The incidence of cardiotoxicity was increased when trastuzumab was used in combination with anthracyclines. The BCIRG-006 trial compared three chemotherapy regimens: doxorubicin, cyclophosphamide and docetaxel (AC-T), ACT plus trastuzumab (ACT-H), and docetaxel, carboplatin plus trastuzumab (TCH) for the treatment of HER-2-positive breast cancer. In this trial, both trastuzumab -containing regimens (ACT-H and TCH) were superior to ACT and similar to each other in terms of cancer efficacy. Importantly, TCH was associated with significantly less asymptomatic cardiotoxicity (> 10% decline in EF 9.4% vs. 18.6%; p < 0.001) and a lower incidence of symptomatic heart failure (0.4% vs. 2%;p < 0.001) than ACTH. In our study, the incidence of symptomatic cardiotoxicity of ACTH treatment was 32%, which was more than that of TCH treatment. Additionally, in our study, the patients who had undergone ACTH treatment were also administered dexrazoxane, which is an effective iron chelator that reduces oxygen free radical production when administered with anthracyclines. Swain and colleagues evaluated the data from three prospective studies to determine both the incidence of doxorubicin-related congestive heart failure CHF and the accumulated dose of doxorubicin at which CHF occurred. The patients who received dexrazoxane had a significantly decreased incidence of cardiac events (defined as a decline from baseline LVEF ≥20%, decline in LVEF ≥ 10% from baseline and < lower limit of normal, or symptomatic CHF) compared with placebo. Furthermore, they showed that dexrazoxane was cardioprotective even when it was given after patients had already received 300 mg/m2 of anthracyclines. In our study, we found that with both ACTH and TCH treatment, none of the patients developed CHF. The cause may be related to the drug conferring a protective effect on the patients’ hearts. However, the FDA currently limits the use of dexrazoxane in women with metastatic breast cancer who need > 300 mg/m2 of anthracyclines. Due to concerns regarding decreased tumor response rates, increased myelosuppression and an increased incidence of the development of delayed hematologic malignancies, the routine use of dexrazoxane was not recommended in patients receiving anthraczycline therapy. We had consulted many references concerning dexrazoxane. A subsequent Cochrane meta-analysis had shown no difference in the oncologic response rates or incidence of secondary malignancies between patients receiving chemotherapy with or without dexrazoxane. In this study, 28% of patients treated with the AC-TH regimen had febrile neutropenia, while the percent of febrile neutropenia was 6% in the TCH groups.
Re-evaluation of the cost effectiveness of the ACTH in the adjuvant treatment of breast cancer was timely given the emergence of TCH as a more effective option than the previous standard and significant changes in the relative costs of ACTH. For the first time, to our knowledge, the current economic analysis directly compared the cost effectiveness of ACTH and TCH in the adjuvant treatment of early breast cancer.
The results showed that TCH was likely to be a cost-effective option compared with ACTH, with ICERs less than $US 52,568 per QALY gained. While there was no set cost-effectiveness threshold in China, the ICERs were below the threshold based on the GDP per capita (approximately $US 34,240 in 2015). Thus, based on this model, TCH would be the preferred option if the health system was willing to pay the additional cost to benefit from the additional health gain. Indeed, our analysis showed that, at WTP thresholds above $US 20,000 per QALY gained, TCH would have a greater probability of producing a more favorable NMB than ACTH. However, if the WTP threshold was less than this, ACTH would be preferred.
However, to our knowledge, no other cost-effectiveness analysis has directly compared different trastuzumab regimens, and the finding that TCH was cost effective compared with ACTH was not surprising. Jitawatanarat et al. evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor-2 (HER2)-positive breast cancer and compared the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (ACTH) and docetaxel, carboplatin, and trastuzumab (TCaH). TCyH was well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab-containing regimens when both were evaluated against non-taxane regimens.
Untch et al. evaluated the efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer. Thirty-nine percent of the 217 enrolled patients achieved a pCR. The three-year disease-free survival (DFS) was 88% in patients with pCR compared with 73% in patients without pCR (P = 0.01). The three-year overall survival (OS) was 96% in patients with pCR compared with 86% in patients without pCR (P = 0.025). Forty-eight recurrences were reported during a median follow up of 41 months corresponding to an estimated 3-year disease-free survival rate of 77.9%.Twenty-three deaths were reported during post treatment observation, corresponding to an estimated 3-year OS rate of 89.4%. Based on the results of the joint analysis of B-31 and NCCTG N9831, this benefit was considerable. At 4 years, the estimated absolute improvement in disease-free survival is 18% (85% minus 67%; 95% CI, 13–24%), and for overall survival, the benefit was 4.8% (91.4% minus 86.6%; 95% CI, 0.6–9.0%).
Kolberg et al. collected data from adjuvant trials and had shown that the combination of docetaxel, carboplatin and weekly trastuzumab (TCH) was well tolerated and as effective as anthracycline-containing regimens. After a median follow up of 48.5 months, the disease-free survival (DFS) was 84.6%, the distant disease-free survival (DDFS) was 87.2%, and the overall survival (OS) was 91%. Bayraktar et al. evaluated the pathologic complete response (pCR) rates and relapse-free survival (RFS) and overall survival (OS) of patients receiving neoadjuvant systemic therapy (NST) with trastuzumab in combination with an anthracycline- or a non-anthracycline-based regimen. The pCR rates were 60.6% and 43.3% for patients who received PH-FECH (n = 235) and TCH (n = 65), respectively (P = 0.016). The three-year RFS rates were 93% and 71% (P < 0.001), and the 3-years OS rates were 96% and 86% (P = 0.008) for patients who received PH-FECH and TCH, respectively. Patients who received PH-FECH had a lower risk of recurrence (hazard ratio [HR]: 0.27; 95% CI: 0.12–0.60; P = 0.001) and death (HR: 0.37; 95% CI: 0.12–1.13; P = 0.08) than those treated with TCH. Chen et al. observed the efficacy of neoadjuvant trastuzumab combined with docetaxel and carboplatin (TCH), and docetaxel, epirubicin and cyclophosphamide (TEC) chemotherapy in human epidermal growth factor receptor2 (HER-2)-overexpressing breast cancer. The TCH group comprised 39 patients, and the TEC group comprised 25 patients. Neoadjuvant chemotherapy was continued for six cycles prior to comparison of the treatment efficacy.
Study strengths and limitations
1) In this study, it was assumed that the transfer probability of the Markov model did not change during the study period. However, in the actual treatment process, the transfer probability between different states changed with time.
2) The incidence of adverse reactions in different disease states of breast cancer was different, and the incidence of adverse reactions generally changed with time. The clinical truth data relied on by this study only provided the incidence of adverse reactions in the entire treatment group without providing the incidence of adverse reactions in different disease states.
3) Due to the lack of research results on the health utility of different states of breast cancer in China, this study adopted the results of Ward et al.