|Year : 2015 | Volume
| Issue : 3 | Page : 612-616
Neoadjuvant chemotherapy in patients with locally advanced breast cancer: A pilot-observational study
Hardik G Dodiya, Alay P Brahmbhatt, Priyanka K Khatri, Ashish M Kaushal, DG Vijay
Department of Clinical Research and Development, Aastha Oncology Associates, HCG-Medisurge Hospitals Private Limited, Ahmedabad, Gujarat, India
|Date of Web Publication||9-Oct-2015|
Hardik G Dodiya
Department of Clinical Research and Development, Aastha Oncology Associates, HCG-Medisurge Hospitals Private Limited, Ahmedabad - 380 006, Gujarat
Source of Support: None, Conflict of Interest: None
Background: Locally advanced breast cancer (LABC) remains major clinical issue with regard to selection and duration of therapy since many years. Neoadjuvant chemotherapy (NACT) is multimodality program, established to treat LABC. Many research tasks are ongoing to develop specific neoadjuvant chemotherapy regimen with specific duration to improve long-term control of LABC.
Patients and Methods: Forty-seven patients diagnosed with LABC were Included and analyzed to compare the outcomes [pathological complete response (pCR), clinical response, overall response rate (ORR), disease control rate, overall survival and progression-free survival]. These patients treated with either combination of anthracycline and taxane-based chemotherapy or anthracycline-based chemotherapy.
Results: There was no any statistical significance with respect to demographic data treated of patients between two arms (P > 0.05). Patients underwent TAC chemotherapy had pCR 20.8% whereas FAC/FEC chemotherapy patients had pCR 13% (P = 0.48). Higher ORR was noted in TAC chemotherapy arm (75%) when compared with FAC/FEC chemotherapy arm (60.9%) (P = 0.29). The study also shows better disease control rate in TAC chemotherapy arm (95.8%) as compared to FAC/FEC chemotherapy arm (82.6%). There was no statistical significance in overall survival (P = 0.31) and progression-free survival (P = 0.51) between two arms.
Conclusion: Despite of the superiority of combination of anthracycline and taxane-based chemotherapy over the anthracycline-based chemotherapy in the present study, further pivotal studies should be conducted to confirm the combination of anthracycline and taxane-based chemotherapy as a better neoadjuvant regimen for treatment of LABC tumors.
Keywords: Anthracycline-based neoadjuvant chemotherapy, taxane-based neoadjuvant chemotherapy, locally advanced breast cancer
|How to cite this article:|
Dodiya HG, Brahmbhatt AP, Khatri PK, Kaushal AM, Vijay D G. Neoadjuvant chemotherapy in patients with locally advanced breast cancer: A pilot-observational study. J Can Res Ther 2015;11:612-6
|How to cite this URL:|
Dodiya HG, Brahmbhatt AP, Khatri PK, Kaushal AM, Vijay D G. Neoadjuvant chemotherapy in patients with locally advanced breast cancer: A pilot-observational study. J Can Res Ther [serial online] 2015 [cited 2019 Nov 13];11:612-6. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/612/146056
| > Introduction|| |
Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths). Breast cancer is the commonest malignancy of females all over the world and the one of the leading cause of death due to malignancy.  In India, 75000-80000 new cases of breast cancer diagnosed annually. , As per register data in India, 27 cases of breast cancer per 100000 in south region whereas around 33 cases in north region.  Locally advanced breast cancers (LABC) accounts for 10-15% of newly diagnosed breast cancer in United States while 30-60% in India.  LABC refers to large breast tumors associated with chest wall involvement or skin or fixed axillary lymph nodes or disease spread to ipsilateral internal mammary node or supraclavicular node. LABC patients have higher rate of relapse and poor survival.  Neoadjuvant chemotherapy (NACT) is one of the standard therapy options for the management of LABC.  The target of the NACT is to downsize the large tumours as well as to treat metastatic disease at the earliest. The effect of neoadjuvant chemotherapy on patient's outcome may depend on the drug or drug combination used as NACT.  Previous study reports that pathological complete response (pCR) is long-term survival marker in LABC patients. 
