|BREAST MINI SYMPOSIUM
|Year : 2012 | Volume
| Issue : 3 | Page : 266-271
Adjuvant chemotherapy with six cycles of AC regimen versus three cycles of AC regimen followed by three cycles of Paclitaxel in node-positive breast cancer
C Roy1, KB Choudhury1, M Pal2, A Saha1, S Bag1, C Banerjee1
1 Department of Radiotherapy, IPGMER and SSKM Hospital, Kolkata, India
2 Department of Radiotherapy,NRS Medical College and Hospital, Kolkata, West Bengal, India
|Date of Web Publication||12-Dec-2012|
Department of Radiotherapy, IPGMER and SSKM Hospital, Kolkata
Source of Support: None, Conflict of Interest: None
Context: Antracycline-Cyclophosphamide (AC) along with Paclitaxel/Docetaxel, either in combination or sequential regimens, is showing superior results than Anthracycline-containing regimens. Aims: This study was designed to determine whether adding Paclitaxel to a standard adjuvant chemotherapy regimen AC for breast cancer patients would prolong the time to recurrence and survival. Settings and Design: Randomized, prospective, open-labeled, single-institutional study. Materials and Methods: Fifty stage II breast cancer patients accruing 25 patients in each arm, treated between July 2007 and January 2010, were included in the study. Initial surgical treatment was Modified Radical Mastectomy. Systemic therapy was to have begun within 4-6 weeks of the patient's surgery. In the control arm, all the patients were treated with six cycles of adjuvant chemotherapy with AC regimen repeated at an interval of 3 weeks. For the study arm, the patients received adjuvant chemotherapy with three cycles of AC regimen followed by three cycles of Paclitaxel, repeated at an interval of 3 weeks. All the patients of both the arms received locoregional external beam radiotherapy (EBRT) after the entire course of chemotherapy. All the hormone receptor-positive patients received Tamoxifen. Statistical Analysis Used: Statistical analysis was performed using the chi-square test and the Kaplan Meier survival analysis with the log-rank (Mantel-Cox) test. Results: Adding Paclitaxel to AC resulted in a statistically significant disease-free survival. The overall survival was also improved significantly. The toxicity profile in both the arms was comparable. Conclusions: In early and node-positive breast cancer, the addition of three cycles of Paclitaxel after completion of three cycles of AC improves the disease-free and overall survival.
Keywords: Adjuvant chemotherapy, Adriamycin, Cyclophosphamide, node-positive breast cancer, Paclitaxel
|How to cite this article:|
Roy C, Choudhury K B, Pal M, Saha A, Bag S, Banerjee C. Adjuvant chemotherapy with six cycles of AC regimen versus three cycles of AC regimen followed by three cycles of Paclitaxel in node-positive breast cancer. Indian J Cancer 2012;49:266-71
|How to cite this URL:|
Roy C, Choudhury K B, Pal M, Saha A, Bag S, Banerjee C. Adjuvant chemotherapy with six cycles of AC regimen versus three cycles of AC regimen followed by three cycles of Paclitaxel in node-positive breast cancer. Indian J Cancer [serial online] 2012 [cited 2019 Aug 22];49:266-71. Available from: http://www.indianjcancer.com/text.asp?2012/49/3/266/104483
| » Introduction|| |
Breast cancer is the most common cancer in the women of developed countries. Survival of breast cancer patients has improved substantially over the years as a result of multimodal treatment. Studies on early-staged breast cancer (EBC) from the developed countries have reported a 20-year survival rate.  Age-specific incidence rates for breast cancer for most of the urban population in India were found to show a steep increase till menopausal years, after which the curves plateau. Most of the registries' data indicate that Christians in India have the greatest risk of breast cancer and Muslims have the lowest rate. In all the populations, breast cancer was found to be less prevalent at the lower education level, and the incidence increased with the education level. The trends for increase in breast cancer incidence over time for most of the populations in India were found to be statistically significant. The rates of breast, cervical and ovarian cancer remain low in comparison with the western countries, and the divergent trends of breast (increasing) and cervical cancer (decreasing) in Mumbai were similar to those observed in several other Asian countries. The changing risk profile in successive generations - improved education, higher socioeconomic status, later age at marriage and at first child and lower parity - may in combination partially explain the diverging generational changes in breast and cervical cancer in Mumbai in the last decades.  This was collaborated by Yeole et al. in the epidemiological study.  Despite the recent increase in incidence, the 1990s have witnessed for the first time the decrease in breast cancer mortality rate. These downturns seem to be related to various factors, namely the implementation of early detection through screening programmes  and the impact of adjuvant therapy. 
