Controversies in Chemotherapy as presented at the SABCS 2009
January 4, 2010 by Vicki Tashman
Controversies in Adjuvant Chemotherapy
Are there groups of patients who don't benefit from chemotherapy?
Presented by Peter Ravdin, MD, PhD
What are the best and most highly effective chemotherapy regimens?
Presented by Eric Winer, MD
Many women diagnosed with Breast Cancer undergo adjuvant chemotherapy as part of their treatment plan. With today's medical advancements however, a number of questions have arisen: do some of these women need chemotherapy at all? Do all women receive the same protective benefits from chemotherapy? And, once the decision to have chemotherapy has been made, what are the best and most highly effective regimens?
Dr. Peter Ravdin spoke about the benefits some women achieve when including adjuvant chemotherapy in their treatment plan. The patient and the doctor base this decision on three things: tumor prognosis, treatment efficacy and the patient's health and comorbidity.
The doctor can use the National Comprehensive Cancer Network's (NCCN) classical and genomic guidelines in determining the risk or benefit of chemotherapy. Using the genomic guidelines, the NCCN recommends ER positive patients with a high or interim recurrence score* (RS) and at least a stage 1b tumor or larger to have a benefit with chemotherapy. The classic guidelines suggest, however, that any ER positive, stage 1c tumor or larger will have a benefit with chemotherapy. These recommendations apply to node negative disease only. Dr. Ravdin also mentioned that in these intermediate scored patients, the cut-off for unacceptable mortality after 10 years without adjuvant chemotherapy is about 5-10%. Therefore, the doctor can look at the treatment efficacy and the patient's overall health to further his decision.
In order to determine the efficacy of chemotherapy, Dr. Ravdin looked at the results from the EBCCTG trial. In older ER+ women, early polychemotherapy regimens resulted in a low amount of benefit, whereas the other groups resulted in a modest amount of benefit. This trial did not include complex anthracyclines and taxanes as well as patients older than 69 years and patients with comorbidities as part of the study.
Dr. Ravdin then refined these results by using the STEPP analysis and the IBCSG IX trials and found no inherent benefit to using CMF chemotherapy and Tamoxifen versus Tamoxifen alone for ER+ women with node negative disease. He continued by stating the results of C9344 trial using AC +/- Paclitaxel as there is no benefit if the patient is ER+ and Her2-. He simplified the view of molecular profiling by stating that all subtypes** of BC have a benefit to chemotherapy except Luminal A, ER+ with low proliferation markers.
Patient Health and Comorbidity
The doctor must evaluate the patient's overall health and comorbidity risks as part of the determination of whether or not to include chemotherapy in the treatment plan. In the CALGB trial in node positive BC, use of Anthracycline resulted in a higher mortality for women over 65 years old. But, it's uncertain if we have to worry about long term toxicity for older patients. The doctor must consider the psychological state of the older patient, her life expectancy at the time and her chance of mortality due to other causes.
In summary, Dr. Ravdin explained that if the prognosis is excellent (any stage 1 ER+, node negative, luminal A), the tumor has a low RS score and the patient has no comorbidity or limited remaining life expectancy, the projected benefit to using chemotherapy would be small. But, of course, the doctor's and patient's opinions need to be taken into consideration as well.
Dr. Winer continued with a discussion about the current chemotherapy regimens available and which regimens are most highly effective. He started his talk by revealing the results of an Oxford Overview Study in 2000. Essentially, women aged 50-69 showed no marked overall survival (OS) benefit when using chemotherapy in node negative or node positive BC. In younger women (<50) there was a slight difference in benefit in node negative BC and a more marked benefit in node positive BC. But the greatest benefit occurred in Her2+ and Triple Negative diseases. But, the decision to include chemotherapy in the treatment plan has been made. Now the doctor must take into consideration the disease subtype, regimen-related toxicities and disease burden in order to get the most favorable therapeutic regimen.
We have a number of choices available to us today. These include traditional CMF, Anthracycline with and without taxanes both sequential and concurrent, and non-Anthracycline regimens. When determining whether or not to use an Anthracycline based regimen, Dr. Winer looked at the cardiac toxicity in a study by Milvia Zambetti as published in the Journal of Clinical Oncology. It states that in patients treated with CMF alone, 2% showed a cardiac effect versus 8% when Anthracycline was included. And, when analyzing SEER Medical Data, women 66-70 yrs old who were treated with Anthracyclines had significantly higher rates of congestive heart failure.
Dr. Winer continued by discussing the use of Taxanes, which has become standard over the past decade. So, the question became, "do you administer a Taxane concurrently, sequentially or to replace the Anthracycline?" He presented evidence that sequential treatment is better than concurrent treatment in disease free survival. However, he also quoted from another study that the TC regimen (a Taxane combined with Cisplatin) represents an acceptable alternative to including Anthracycline, but should not be viewed as equivalent to a sequential Antracycline-Taxane regimen.
In discussing the disease subtypes, Dr. Winer stated that at present, for Her2- but high risk patients, there are no alternatives to an Anthracycline/Taxane regimen. For Triple negative disease with high risk either node negative or positive, it's beneficial to use a sequential Anthracycline/Taxane regimen. And many women with ER+ and Her2- disease should not receive adjuvant chemotherapy, except those with a high grade, high recurrence score or luminal B qualities. In Her2+ disease, studies showed that the AC-TH regimen (AC followed by Taxane and Herceptin) was equivalent to TCH.
In Summary, Dr. Winer stated that we need subtype specific trials that address clinical and biologic principles, including targeted therapies. Mandatory tissue collection is critical and the doctor must consider the disease burden when making their decision of which chemotherapy regimen to use.
*RS is determined by the Oncotype testing using the following scoring model:
Low Risk - <11
Intermediate Risk -11-25
High Risk - >25
** BC subtypes are Luminal A and B, Her2+ or -, Basal profile