Various factors affecting complete pathological response to neoadjuvant chemotherapy such as age, clinical tumor size, menopause status, type of chemotherapy, number of chemotherapy cycles, receptor status, excess of intraductal component and lymphatic and vascular invasion.  Previous randomized and controlled clinical trials have reported superiority of anthracycline-based chemotherapy regimens over conventional regimens. ,, In one of the clinical study conducted in India (North-Western region) for evaluation of efficacy of NACT for LABC, revealed more effectiveness of taxane-based chemotherapy as compared to anthracycline-based chemotherapy.  Taxanes (docetaxel or paclitaxel) are extensively used either alone or in combination with anthracyclines to improve LABC patient's outcome more effectively.  The National Surgical Adjuvant Breast and Bowel Project (NSABP) B18/B27 study revealed that preoperative administration of docetaxel to Adriamycin plus cyclophosphamide (AC) regimen increased pCR rate from 15.7% to 28.2%.  However, alone anthracycline-based regimens also used to treat LABC.  Evidences supports that taxanes are a better NACT regime for locally advanced breast cancer are sparse. Thus, the present pilot study was designed to analyze and compare the outcome of patients with LABC undergoing either combination of anthracycline and taxane (TAC: Docetaxel + Adriyamycin + Cyclophosphamide)-based NACT or anthracycline-based NACT (FAC/FEC: 5-Flurouracil (5-FU) + Adriyamycin/Epirubicine + Cyclophosphamide).
| > Patients and methods|| |
In this pilot study, 47 (≥18 years old) institutional registered cases of LABC with confirmed histopathological diagnosis from 2008 to 2011 were included. Inclusion and exclusion criteria are mentioned in [Table 1].
Institutional Ethics Committee (IEC) approval was obtained prior to start any study-related analysis. All activities were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments as well as in accordance with Indian guidelines, schedule Y, Good Clinical Practices and other applicable regulatory guidelines.
All patients gave their written consent before the enrolling in the study. Identity of the patients was kept confidential. Diagnosis was confirmed with core biopsy in all patients. Patients underwent investigations such as vital signs, physical examinations together with breast ultrasonography and mammography, echocardiography, laboratory investigations (Complete blood cell count, liver function tests, kidney function tests, electrolytes), and urine routine analysis prior to start of neoadjuvant chemotherapy. Baseline information such as demographics (age and weight), clinical stage, clinical nodal status, histology, and tumor size and receptor status were collected. Additional necessary investigations were done when indicated either clinically or from blood tests.
After completion of baseline investigations, all eligible patients had received at least three cycles of chemotherapy every 3 weeks as per below regimen. , The regimen of the chemotherapy was selected for each patient as per clinical examination of the patient and respective investigator discretion.
FAC regime: 5-FU 500 mg/m 2 , Adriamycin 50 mg/m 2 , Cyclophosphamide 500 mg/m 2 or FEC regime: 5-FU 500 mg/m 2 , Epirubicine 75 mg/m 2 , Cyclophosphamide 500 mg/m 2 TAC regime: Docetaxel 75 mg/m 2 , Adriamycin 50 mg/m 2 , Cyclophosphamide 500 mg/m 2 .
After completion of at least three cycles of chemotherapy, tumor size was assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. If patient had complete response or partial response after at least three cycles of chemotherapy; underwent three more cycles of chemotherapy and then appropriate surgery and radiation therapy. The time and choice of this surgery and radiation therapy was left to oncologist's best standard practice. However, if patient had progressive disease or stable disease after at least three cycles of chemotherapy, patient would be removed from the follow-up period of the study and would be treated as per best standard care. These patients had received new treatment for LABC or lost follow-up from the hospital. Patients with complete response or partial response were followed up every 3 months till 2 years (before January 2013) only for survival analysis.
Receptors status before chemotherapy treatment was analyzed by Immunohistochemical (IHC) method.
Immunohistochemical analysis (IHC)
Formalin-fixed, paraffin-embedded tissues obtained for diagnostic core biopsy were used for this study. Immunohistochemistry was conducted on 4 micron or 5 micron-thick tissue sections. A single section showing both tumor and preferably with the adjacent uninvolved breast tissue was routinely submitted for immunohistochemistry, and stained with antibodies against estrogen receptor (ER) (Immunotech, clone1D5) and progesterone receptor (PR) (Immunotech, clone PR636). Tumor ER and PR status is reported using the Quick Scoring Method. Sections were interpreted positive if at least 1% of tumor nuclei stained positive. Her2/neu IHC was performed using the antibodies (Immunotech, CB11) and results were interpreted according to ASCO/CAP (American Society of Clinical Oncology-College of American Pathology) guidelines.
