Thomas Budd, MD
Staff Physician, Department of Hematology/Oncology Director, Medical Oncology Breast Cancer Program Director, Cancer Center Chemoprevention Program Associate Program Director, Experimental Therapeutics Taussig Cancer Center Cleveland Clinic Foundation

Edited comments by Dr Budd

SWOG-S0221: A new Phase III adjuvant Intergroup trial evaluating chemotherapy schedules

In SWOG-S0221, the combination dose-dense arm of CALGB-9741 was selected for the initial randomization instead of the sequential arm. Our rationale was to shorten the duration of treatment and to make it more comparable to the AC regimen in the experimental arm.

In the second randomization, we were originally going to compare docetaxel alone to docetaxel plus capecitabine. There were a couple of reasons we decided to compare paclitaxel every two weeks to paclitaxel every week. First, the docetaxel/capecitabine combination is being investigated in several other multicenter adjuvant trials.

Second, it was felt that we should preserve the control arm from CALGB- 9741, which administered paclitaxel every two weeks. At the end of SWOGS0221, we hope we will know the optimal way to administer paclitaxel in the adjuvant setting.

SWOG-SO221: Rationale for daily oral cyclophosphamide

Daily oral cyclophosphamide seems to be superior. In the metastatic setting, an EORTC trial comparing intravenous CMF to a regimen with oral cyclophosphamide found the oral cyclophosphamide regimen — the so-called “classical” regimen — to be superior. Furthermore, in the adjuvant trials comparing CAF and CMF regimens, only when cyclophosphamide is given in the same way — either both arms receive intravenous or oral cyclophosphamide — is there a difference seen with the addition of the anthracycline.

Why does the oral method of administration seem to be superior? One reason could be dose density — you deliver more milligrams in per unit time. By giving cyclophosphamide orally and doxorubicin weekly, the dose density in terms of mg/m2 per week compared to the accelerated regimen, at least for doxorubicin, is not necessarily superior but is denser. Bob Livingston sometimes calls this the “dense and denser” protocol, because we are giving what we believe to be an effective dose of an anthracycline on a more frequent schedule.

Metronomic chemotherapy

The third way of looking at this is the concept of metronomic chemotherapy, which suggests that more frequent drug administration at lower doses — sometimes even very low doses — might actually be superior to higher doses given less frequently. It appears that this advantage is based upon the antiangiogenic effects of the chemotherapy. Giving a low dose of chemotherapy frequently appears to optimize its antiangiogenic effects.

A number of preclinical models have evaluated this concept. When cyclophosphamide-resistant cell lines are put into animals and the animals are given cyclophosphamide on an infrequent bolus schedule, responses are rarely seen. However, if cyclophosphamide is given frequently (every six days) at a lower dose, responses may occur. In these animal models, the results appear to be due to the antiangiogenic effects. This metronomic schedule seems to be optimal for the addition of other antiangiogenic factors.

Some clinical studies also support the concept of metronomic chemotherapy. If you look back at the old Cooper regimen (CMFVP), maybe that was the secret to its efficacy. In Europe, there was a very interesting trial involving patients with refractory advanced breast cancer who were treated with very low doses of cyclophosphamide and very low doses of weekly methotrexate, and some responses were observed. These clinical studies offer evidence suggesting that there might be something to this concept.

It could be argued that another mechanism of action for these regimens is that daily oral cyclophosphamide is more likely to induce ovarian dysfunction. I think, however, that chemotherapy has cytotoxic effects in and of itself. Part of the effect of chemotherapy in premenopausal women may be related to its effects on ovarian function, but it’s certainly not the whole story.

SWOG-S0221: Use of growth factor support

Pegfilgrastim is used in the dose-dense arm of the new SWOG-S0221 trial because it certainly makes the regimen more acceptable to patients. Looking at the time course to recovery of neutropenia, it appears that administration every 14 days is possible. There are anecdotal results indicating this is quite tolerable.

Initially, filgrastim will be used in the experimental arm of weekly doxorubicin and daily oral cyclophosphamide. At the University of Washington, pilot studies are being performed to evaluate pegfilgrastim with this regimen. If those studies show that this combination is safe, as expected, then we hope to amend the protocol and use pegfilgrastim in both arms of the study.

Results of CALGB-9741 trial

CALGB-9741 is a very interesting and provocative study, particularly the 31 percent relative reduction in mortality. However, the results are preliminary because it is very early in follow-up. At least in the first few years, the results should be stable. Dr Piccart's accompanying editorial was intriguing and laid the groundwork for the trial we are launching.

Also, it was of interest that in CALGB-9741, there was no clear difference between patients with ER-positive and ER-negative disease. I feel comfortable offering this every-two-week regimen to patients with ER-positive or ER-negative disease.

It is also interesting that these were not new agents being studied in CALGB-9741. There is a lot to be learned using currently available agents, and we can continue to take incremental steps in treating breast cancer.

Impact of CALGB-9741 on clinical practice and ongoing trials

On the practice level, physicians have been quite willing to adopt dose-dense regimens, partly because there is no increase in toxicity. In fact, in terms of neutropenic fever or documented myelosuppression, the every-two-week regimen is less toxic. More transfusions are required, but this is something we can deal with if we monitor counts and start replacement therapy with erythropoietic agents.

In terms of ongoing Phase III studies, the trials that I see in need of modification are N9831 and other trastuzumab trials. If a patient was randomized to the standard arm of doxorubicin/cyclophosphamide given every three weeks and followed by a taxane, there would be a nagging concern that the patient was not receiving optimal therapy. I think there has to be strong consideration made to amend those trials.

Managing patients with node-positive breast cancer

In the nonprotocol setting, I feel obligated to discuss the results from CALGB-9741 with patients who have positive nodes. After discussing the fact that these were very early results but perhaps relevant to a particular patient’s care, I have treated some patients at high risk with this dose-dense regimen.

I also discuss standard treatment options, including the combination of doxorubicin and cyclophosphamide followed by a taxane, although I also discuss CAF-type regimens

Case discussion: Dose-dense chemotherapy for locally advanced disease

This is a very intelligent woman in her late 40s, in whom locally advanced breast cancer developed over a period of time. She was quite panicked and very anxious to begin therapy, but at the same time quite fearful of starting treatment. She was on vacation when she first noticed the tumor, so there was a delay in seeking medical care, and naturally she was quite concerned about the possible result of this delay.

On physical examination, she had a breast mass on the left side that was about 8-cm. There was some erythema over the tumor, although it was not a true inflammatory breast cancer. There was palpable adenopathy, which was not fixed. I think it was a relatively rapidly growing tumor, but perhaps not the most aggressive that I’ve seen. The hormone receptor and the HER2 status are currently pending.

I wanted to start her on treatment, but the locally advanced study at our institution was not open. I discussed a variety of treatment options with her. In my mind, the standard treatment is an anthracycline-containing regimen, and I believe a taxane should generally be used.

I presented the every-two-week doxorubicin/cyclophosphamide regimen as an option, believing we could generalize the results from CALGB-9741 to her situation. We reached a mutual decision to embark on that regimen and, as part of that, she is receiving pegfilgrastim.

A week after starting treatment, her tumor already seems to be responding and surgery is planned. I had discussed giving her doxorubicin/ cyclophosphamide for four cycles followed by a taxane, which can be given preoperatively or postoperatively. If an extensive reconstruction (i.e., a TRAM reconstruction) is planned, there may be advantages to giving the taxane prior to surgery, so there’s no delay in administering the taxane.

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