Over the past 40 years, concepts about the natural history of breast cancer have changed. Instead of a local disease, in majority of the cases, it is a systemic one at the time of diagnosis. As micro-metastases is a common feature in breast cancer, local therapy with surgery, radiotherapy or a combination of both is not adequate for breast cancer, and adjuvant chemotherapy is beneficial for both node-negative and node-positive cases.
In advanced breast cancer patients, chemotherapy offers substantial palliation and prolongation of life. Over the past four decades, the clinical introduction of chemotherapies has progressed through several stages. The combination of Cyclophosphamide, Methotrexate and Fluorouracil (CMF), when used as adjuvant systemic therapy, reduces the annual odds of recurrence and death of patients with early breast cancer (±SD) by 24% (±3%) and 14% (±4%), respectively.  An overview of trials, adding Anthracycline, either Doxorubicin or Epirubicin, to Cyclophosphamide (with or without a Vinca Alkaloid, Methotrexate or Fluorouracil) demonstrated that there is a reduction in annual odds (±SD) of 12% (±4%) and 11% (±5%) in recurrence or death, respectively, compared with CMF.  Because of its shorter duration of therapy, and less toxicity, four cycles of AC became one of the most commonly used adjuvant therapies in the United States before the overview demonstrated the superiority of the Anthracycline regimen. The Taxanes (Paclitaxel and Docetaxel) have emerged as a powerful group of compounds among the novel therapeutic agents introduced in the last decade. Either as mono- or polychemotherapy, they have entered clinical practice as a standard therapy in metastatic breast cancer. Their role, as first-line therapy, in combination with Anthracyclines, in advanced breast cancer, is emerging. They have increased the survival of advanced breast cancer, but have not, so far, increased the curability of breast cancer. AC along with Paclitaxel/Docetaxel, either in combination or in sequential regimens, is showing superior results than Anthracycline-containing regimens. Today, in clinical practice, Taxanes are considered as part of the therapeutic armamentarium for the adjuvant treatment of patients with node-positive breast cancer. 
The study reported here was designed to determine whether the benefits from three cycles of AC could be increased by adding Paclitaxel, a drug known to be non-cross-resistant with Anthracyclines.
| » Materials and Methods|| |
The study was on 50, stage II breast cancer patients accruing 25 patients in each arm, treated between July 2007 and January 2010, at the Department of Radiotherapy of our institution. Only the patients of age between 20 and 70years, Karnofsky Perfomance Status (KPS) ≥70, clinical TNM staging II (T0NIM0 to T3N0M0), post-mastectomy, histologically proven infiltrating duct carcinoma and positive axillary lymph nodes were included. X-ray chest (CXR) and ultrasonography (USG) of whole abdomen revealed no metastatic deposits, and echocardiography and hematological parameters were within normal limits. All the patients were psychologically sound to withstand the stress of the treatment and signed the informed consent. Patients with present or past history of any second malignancy, evidence of clinically suspected or imaging-proven metastatic disease or associated co-morbid condition (cardiac disease, diabetes mellitus or psychiatric illness) were excluded.