Study end points
Primary end point
The primary endpoint of the study was pCR rate. Based on the histopathology of the operative specimen following neoadjuvant chemotherapy, patients were divided into complete responders and incomplete responders (pINV). The pCR was defined as no histological evidence of invasive tumor cells in breast and axilla. The pINV was defined as residual histological evidence in breast, axilla or both. Core biopsy was used to analyze pathological response. All specimens excised from the breast were sectioned (8-10 sections per patient) into 4 micron or 5-micron-thick slices and were microscopically analyzed for the presence of residual tumor in breast, axilla or both by certified pathologist. Regional lymph node status post-chemotherapy was also evaluated in the study.
Secondary end point
The secondary endpoints were clinical response, overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Clinical response was assessed as per RECIST guidelines. ORR defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR). DCR defined as the percentage/number of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a chemotherapeutic intervention. PFS was defined as the time from the date of histological diagnosis to the first date of disease relapse or the date of death due to any cause or date of last health check. OS was defined as the time from the date of diagnosis to the date of death due to any cause or date of last health check. The response assessment (clinical and pathological response) and survival analysis (PFS and OS) was limited to those patients who had received at least three cycles of chemotherapy.
Patients were monitored for adverse events and serious adverse events during entire course of study. Adverse events were evaluated based on severity grades (mild, moderate, severe, life threatening or disability and death related), system wise and causality. Serious adverse events were evaluated by criteria like medically significant events, life-threatening events and AE requiring new/prolonged hospitalization. Patient's safety was also assessed according to Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) criteria by clinical and laboratory evaluation at day 21 of each cycle and a complete blood cell count was performed whenever required.
Statistical significance was set to at P < 0.05 and P < 0.01. The PFS and OS were estimated using the Kaplan-Meier analysis. Other data were analyzed by Chi-square test. Statistical analysis was performed using Graph Pad Prism Version 5.00.
| > Results|| |
Comparison of patient characteristics between FAC/FEC arm and TAC arm.
In FAC/FEC arm 23 (14 in FAC arm and 09 in FEC arm) whereas in TAC arm 24 patients (24 in docetaxel arm) were evaluated. There was no significant difference between two arm (FAC/FEC and TAC) with regard to age, tumor size, nodal status, histology, stage and receptor status [Table 2].
|Table 2: Comparison of patient characteristics between FAC/FEC arm and TAC arm|
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Comparison of pathological response, clinical response, overall response rate and disease-control rate between FAC/FEC arm and TAC arm.
In FAC/FEC arm, 14 patients (60.9%) showed primary tumor reduction (overall response) after at least three cycles of chemotherapy. Three patients (13.1%) had complete clinical response and all are alive and progression-free till follow-up. Those three patients also had complete pathological response (13.1%) and were all alive and progression-free till follow-up. In TAC arm, 18 patients (75%) showed primary tumor reduction (overall response) after at least three cycles of chemotherapy. Seven patients (29.2%) had complete clinical response and all are alive and progression-free till follow-up. In those seven patients, five patients had complete pathological response (20.8%) and all were alive and progression-free till follow-up [Table 3]. There was no statistical significance for complete pathological response and clinical response including ORR and disease-control rate between two arms.
|Table 3: Comparison of pCR, clinical response, disease control rate and response rate between FAC/FEC arm and TAC arm|
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Comparison of PFS and OS between FAC/FEC arm and TAC arm
In FAC/FEC arm, five patients had stable disease and four patients had progression of disease after at least three cycles of chemotherapy. During 24 months follow-up, four patients out of 14 patients (CR and PR patients) relapsed. Two patients had relapse at 18 months whereas two patients had relapse at 21 months. From these four relapsed patients one patient died at 21 month and one patient at 24 month and other two were alive till 24 months. In TAC arm, five patients had stable disease and one patient had progression of disease after at least three cycles of chemotherapy. During 24 months follow-up, two patients out of 18 patients (CR and PR patients) relapsed. One patient had relapse at 21 months and died at 24 month after diagnosis whereas one patient had progression at 21 months but alive at 24 month. All other patients remained alive till 24 month. There was no statistical significance for OS and PFS between two arms [Table 4].
