Edith Perez, MD
Professor of Medicine Mayo Medical School Chair, NCCTG Breast Cancer Committee

Edited comments by Dr Perez

NCCTG-983252: Randomized Phase II trial comparing two schedules of paclitaxel, carboplatin and trastuzumab

We compared a weekly schedule to a once-every-three-week schedule of paclitaxel, carboplatin and trastuzumab in patients with HER2-positive metastatic breast cancer. Tolerability was much better for the weekly schedule. Although I thought this would be the case, I was surprised how great the tolerability was for the weekly regimen. Essentially, there was no significant toxicity and the activity was very high.

Our trial fits in very well following Nick Robert’s data demonstrating the benefits of adding carboplatin to paclitaxel and trastuzumab, administered once every three weeks.

We will present our results at ASCO 2003. The target accrual for our study was 92 patients, and we will report data on approximately 75 percent of these patients. Because we found the weekly schedule to be better tolerated, after a certain number of patients enrolled, we actually closed the once-every-threeweek arm and continued accrual only to the weekly regimen.

For the weekly schedule, we administered paclitaxel three out of four weeks. I believe it is critically important to take that fourth week off of chemotherapy to really optimize tolerability.

In both arms, we administered the chemotherapy concurrently with trastuzumab for the first six months. Then at the six-month point, we discontinued the chemotherapy and continued trastuzumab alone — trying to maximize the activity of the interaction of the three drugs while ameliorating long-term toxicities.

NCCTG-N9932: Phase II docetaxel and carboplatin trial

We submitted to ASCO 2003 the results from our Phase II trial evaluating docetaxel and carboplatin, administered every three weeks, as first-line therapy in patients with metastatic breast cancer. There were various reasons for conducting this trial. First was the activity of docetaxel. Second was the desire to test the other taxane, and we were the first cooperative group in the United States to test paclitaxel and carboplatin. Third were data from the UCLA group and the BCIRG evaluating docetaxel, carboplatin and trastuzumab, but there was no solid data for the chemotherapy alone.

Treatment was continued until progression or toxicity. The study demonstrated that the activity was very comparable to the activity for paclitaxel and carboplatin. Slightly more myelosuppression occurred because we did not use prophylactic growth factor support — although it was allowed. There was very little peripheral neuropathy.

Clinical trials of epidermal growth factor receptor (EGFR) inhibitors

We are developing new trials to address the issue of anti-EGFR therapy in patients with metastatic disease. There has been some preclinical, initial Phase I and Phase II data demonstrating that there is indeed activity for these drugs. We are going to conduct a trial evaluating gemcitabine in combination with OSI-774, also known as erlotinib, in patients with refractory breast cancer.

Within the NCCTG and the rest of the breast Intergroup, we are also developing a large first-line trial, which will take a few months to be activated, exploring gefitinib (Iressa®). We plan to manage patients initially with chemotherapy consisting of docetaxel and capecitabine. Patients who have at least disease stabilization will be randomized to receive gefitinib or placebo. We are exploring the potential for this targeted therapy to maintain the response seen with initial chemotherapy.

Recently, we’ve seen some exciting results in terms of survival with the docetaxel/ capecitabine combination, and we are actually planning to utilize a slightly modified schedule from the one published by Dr O’Shaughnessy. Although this regimen is very appealing, the issue of toxicity has prevented many physicians from incorporating it into their practices. Since that initial study, other analyses have documented that we can start with lower doses of the chemotherapy drugs. That is why we want to incorporate the combination in this new clinical trial.

Sequential single-agent versus combination chemotherapy in metastatic disease

I’m really happy Dr Sledge published the data from ECOG-1193, because I believe it will dispel a number of myths. For example, there is a myth that combination chemotherapy is more toxic and leads to a worse quality of life than single-agent chemotherapy.

In patients eligible to receive first-line chemotherapy for metastatic breast cancer, ECOG-1193 demonstrated that the combination of paclitaxel concurrent with doxorubicin led to a better response rate and time to progression with a similar quality of life and survival compared to a sequential taxane and anthracycline regimen. This study supports the use of combination therapy, because those patients had a higher possibility of responding and living longer without disease progression and without an adverse effect on quality of life.

In my practice, if a patient has a good performance status and symptoms from the malignancy, it makes sense to ameliorate the symptoms from the tumor as soon as possible, while really paying attention to tolerability. That’s where there is a big difference between using good combination chemotherapy and highdose chemotherapy with transplant, because the latter approach led to high response rates with significant toxicity.

I believe single-agent chemotherapy is also a very good option for the patient who is relatively asymptomatic and doesn’t have rapid disease progression or visceral crisis. It’s not that I use combination chemotherapy for all patients or that I insist on single-agent sequential therapy; however, we are planning to do a study to address this in patients with refractory disease.

Combining capecitabine and irinotecan in patients with metastatic breast cancer

We conducted a large, multi-institutional, community-based, randomized Phase II trial that clearly demonstrated the activity of irinotecan. In a subset of patients with prior exposure to both anthracyclines and taxanes, the response rate for weekly irinotecan was 27 percent.

We plan to build on these data and the experiences with capecitabine in the advanced breast cancer setting. We don’t yet know anything about the combination of capecitabine and irinotecan in patients with breast cancer, but that’s one of the arms we will use in our Phase III trial. We will randomize patients with disease that is refractory to anthracyclines and taxanes to combination or sequential therapy with capecitabine and irinotecan. We will focus on time to progression as the main endpoint, while evaluating quality of life.

I feel that the gastrointestinal toxicity may be somewhat lower with irinotecan in breast cancer patients compared to colorectal cancer patients. There are several reasons for that: (1) patients with colorectal cancer — at least most of the time — have had surgery on the gastrointestinal tract and that may have an impact on irinotecan’s tolerability, and (2) in the colorectal trials, irinotecan is typically combined with 5-fluorouracil, which can also enhance toxicity. We are taking a different approach in the breast cancer trials by evaluating irinotecan alone or in combination with capecitabine.

Fulvestrant in the metastatic setting

We have had an interest in fulvestrant at the Mayo Clinic and in the NCCTG for many years. We participated in one of the pivotal trials conducted in the United States, which was eventually published by Dr Osborne in the Journal of Clinical Oncology.

Fulvestrant is a very well-tolerated drug. It provides an alternative to oral therapy, which could be very important for patients who have difficulty remembering to take tablets on a daily basis or patients who do not have prescription coverage for oral medications.

In patients with estrogen receptor-positive metastatic breast cancer who have had prior exposure to tamoxifen and aromatase inhibitors, we have been conducting a Phase II trial, through the NCCTG, evaluating the activity and tolerability of fulvestrant. Our accrual is going very well. Activity has been clearly demonstrated, and we have not had any problems with hot flashes.

Data was presented at the San Antonio Breast Cancer Symposium by another group demonstrating the feasibility and activity of fulvestrant after aromatase inhibitors. Hopefully, this larger clinical trial will corroborate the activity of fulvestrant in this patient population.

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