The study was designed as an interventional, prospective, open-label, single-institutional randomized control clinical trial. Initial surgical treatment was Modified Radical Mastectomy. Systemic therapy was to have begun within 4-6 weeks of the patient's surgery. The patients were randomly assigned into two arms by a computer-based randomization procedure. In the control arm, all the patients were treated with six cycles of adjuvant chemotherapy with AC (Doxorubicin 60 mg/m 2 and Cyclophosphamide 600 mg/m 2 ) regimen repeated at an interval of 3 weeks. For the study arm, the patients received adjuvant chemotherapy with three cycles of AC regimen (Doxorubicin 60 mg/ m 2 and Cyclophosphamide 600 mg/m 2 ) followed by three cycles of Paclitaxel 175 mg/m 2 , repeated at an interval of 3 weeks. Radiotherapy was added wherever indicated after pathological assessment after the entire course of chemotherapy. Patients with inadequate axillary dissection (considered less than 10 lymph nodes resection) or those with nodes positive with extensive extracapsular extension greater than 2 mm were considered for axillary lymph nodal irradiation. Supraclavicular irradiation was considered for those with ≥4 positive axillary lymph nodes and in those with one to three positive nodes with inadequate nodal dissection, extracapsular extension more than 2 mm, lymphovascular invasion (LVSI) positive and primary tumor size more 4 cm. For chest wall irradiation, post-mastectomy irradiation was for ≥4 positive pathological axillary lymph nodes, for lymph nodes 1-3(+)ive radiation to chest wall was added depending on tumor size >4 cm, LVSI positive and primary tumor size more than 5 cm, i.e. T3 stage. External beam radiation therapy was delivered using the Telecobalt machine, ATC-C9, at SSD-80 cm. A separate internal mammary chain (IMC) field was used when the interfield distance of the medial and lateral tangential fields was >18 cm. The total dose for each of the fields was 5000 cGy in 25 weeks and 200 cGy in each fraction over 30 days. Patients, whose tumors expressed either estrogen or progesterone receptor, or both, received Tamoxifen. Twenty percent of the unknown hormone status do benefit with the addition of Tamoxifen. For this purpose, all unknown patients were prescribed Tamoxifen. Because of financial constraints of the patients included in the study, HER-2 neu status could not be carried out. Throughout the treatment period, for patients in both the arms, a 3-weekly examination was done, just prior to starting the next the cycle of chemotherapy, to note the response and the adverse effects, if any. During this check-up, patients were subjected to a complete blood count, liver and kidney function test. The treatment was deferred if haemoglobin was less than 10 gm%, total leukocyte count <4000/cmm with absolute neutrophil count (ANC) less than 2000/cmm and platelet count <100,000/cmm, and were restarted after bone marrow recovery by conservative management. On completion of therapy, first assessment was performed after 3 weeks. Evaluation included physical examination with complete blood count, liver function test (LFT) and renal function test (KFT). Thereafter, the patients were evaluated 2-monthly for the first year and 3-monthly till the end of study. Mammography of the opposite breast, CXR, and in patients receiving Tamoxifen, pelvic and rectal examination with Pap smear More Details were performed annually. Bone scan and imaging of the chest, abdomen, pelvis and brain were performed if symptoms and laboratory abnormalities indicated this. Patients were advised to perform monthly breast self-examination. Left ventricular ejection fraction was measured at baseline and at 18 months. Assessment of toxicities was carried out in accordance with ECOG criteria. The primary end point of this study was disease-free survival (DFS). Overall survival (OS) and toxicity assessment were the secondary end points. DFS is the interval from the study entry to first local recurrence or distant metastases, or death as a result of any cause. All patients were observed separately for first local and first distant recurrence, second malignancy, delayed cardiotoxicity and death. Statistical analysis was performed using the chi-square test to compare the baseline profiles. The Kaplan-Meier survival analysis with log-rank (Mantel-Cox) test was used to compare the DFS and OS in both the arms.
| » Results|| |
Between July 2007 and January 2010, 50 patients were selected for the study and randomly assigned to any one of the treatment arms. Median follow-up was 24 months, the minimum being 12 months and maximum being 30 months. There was no loss of patients in any of the arms due to "lost to follow-up." The pre-treatment characteristics were compared by the Chi-square analysis test. The accrual in both the arms was comparable. The characteristics of the patients enrolled are listed in [Table 1]. Fifty-six percent of the patients in study arm did not receive irradiation in the post-mastectomy pathological review, against 52% in the control arm [Table 2].
