Chemotherapy: Picking a Regimen

(In my case, ACTH, TCH, or clinical trial?)

The choice of which chemotherapy regimen to take was a very difficult one for me, because all options carry risks.  Unfortunately, clinical medicine can be more of an art than a science- ultimately it comes down to personal preference which option is the best.

Phase 1: Surgery

I have Stage 1B triple-positive (ER+/PR+/Her2+) invasive intraductal carcinoma, grade 3. My tumor strongly expresses all three receptors. I was tested for both BRACA1&2, as well as the BART rearrangement; all were negative. Had I been BRACA-positive, given the risk of recurrent or secondary breast cancer, my plan was to opt for a double mastectomy with reconstruction, however, as I was BRACA-negative, I chose to opt for a lumpectomy with radiation. I love my breasts, and, as lumpectomy plus radiation, if anything, has better long-term outcomes than mastectomy. Additional studies have similarly found no benefit of mastectomy versus lumpectomy plus radiation, even in younger patients. Furthermore, lumpectomy is associated with better long-term quality of life and lower rates of loss of sexual desire than mastectomy (I am a young married woman in a healthy, happy marriage. I want to keep it that way!). So, given no survival benefit to mastectomy and clear upsides to lumpectomy, I opted for lumpectomy.

Phase 2: Chemotherapy 

Given my age, my stage of disease, and the characteristics of the tumor, I was given the choice of either ACTH (adriamycin/cytoxan/taxol/herceptin) or TCH (taxotere/carboplatin/herceptin). While the jury is still out, there appears to be perhaps a slight advantage to ACTH in terms of breast-cancer recurrence (this is not statistically significant, even among patients with more advanced disease than I). Unfortunately, the ACTH also comes with an increased risk of heart failure and leukemia. These risks also do not take into account the subtle heart disease that may occur with adriamycin; we simply do not have enough long-term data to answer that question.

Cardiac Outcomes with Adriamycin and Herceptin

There is clearly an increased risk of heart failure with the combination of adriamycin and herceptin. Typically, this risk is quoted as a 4% rate of heart failure, however, may be higher, particularly in older populations and patients with pre-exisiting hypertension. Herceptin alone carries some risk, however, the cardiotoxicity associated with herceptin is primarily reversible.

In addition, these numbers do not take into account subtle changes in cardiac function that are of undetermined clinical significance. In other words, a large proportion of patients who receive adriamycin experience a decrease in the output (known medically as the "ejection fraction") of their left heart. This decrease in functioning may have no clinical significance, or may manifest as a problem many years down the line. The key point is that there is clearly a change, and there is simply not enough data to determine if this change will have an effect on quality or quantity of life down the road-- cardiovascular disease remains the number one killer of women, which may be why more recent data suggests that drinking alcohol after a breast cancer diagnosis may actually be associated with decreases in mortality, despite a trend toward an increase in breast cancer recurrence.

Another consideration is that, while there may be a slight advantage to ACTH versus TCH in terms of breast-cancer survival in clinical trials, in real-world practice, due to the combined cardiac toxicities of ACTH versus TCH, patients with ACTH are less likely to receive 12 months of herceptin, and longer duration of herceptin therapy is associated with improved outcomes.

Calculating the Risk-Benefit Profile of TCH versus ATCH for me: A Basic Clinical Decision Analysis

Each phase of breast cancer treatment is associated with some reduction in recurrence. Below is a rough estimate of the benefits of each therapy, with some risk of harm included. Note that I am including in this rough decision analysis a potential benefit to ACTH in terms of breast cancer recurrence, even though clinical trials have shown no difference between the two groups. This effectively biases the analysis in favor of ACTH. I did not include the risk of heart failure for herceptin alone (0.5%) because this risk is the same in both the TCH and ACTH arm, and thus falls out of the analysis.

Tamoxifen: 50% risk reduction
Herceptin: 40% risk reduction
ACTH: 30% risk reduction
TCH: 25% risk reduction

So, let's start with a 25% risk of recurrence prior to starting any treatment...

