Trastuzumab (Herceptin, Roche/Genentech) in combination with chemotherapy remains the standard of care for the adjuvant treatment of HER2+ breast cancer, but there is still a question over which chemotherapy regimen is best.
The two most commonly used regimens in the United States are ACTH (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab) and TCH (docetaxel, carboplatin, and trastuzumab). No clinical trials have been designed to compare the two. However, the two chemotherapies have been compared in a real-world study by researchers at the University of North Carolina at Chapel Hill, using outcomes for patients aged 65 years and older from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database.
The study was published online July 21 in the Journal of Clinical Oncology.
In this retrospective, claims-based dataset, there were no significant differences in breast cancer–specific survival, nor in the number of serious adverse events or hospitalizations between the patients who received ACTH and those who received TCH.
However, significantly fewer women who received ACTH completed the full course of adjuvant trastuzumab therapy — 77% for ACTH vs 88% for TCH (P = .001).
There was also a change in choice of chemotherapy during recent years — ACTH usage has dropped for this older population of patients with early-stage breast cancer, from 88% in 2005 to only 15% in 2011.
Comparing ACTH and TCH in Older Women
"Although there are more and more choices for women with HER2+ breast cancer in the adjuvant setting, physicians are often faced with choosing between ACTH and TCH, two trastuzumab-based regimens that are considered standard," corresponding author Katherine E. Reeder-Hayes, MD, of the University of North Carolina at Chapel Hill, told Medscape Medical News.
"Comparative-effectiveness studies [such as this one comparing ACTH with TCH] can fill a crucial knowledge gap when clinical trial data have limited applicability to a patient population or when a comparative trial is unlikely to be conducted," Dr Reeder-Hayes and colleagues write in their discussion.
They note the difference in the patient population in their real-world study (in which 80% of the women were aged 65 to 74 years) and in previous clinical trials, in which women were on average aged 49 years, were mainly white, and had few comorbidities. In clinical trials, only approximately 15% of women were older than 60 years, and older women with cardiac conditions were excluded from these studies, the researchers note.
"Prior research has shown surprisingly low rates of adjuvant trastuzumab use among older, particularly minority women with HER2-positive breast cancer, possibly because of these data limitations," the team writes. Many of these women receive nonstandard regimens and do not complete therapy.
Approached for comment, Daniel F. Hayes, MD, Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Comprehensive Cancer Center, was not surprised with the increased uptake of TCH. "These data are consistent with good medical care for many patients in this dataset [older than 65 years]," he told Medscape Medical News.
Dr Hayes is not related to Dr Reeder-Hayes and was not associated with the study.
He explained that a number of prospective clinical studies have been directed toward reducing treatment for patients who do not need it or will not benefit from it, while ensuring that those who do need it receive appropriate therapy.
He explained that the advent of multigene panels such as Oncotype DX and similar assays has permitted identification of patients with node-negative, estrogen receptor–positive, and HER2-negative cancers, whose prognoses are so favorable that even in cases in which chemotherapy is efficacious, so few patients can benefit that, overall, the toxicities outweigh those benefits. "Thus, medical care is determined based on risk of cancer recurrence rather than just one size fits all," he said.
In light of this, from what is known from clinical studies about the reduction in risk for recurrence associated with ACTH and TCH, as well as the risk for toxicities, especially cardiac dysfunction and the risk for secondary malignancies associated with ACTH, the increased use of TCH from 2005 to 2011 is not surprising, he remarked.
He echoed what the authors note — that ACTH was approved for use in 2006 (at which time its uptake was 88%), and TCH was approved 2 years later, in 2008. "The increased use of TCH over this period is not surprising, especially after the results of the BCIRG [Breast Cancer International Research Group] 006 study," Dr Hayes said.
The BCIRG 006 study compared ACTH and TCH with the ACT chemotherapy regimen (doxorubicin + cyclophosphamide followed by docetaxel), which served as control. However, because this is the only trial with separate arms for the two regimens, clinicians looked to BCIRG 006 to provide evidence as to whether anthracyclines should be used at all for patients with HER2+ breast cancer.
There was a perception that the risk-benefit ratio favored TCH over the anthracycline-containing ACTH, Dr Hayes indicated. On the basis of this trial, the TCH regimen was approved for the adjuvant treatment of HER2+ breast cancer and became an acceptable regimen.
BCIRG 006 was not powered to show whether ACTH was better than TCH; however, there was a small difference in efficacy that favored ACTH (a 3% absolute improvement in disease-free survival through 5 years) in both node-negative and node-positive disease, Dr Hayes explained. "TCH was less effective, although not statistically significantly so, but was slightly less toxic," he said.
"The perception that TCH is as good as ACTH may not be true, since there is a numerical superiority for the latter, but, again, it is not statistically significant," he said.
However, doxorubicin (ie, an anthracycline) may be associated with greater risk when used in older patients, such as those from the SEER-Medicare database, than in younger women. Moreover, several studies have suggested that cardiac risk associated with trastuzumab, given after AC (doxorubicin + cyclophosphamide), is most common in older women. "Therefore, it is not surprising, nor inappropriate, that use of TCH is common in this age group," Dr Hayes said. He did note that that in some subsequent clinical trials, and in his own practice, cyclophosphamide has been substituted for carboplatin in combination with docetaxel and trastuzumab, which may reduce toxicities.
"It is important to use a risk-based assessment of whether to add an anthracycline to the chemotherapy regimen in these patients," Dr Hayes said. There is a perception that an anthracycline is toxic in older patients, he explained. "With many older women having preexisting heart failure or other risk factors for heart disease, such as diabetes, anthracyclines may pose a liability. But in an otherwise healthy woman, especially if she has a worse prognosis (such as positive axillary lymph nodes), I still think ACTH is a preferred regimen," he told Medscape Medical News.
The real-world study conducted by Dr Reeder-Hayes and colleagues searched the Medicare database and identified women for whom there was a claim for trastuzumab within 1 year of their diagnosis, who had undergone cancer surgery within 6 months of diagnosis, and who did not receive neoadjuvant therapy. Chemotherapy-related toxicities were identified from inpatient and outpatient claims within 6 months of beginning chemotherapy.
The full cohort analysis included 1077 women (ACTH: 365; TCH: 712). To reduce bias, the researchers used propensity score matching, a statistical method that matches a patient from one cohort with a corresponding patient in the second cohort on the basis of pretreatment characteristics. Factors in matching included demographic information and disease stage characteristics. After propensity score matching, the study population was reduced to 208 women in each group.
Data for the propensity score–matched cohort were commensurate with those reported for the full cohort. For the full study cohort, neutropenia (57% vs 45%) and anemia (59% vs 46%) were significant for ACTH vs TCH but not for the propensity-matched cohort. Similarly, the incidence for heart failure was numerically higher but was not statistically significant for ACTH (7.2% vs 3.9%). Fewer than 1% of patients in each cohort had claims related to postchemotherapy acute myeloid leukemia.
For the overall cohort, hospital stays related to adverse events were also similar between the groups (21% for ACTH vs 24% for TCH). Hospital services that included emergency visits and observation visits were also similar (34% for ACTH vs 36.5% for TCH).
The difference in 5-year overall survival was not significant between the two cohorts: 88% for ACTH vs 93% for TCH. For the matched subset, a similar finding was reported (90% for ACTH vs 92% for TCH). Five-year breast cancer–specific survival was also similar between the two groups: 90% for ACTH vs 96% for TCH. For the matched subset, corresponding rates were 92% and 96%, respectively. When analysis took into consideration patients who had completed trastuzumab therapy, there was no significant difference between the ACTH and TCH groups.