|Table 2: Patients receiving radiation on the basis of the pathological report|
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Adding Paclitaxel to the AC led to a significant increase in DFS [Table 3], with "log-rank (Mantel-Cox) test" P value 0.021 (<0.05). The hazard ratio was 0.295 (95% confidence interval, 0.104-0.835; [Figure 1]). The OS was also significantly improved [Table 3], with "log-rank (Mantel-Cox) test" P value 0.034 (<0.05), hazard ratio 0.308 and 95% confidence interval ratio 0.103-0.917 [Figure 2].
|Figure 1: Kaplan-Meier survival curve analysis with log-rank (Mantel- Cox) test shows a statistically significant disease-free survival in favor of the Paclitaxel-containing study arm, P value 0.021 (<0.05), hazard ratio of 0.295 and 95% confidence interval ratio 0.104-0.835. The median disease-free survival in the study arm and the control arm are 23.72 months and 24 months, respectively|
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|Figure 2: Kaplan-Meier survival curve analysis with log-rank (Mantel- Cox) test shows a statistically significant disease-free survival in favor of the Paclitaxel-containing study arm, P value 0.034 (<0.05), hazard ratio of 0.308 and 95% confidence interval ratio of 0.103-0.917. The median overall survival in the study arm and the control arm are 24.52 months and 24 months, respectively|
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In 5% of the patients, during Paclitaxel administration, hypersensitivity reactions, mainly in the form of urticaria, fever (>38 o C) and bronchospasm, were seen. Twelve percent of the patients receiving Paclitaxel had moderate paresthesia. In up to 2% of the patients, clinically important cardiac dysrhythmias, congestive heart failure (CHF), change in the left ventricular ejection fraction or any other heart symptoms occurred regardless on any possible relationship to treatment [Table 4].
|Table 4: Early treatment toxicities, analyzed every 3-weekly during treatment. The toxicities in both the arms were comparable. There was no statistical difference in both arms using the chi-square test|
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| » Discussion|| |
Breast cancer is by far the most commonly diagnosed cancer in women worldwide. With Fisher describing the disease as a systemic one, early diagnosis and management, more so in carcinoma-in-situ and node-negative stages, provides the best solution rather than treating a locally advanced or metastatic disease. The Indian scenario presents a contrast to the western world, with most cases being diagnosed in advanced stages. Patients coming with early node-positive disease are less-common presentations at oncology centers. The important components of a multimodality approach for breast cancers include radiotherapy for locoregional control and chemotherapy for both primary as well as metastatic disease. Most chemotherapy trials were initiated in metastatic settings and then preceded in a retrograde fashion to treat locally and, finally, early breast cancer patients. Adjuvant chemotherapy has proven to reduce the risk of relapse and death significantly in operable breast cancer at initial presentation. However, the lymph nodal status remains the most important prognostic factor for resulting in the dismal survival in patients, especially presenting with extensive nodal involvement.
Chemotherapy has come a long way, evolving from traditional CMF regimes to Anthracyclines to Taxanes to modern innovations in targeted therapies. Anthracycline-based chemotherapy is better tolerated in terms of acute side-effects, but long-term sequel (cardiotoxicity, secondary leukaemia) are worrisome. The reported trials with Taxanes demonstrated comparable reduction in the risk of recurrence and death. , The introduction of Taxanes in early-staged breast cancer treatment constitute an important advance over the historic experience with alkylator and Anthracycline-based chemotherapy. The first report on adjuvant Taxane therapy was CALGB 9344. In this much-scrutinised study, node-positive disease patients were randomly assigned to receive either four cycles of AC or the same regimen followed by four cycles of Paclitaxel. The Paclitaxel-containing regimen had a consistently lower rate of relapse, which became apparent at early 21 months of follow-up and has been sustained in 5 years. This study showed that AC-Paclitaxel is superior to AC chemotherapy. 