... With tamoxifen: 12.5%
... Adding herceptin: 7.5%
... With ACTH chemotherapy regimen: 5.25%
... With TCH regimen: 5.63%

Now including the other potential harms of treatment:

ACTH: 1-8% risk of heart failure (this risk is regardless of risk of breast cancer recurrence, and is higher in patients with pre-exisiting hypertension)
ATCH: 0.1% risk of leukemia

ACTH: 5.25% risk of breast cancer recurrence + 1% risk of heart failure + 0.1% risk leukemia = 6.35% total risk adverse outcome

TCH: 5.63% risk of breast cancer recurrence + 0% risk of heart failure + 0.1% risk leukemia = 5.63% total risk adverse outcome

So, in this case, the risk of harms other than breast cancer tip the optimal risk-benefit profile in the favor of TCH. If the risk of breast cancer recurrence were higher, assuming that ACTH is, in fact, more effective against breast cancer than TCH, then the optimal choice of chemotherapy regimen would change.

Note that I did not model all types of risk-- just major ones (ie, I only included heart failure, not subtle changes in cardiac function). I also weighted breast cancer recurrence, heart failure, and leukemia all as equally "bad" adverse outcomes, which is probably not fair (leukemia should probably be weighted much, much more strongly).

My choice

By now (even if you have read no other part of this blog), you have probably figured out that I chose TCH. There is no statistical benefit to ACTH, and clear harms (in terms of cardiac toxicity, long-term quality of life, and leukemia).

My parents had a really, really hard time with this decision. They felt strongly-- and put a lot of pressure on me-- to opt for ACTH, because they were/ are both scared out of their minds about my diagnosis.

My take on it is this: Why would I ever take a definite harm for a probable no-benefit? Simply put, that would be insane. Had my risk of breast cancer recurrence been higher, I would have had a really hard time with this decision. But any conceivable benefit of ACTH in my case is outweighed by its definite harms.

Patients, in general, tend to over-estimate known risks and tend to under-estimate risks that are unknown. In my opinion, picking ACTH is favoring fear of a known risk (ie, breast cancer recurrence) over unknown risks (ie, leukemia and heart failure). As a physician, I assure you, there are far worse things than breast cancer recurrence (and immediate, treatment-refractory leukemia certainly applies. Heart failure is also no cake walk).

Ultimately, picking a chemotherapy regimen comes down to a question of personal preference and weighing risks. If you are in the unfortunate situation of having to chose, think about what scares you the most and how you want to live your life.... After breast cancer. I want to be able to climb Mount Kilimanjaro with my husband-- and I sleep at night knowing that my heart is in good enough shape that I still might be able to.

A Foot Note on Clinical trials

I did consider two clinical trials, and had I been a good candidate for either one, I was leaning toward participating. The first trial is comparing adding a second monoclonal antibody to herceptin plus chemotherapy. Pertuzumab has been shown to prolong survival in the metastastic setting. I was put on the wait list for this trial, however, given my nodal status was considered on the border of being "too low risk," the wait list was very long, and I did not want to delay treatment for months only not to be enrolled (initiating adjuvant therapy longer than 12 weeks post-surgery is associated with worse outcomes).

The second trial, the ATEMPT trial, is a Phase II trial comparing taxol/herceptin to a kadcyla, a novel "smart bomb" that was recently found to improve disease-free progression in the metastatic setting, but data in the adjuvant setting are limited. I was strongly leaning toward joining the trial, but when the tumor board* recommended against it, I decided to go with a standard regimen. At the 11th hour, some members of the tumor board did reverse their original position, but, at that point, I had long accepted losing my hair and did not want to delay treatment any further.

*Tumor board is a group of physicians, typically consisting of some combination of oncologists, pathologists, radiologists, radiation oncologists, and surgeons who discuss clinical cases and attempt to come to a consensus decision for the best treatment course for an individual patient.