Survival analysis using Kaplan-Meier method aims to look at the survival of patients with survival percentage parameters. The results of the observations were plotted on the survival curve. The log-rank test was performed after the Kaplan-Meier survival curve results were established to compare whether there was a difference between the survival curves of the two groups of regimens. In addition, an analysis was carried out on factors that were assumed to affect survival. Side effects that occured during the course of a patient undergoing chemotherapy treatment were treated descriptively.
The one-year and two-year survival percentages of anthracycline-taxane based combinations were 93.6% and taxane-based 83.3% (p > 0.05). Based on these data, taxane-anthracycline based combination regimens have a greater probability of survival than taxane-based, but not statistically significant. This is similar to a meta-analysis study by Zheng et al., (2015), which compared the benefits of using a combination of anthracyclines along with taxanes versus a single agent-based chemotherapy regimen. The results showed that chemotherapy with a combination of anthracycline and taxane did not significantly improve OS of breast cancer patients when compared to OS achieved using taxane or anthracycline single agents (Zheng et al., 2015).
Several other studies compared combination versus taxane-based regimens in breast cancer patients. Caparica et al. (2018), in their systematic review and meta-analysis study comparing taxan-based regimens versus anthracycline- and taxane (AT) -based regimens in the treatment of breast cancer. Overall, no difference was observed between taxane-based and AT regimens against OS (HR 1.05; 95% CI 0.90–1.22). The incidence of nausea, vomiting, mucositis and thrombocytopenia significantly occurred in the combination regimen (Caparica et al., 2018).
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2023), noted that no significant reduction in the risk of recurrence was found for taxane and anthracycline administration when compared to docetaxel plus cyclophosphamide (RR 0.94; 0.83—1.06; p = 0.30). Therefore, the results of this study have shown the same results as previous studies. A meta-analysis of EBCTCG showed that anthracycline-containing and taxane-containing chemotherapy reduced the 10-year mortality rate of breast cancer by about a third. Four doses of anthracycline followed by four doses of docetaxel were as effective as the same drug combination, six times TAC but had different toxicity patterns. TAC requires granulocyte support due to high rates of neutropenic fever (Harbeck & Gnant, 2017).
Taxans (paclitaxel and docetaxel) work by inhibiting microtubule dynamics that form microtubule polymerization as well as inhibiting depolymerization and resulting in cell cycle termination in G2 and M phases leading to cancer cell death (Basuki et al., 2020; Hassanzadeh et al., 2018). Paclitaxel and docetaxel are administered intravenously. Taxanes are metabolized by P450 in the liver with > 90% bound to plasma proteins. About 70% − 80% of the drug is excreted through the feces, while through the kidneys a relatively small less than 10% (Chu & Devita, 2019).
The cytotoxic mechanism of anthracycline works by causing damage to the cell's DNA. Two major mechanisms are involved in anthracycline's toxic effects on cells. The anthracycline compound has a structure that allows it to fit into the DNA strand by interacting non-covalently resulting in anthracyclines being intercalated between DNA base pairs. This leads to disruption of the process of cell DNA synthesis. In addition anthracycline inhibits topoisomerase, which is an enzyme that opens the double strand of DNA in order for it to be replicated and synthesized. By disrupting the function of topoisomerase, anthracycline causes the cessation of cell growth and leads to apoptosis. Anthracyclines also form free radicals (ROS) that can cause single- and double-stranded DNA damage (Geisberg & Sawyer, 2010).
The structure of anthracyclines is formed from anthraquinones bound to aminoglycosides (Corremans et al., 2018). Anthracycline is administered intravenously because it has low intestinal solubility and permeability and a high intestinal first-pass effect (Lee et al., 2023). About 75–80% of anthracyclines and their metabolites are bound to plasma proteins. Anthracycline is metabolized in the liver to active metabolites. About 40–50% excretion is through the fecal with less than 10% by the kidneys. Anthracycline has a higher risk of cardiotoxicity in patients > 70 years of age, in patients with a history of hypertension or heart disease. This is largely due to the mechanism of doxorubicin free radical formation (Chu & Devita, 2019). The main mechanism of doxorubicin cardiotoxicity is the increased oxidative stress shown from increased reactive oxygen levels of the species and lipid peroxidation (Chatterjee et al., 2010).