We conducted this study to evaluate whether addition of Paclitaxel to a standard adjuvant chemotherapy regimen (AC) in node-positive breast cancer would prolong time to recurrence or survival. The recruitment was much less mainly due to financial reason and presentation of patients with borderline hematological parameters. The compliance of our patients to this study was satisfactory, evidenced by the fact that 98% of our patients received all the doses of full-course chemotherapy. However, the financial constrains and total duration of treatment time resulted in low compliance of our patient in our previous clinical trials who received standard four cycles of AC followed by four cycles of single-agent Taxane (Paclitaxel or Docetaxel), which was compared with six or eight cycles of AC, and only 80% of them completed four or more cycles of chemotherapy. Therefore, we compared the response and toxicity profiles of three cycles of AC followed by three cycles of Paclitaxel with six cycles of AC in this study.
Our results with 3AC-3P (DFS 80% and OS 84%) were statistically significant when compared with patients treated with six cycles of AC (DFS 56%, OS 60%). The results of the trial were similar to the outcome of different clinical trials. Because of the small number of our patients, we could not carry out a subset analysis of the effects of adding Paclitaxel on estrogen receptor-negative tumors.
In the NSABP-28 study, 3060 patients were randomly assigned to AC (AC-1529) versus AC followed by Paclitaxel (AC-PTX 1531). Addition of Paclitaxel to AC significantly reduced the hazard for DFS by 17%. The 5-year DFS was 76% (±2%) for patients with AC-PTX compared with 72% (±2%) for AC.  Sarter et al. assigned patients to receive AC versus AC followed by Paclitaxel (AC-T) as adjuvant chemotherapy for the patients with breast cancer treated with breast conservative surgery and radiotherapy. The 5-year cumulative incidence of isolated locoregional recurrence (LRR) was 9.7% in the AC arm and 3.7% in the AC-T arm (P=0.4) and of LLR as any component of failure was 12.9% versus 6.1%, respectively (P=0.04). 
To assess the advantage of adjuvant Taxane chemotherapy over standard chemotherapy, Bria et al. performed a pooled analysis of phase III trials. The absolute benefits in DFS and OS were in favor of Taxanes, ranging from 3.3% to 4.6% and from 2% to 2.8%, respectively. Considering all the phase III trials, Taxane-based adjuvant chemotherapy for early breast cancer seems to add a significant benefit in both DFS and OS over standard chemotherapy. 
Anan et al. conducted a study to evaluate the feasibility of Doxorubicin plus Cyclophosphamide (AC) at a dose of 50 mg/m 2 plus 500 mg/m 2 every 3 weeks for four cycles, followed by weekly Paclitaxel at a dose of 80 mg/ m 2 for 12 cycles, with a 1-week pause, after three consecutive weekly administrations as adjuvant therapy for node-positive breast cancer. Grade 3 neutropenia and nausea-vomiting were more common during AC (28.6%) than during Paclitaxel (6.7%) therapy. 4.4% showed allergic reaction during Paclitaxel therapy, of which 12.8% needs treatment discontinuation. 
It can be well interpreted from these studies on breast cancer that incorporation of Taxanes, either Paclitaxel or Docetaxel, as substitute or sequential addition to Anthracycline-based regimens can contribute significant improvement in outcomes, especially among women with node-positive breast cancer in whom the vast majority of these trials have been conducted. The addition of Paclitaxel to AC consistently proved advantageous. However, the effect was largest among those whose tumors were hormone receptor negative and who received no adjuvant Tamoxifen compared with all other patients.
In this study, the administration of a non-cross-resistant drug, Paclitaxel, as a single agent, after completion of treatment with a standard therapy AC, improved the DFS and OS, which were statistically significant, with acceptable toxicity. Because of the small accrual of patients, the impact of tumor size, nodal status (N1, N2) and hormonal positivity status could not be used for multivariate Cox regression analysis. Because of the limited accrual of patients and also the period of median follow-up, it is inappropriate to conclude the survival advantage in our study. With subsequent follow-up, more information regarding DFS will be gathered. Increasing accrual of patients in the trial and a longer median follow-up will definitely give us a clearer picture.
| » Acknowledgment|| |
The authors would like to thank their patients who braved their disease and suffering during the course of this work.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]