The toxicities associated with respective chemotherapy treatments are summarized in [Table 5]. Hematological toxicity at grade-3 was predominantly in TAC arm (37%) as compared to FAC/FEC arm (24%). The other principal non-hematological toxicities at grade-III were alopecia (65%) and anorexia (12%) in FAC/FEC arm whereas. In TAC arm, alopecia (81%) and anorexia (17%) were reported. Five subjects were treated with oral antibiotics in FAC/FEC arm whereas 11 subjects were treated with oral antibiotics in TAC arm. Only one subject treated with injectable antibiotic for infection in TAC arm while none of patient was treated with injectable antibiotic in FAC/FEC arm.
| > Discussion|| |
Locally advanced breast cancer is heterogeneous group of diseases include stage II, stage III and inflammatory breast cancer patients. Approximately 7% of the patients have stage II disorders at the time of diagnosis as per data from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER). The risk of reoccurrence and death is extremely high in patients, not responding to NACT. NACT is standard treatment program to treat LABC patients. However, research in this field with regard to selection and duration of regimen (anti-HER2 therapy, angiogenesis targeting treatments, taxane therapy) are ongoing, to improve long-term control of LABC. The choice of optimal chemotherapy regimen and the duration of treatment have been extensively assessed in previous studies but no consensus has been developed so far. Data in LABC, comparing various NACT regimens are also limited.  So, this pilot study was designed to analyze and compare the outcome of patients with LABCs undergoing combination of anthracycline and taxane-based chemotherapy (TAC) or anthracycline (FAC/FEC)-based chemotherapy.
In the present study, 47.9% patients had age >50 years in FAC/FEC arm whereas in TAC arm, 50% patients had age in range of 35-50 years. Reported median age was 49 years in FAC/FEC arm whereas TEC arm reported median age was 51 years. , In this study, majority of the patients had T2 and T3 stage tumors. However, previously conducted study in India reported majority of patients had T4 (90%) stage tumors.  Majority of patients had N1 and N2 nodal status in both arms which is also consistent with previously published data. Most of patients participated in this study had stage II and stage III tumors. However, recently published study in India reported only stage III tumor patients.  Expression rate of estrogen receptor (ER), progesterone receptors (PR) and human epidermal growth factor receptors (Her2/neu) in the present study is similar with previously reported ER, PR and Her2/neu expression rate. , In both arms, most of patients had ductal carcinoma.
Complete pathological response and overall clinical response are important indicators of survival in LABC patients.  In our study, TAC arm had pCR 20.8% whereas FAC/FEC arm had pCR 13%. Earlier studies conducted in India reported 18.9% pCR for docetaxel chemotherapy and 13.2% pCR for anthracycline chemotherapy.  NSABP-B27 study and GeparTrio trial also reported 26% and 21% pCR for TEC chemotherapy, retrospectively. , This study reports 60.9% and 75% overall clinical response in FAC/FEC arm and TAC arm, respectively. In previously published study, overall clinical response for anthracycline chemotherapy was 53.7% while 74.3% for docetaxel chemotherapy.  The use of taxanes in advanced breast cancer patients who had failed with anthracycline based chemotherapy has shown improved overall response rate.  Similarly in National surgical adjuvant breast and bowel project B27, involving 2411 patients with operable breast cancer, addition of docetaxel to anthracycline-based chemotherapy preoperatively, improved the complete clinical and pathological response rate compared to preoperative anthracycline-based chemotherapy alone (clinical complete response- 40.1% vs 63.6%; P = 0.001, complete pathological response- 13.7% vs 26.1%; P = 0.001).  Further, current study shows better disease control rate in TAC chemotherapy arm (95.8%) as compared to FAC/FEC chemotherapy arm (82.6%). Overall survival (OS) analysis after 2 years follow-up revealed that patients underwent TAC chemotherapy had better median survival time (24 months) when compared with FAC/FEC chemotherapy (22.5 months). TAC arm (22.5 months) had improved PFS as compared to FAC/FEC arm (21 months). Previously, NACT study in India reported three-year disease-free survival (DFS) was 56.84% for docetaxel group (median not reached) while 61.16% for anthracycline group (median 75 months). 
In summary, this study concludes superiority of combination of anthracycline and taxane-based chemotherapy over anthracycline based chemotherapy to treat LABC. However, this results need to be further confirmed by large sample size study.
| > Acknowledgment|| |
The authors thank to Ms. Jalpa Chothani and Ms. Hetal Joshi for their operational support.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]