Further analysis was performed on the Cox proportional hazard regression test to determine the factors that affect the survival of breast cancer patients. Bivariate analysis shows that stage factors, presence of comorbidies/complications and chemotherapy delay of > 14 days may affect survival. Simultaneous multivariate analysis showed that the stage factor increased the risk nine times based on the hazard ratio obtained from the Cox regression test (HR 9.602; 95% CI 1.602–57.536; p = 0.013). 2-year survival in stage I and stage II patients reached 100%, stage III 97.4% and stage IV 45.5%. Another significant factor in the multivariate analysis was that chemotherapy delay increased 5-fold the risk of survival (HR 5.576; 95% CI 1.16–27.850; p = 0.036). The probability of survival in the group of patients without delay of chemotherapy (< 14 days) was 96.5% while in the group > 14 days it was 64.3%.
This shows that increased stages can affect survival probability as in Alkabban & Ferguson (2022), stated that stage 0 and stage I had a 5-year survival rate of 100%. The 5-year survival rate for stage II and stage III breast cancer was approximately 93% and 72%, respectively. Systemic or stage IV spread of cancer caused the prognosis to deteriorate to 22% for 5-year survival. An estimated 20–30% of early-stage breast cancers metastasized to an advanced stage. A total of 6–10% of women with breast cancer in the United States was found to have stage IV disease at diagnosis (Wang et al., 2019). Early detection efforts were very important because if breast cancer could be detected at an early stage and treated appropriately, the cure rate was quite high (80–90%). Early detection of breast cancer aims to detect and identify the presence of breast cancer early, so that patients receive therapy with a greater chance of cure (Kemenkes, 2013).
Modification of the chemotherapy schedule increases the duration between cycles of chemotherapy, which consequently reduces the intensity of the treatment dose. Cytotoxic antitumor activity depends on the drug used and on the schedule of drug administration. Based on previous studies, cumulative delays of ≥ 14 days significantly increased mortality by 2.56 times (HR 2.56; p = 0.030) (Gunasekaran et al., 2020). Another study reported a delay variable in the administration of anthracycline-based chemotherapy with the number of days of delay of more than 14 days or a delay in two cycles of chemotherapy can have a lower probability of survival without recurrence of the disease for ten years (Chirivella et al., 2009). Hence, the duration of delay between cycles should be reduced whenever possible in order to achieve maximum chemotherapy benefits (Chirivella, 2009; Gunasekaran et al., 2020).
The results of multivariate cox regression analysis showed that comorbidities/complications were not a significant factor affecting survival. Comorbid is a condition accompanied by other systemic diseases or complications of breast cancer that spreads to other organs. These results are in line with studies by Netchuta et al showing that none of the comorbidities (comorbidities) studied (hypertension, chronic gastritis, diabetes mellitus, chronic bronchitis/asthma, CHD, stroke, chronic hepatitis and rheumatoid arthritis) significantly affect the risk of breast cancer recurrence (Netchuta et al., 2013).
Tests on age factors, and characteristics of ER/PR and HER-2 showed no significant differences in bivariate and multivariate assays. This indicates that these variables were not statistically significant. A study by Mirsyad et al. (2022), breast cancer patients at Makassar Ibnu Sina Hospital showed that there was no significant relationship between patient age and clinical stage level (p > 0.05). Patients' awareness of early examination/early detection also influences the patient's cancer stage (Mirsyad et al., 2022).
The characteristics of ER/PR and HER-2 were carried out through medical records. Estrogen receptors or progesterone receptors are proteins found on the surface of breast cancer cells. When estrogen or progesterone binds to its receptors, this can activate signaling pathways that promote breast cancer cell growth (Oza & Ma, 2017, Hart et al., 2020; Li et al., 2022). ER/PR positive cancer cells are sensitive to the presence of the hormones estrogen and progesterone. Cancer cells of this type are sensitive to hormonal therapy and have better cure rates compared to cancer cells that have neither estrogen receptors nor progesterone receptors (Kristian & Sandhika, 2021). Breast cancer cells with a positive HER-2 test result will be sensitive to anti-HER-2 monoclonal antibody therapy. In addition, it also has a high cell proliferation rate so that the cancer is more sensitive to chemotherapy (Kristian & Sandhika, 2021; Wawruszak et al., 2021).
A study by Kristian & Sandhika (2021), concluded that the increased degree of differentiation in cancer cells (grade) would be followed by a decrease in estrogen receptors and progesterone receptors in cancer cells, but there was no correlation between HER-2 examination results and the degree of histological differentiation of breast cancer cells. This shows that lower grade cancer cells have properties that are more similar to normal cells: they have estrogen and progesterone receptors and thus have lower cell growth rates compared to higher grade breast cancers that lose estrogen and progesterone receptors. HER-2 having no correlation with the degree of histological differentiation of cancer cells means that HER-2 can be possessed by breast cancer cells with varying degrees of malignancy (Kristian & Sandhika, 2021).
In addition to factors that affect survival, the presence of incidences or events of adverse events is also an important factor affecting the quality of life of patients undergoing chemotherapy (Matwin et al., 2021). In this study, due to the limited number of samples, there was no further statistical analysis could be performed. However, the data were descriptively processed to see the mean and day range of chemotherapy delays in breast cancer patients receiving anthracycline-taxane-based combination regimens and those receiving taxane-based regimens.
The most common side effects judging by the percentage incidence of anthracycline-taxane-based combination regimens were nausea, vomiting (34%), diarrhea (29.55%), tingling (22.73%), fever (18.18%), and dizziness (13.64%). The use of the taxane-based regimen hasd almost the same side effects as the combination regimen, most of which included diarrhea (41.67%), tingling (33.33%), nausea vomiting (25%), fever (16.67%), neutropenia (8.33%). These results are in line with studies from Capatirca et al., (2018) which concluded emesis/vomiting, mucositis and thrombocytopenia were significantly more frequent with anthracycline alongside taxanes. The effects of fatigue and nausea were the most frequently reported nonhematologic toxicities in the first cycle (Gadisa et al., 2020). The same results were shown by the meta-analysis study of Zheng et al. (2015), which stated that taxane-based regimens had lower side effects in the form of neutropenia, infection/fever, nausea, and vomiting, but higher for hand-foot syndrome and diarrhea.
In general, all chemotherapy drugs are at risk of causing nausea/vomiting, as they can damage the gastrointestinal tract and cause enterochromaffin cells present in the digestive tract especially in the small intestine to release nerve signals through the release of neurotransmitters, namely serotonin (5-HT). These neurotransmitters then activate the afferent fibers of the sarafvagus by binding to 5-HT3 receptors which then stimulate the dorsal complex of the vagus nerve, the chemoreceptor trigger zone, to trigger the motor response of nausea and vomiting (Kholida et al., 2020).
Diarrhea was the most common side effect found with the use of taxane-based regimens. The cytotoxic mechanism of paclitaxel stabilized the polymer structure of microtubules and inhibits depolymerization of microtubules back to tubulin. This process inhibited free tubulin and created an inefficient array of irregular microtubules for cell replication, thereby blocking mitosis. The toxic effect of paclitaxel was most pronounced on tissues with rapid cell turnover, including hematopoietic, lymphatic, gastrointestinal (GI), and reproductive tissues, as well as tissues affected by alopecia. Studies had identified neutropenia, neuropathy, mucositis, asymptomatic bradycardia, myalgia, arthralgia and diarrhea as major side effects of paclitaxel therapy (Ismail & Killeen, 2023).
The side effects experienced by the patient became one of the causes of the delay until the discontinuation of the patient's chemotherapy which would have an impact on the progression of the disease. Additionally, observation of adverse events was important in improving the patient's quality of life making it necessary to monitor and alert pharmacists to these ESO events.
The limitation in this study is to analyze the short-term viability (1 year and 2 years) only due to limitations in the study period. The next study is expected to analyze the medium term (3 years) and long-term (5 years) survival of breast cancer patients. In addition, other studies related to the cost aspects of treatment and observations on combinations of other types of therapy are needed so that comprehensive treatment results can be achieved. Addressing the side effects of therapy also improves quality of life, so further research is expected to focus on post-chemotherapy side effects of breast cancer.