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|    | | ORIGINAL ARTICLE | | | | | Year : 2011 | Volume : 48 | Issue : 1 | Page : 80-85 | | | Outcome of combined modality treatment including neoadjuvant chemotherapy of 128 cases of locally advanced breast cancer: Data from a tertiary cancer center in northern India
V Raina, M Kunjahari, NK Shukla, SVS Deo, A Sharma, BK Mohanti, DN Sharma
Department of Medical Oncology, Surgical Oncology, and Radiation Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi -29, India
| Date of Web Publication | 10-Feb-2011 | Correspondence Address:
V Raina
Department of Medical Oncology, Surgical Oncology, and Radiation Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi -29
India
  | 2 |
DOI: 10.4103/0019-509X.75838 PMID: 21248440 Background: Breast cancer is now the most common cancer in many parts of India and the incidence varies from 12 to 31/100000, and is rising. Locally advanced breast cancer (LABC) accounts for 30 - 35% of all cases of breast cancers in India. LABC continues to present a challenge and imposes a major health impact in our country. Materials and Methods: We carried out a analysis of our LABC patients who received neoadjuvant chemotherapy (NACT) at our hospital over a 10-year period, from January 1995 to December 2004. We analyzed the response to NACT, disease-free survival (DFS), and overall survival (OS). Results: Patients with stages IIIA, IIIB, and IIIC were included. LABC comprised of 26.24% (609 patients) of new patients. One hundred and twenty-eight (31.1%) patients received NACT. Median age was 48 years and estrogen receptor was positive in 64%. Chemotherapy protocol was an FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) regimen in the following doses: Cyclophosphamide 600 mg/m2, 5-FU 600 mg/m2, and Epirubicin 75 mg/m2 given every three weeks, six doses, followed by modified radical mastectomy (MRM) and locoregional radiotherapy. The overall response rate (complete response (CR) + partial response (PR)) was 84.4%, clinical CR (cCR) was 13.3% and pathological CR (pCR) was 7.8%. Median DFS and OS were 33 and 101 months, respectively. The disease-free survival (DFS) and overall survival (OS) at five years were 41 and 58%, respectively. Conclusions: This study analyzes the outcome in patients who received NACT, in the largest number of LABC patients from a single center in India, and our results are comparable to the results reported from other centers.
Keywords: Locally advanced breast cancer, neoadjuvant chemotherapy, combined modality treatment
How to cite this article:
Raina V, Kunjahari M, Shukla N K, Deo S, Sharma A, Mohanti B K, Sharma D N. Outcome of combined modality treatment including neoadjuvant chemotherapy of 128 cases of locally advanced breast cancer: Data from a tertiary cancer center in northern India. Indian J Cancer 2011;48:80-5 |
How to cite this URL:
Raina V, Kunjahari M, Shukla N K, Deo S, Sharma A, Mohanti B K, Sharma D N. Outcome of combined modality treatment including neoadjuvant chemotherapy of 128 cases of locally advanced breast cancer: Data from a tertiary cancer center in northern India. Indian J Cancer [serial online] 2011 [cited 2014 Mar 7];48:80-5. Available from: http://www.indianjcancer.com/text.asp?2011/48/1/80/75838 |
| » Introduction | |  |
Breast cancer is now the most common cancer in many parts of India and the incidence varies from 12 to 31/100000, and is rising.[1] Locally advanced breast cancer (LABC) refers to large breast tumors (> 5 cm) associated with either skin or chest wall involvement or with fixed axillary lymph nodes or with involvement of the ipsilateral internal mammary or supraclavicular nodes.[2] LABC accounts for 10 - 20% in the West[3] while in India it accounts for 30 - 35% of all cases.
Locally Advanced Breast Cancer (LABC) poses a significant clinical challenge. With the broad spectrum of presentations, survival rates for LABC vary significantly among the series, reflecting institutional differences in therapeutic policies and patient selection. Although some series report five-year survival rates of greater than 70%, [4],[5] these series exclude patients with inflammatory disease, the most aggressive form of non-metastatic breast cancer. Overall the results of the treatment of LABC patients are dismal and no more than 30 - 40% of the patients are expected to be long-term survivors.[6],[7],[8],[9],[10] Advanced stage of breast cancer and poor results of treatment represents a major public health problem of our country.
The present standard of treatment for LABC is still evolving. In the past decade anthracycline-based chemotherapy in the neoadjuvant setting followed by surgery and locoregional radiotherapy, followed by hormonal therapy in hormone receptor positive patients, has been the standard. Taxanes are under intense investigation. [11],[12] Combined or sequential use of anthracyclines and taxanes are both acceptable. Capecitabine and Gemcitabine have been recently incorporated into trials assessing NACT [13],[14]
The first report of the use of induction chemotherapy for LABC was published in the 1970s. [15] The administration of systemic chemotherapy prior to local therapy is advantageous for women with locally advanced breast cancer, as it can render inoperable tumors resectable and can increase the rates of breast conservative surgeries. [16],[17],[18],[19] Induction chemotherapy also has a theoretical advantage of the early initiation of systemic therapy, delivery of drugs through intact vasculature, in vivo assessment of the response to therapy, and the opportunity to study the biological effects of chemotherapy. First large trial to compare neoadjuvant with adjuvant chemotherapy, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18, [20] demonstrated that neoadjuvant chemotherapy produces a significant clinical and complete response rate, pathological complete response rates, as well as increased rates of breast conserving surgeries. Although no significant difference was noted in terms of overall survival and disease free survival, pathological CR was correlated with long-term survival.
In view of the major health impact of LABC and lack of adequate information regarding its clinical outcome, neoadjuvant chemotherapy, and its response rate, we carried out an analysis of our LABC patients who received induction chemotherapy.
The aim of this study was to analyze the response to neoadjuvant chemotherapy (NACT) and the outcome (DFS and OS) of Locally Advanced Breast Cancer patients who received NACT at our hospital over a 10-year period. (January 1995 - December 2004)
| » Materials and Methods | | |
This is a study of LABC patients who received NACT at our hospital over a 10-year period (January 1995 - December 2004).
Inclusion criteria
- LABC: Stages included were IIIA, IIIB, and IIIC (TNM staging was done according to AJCC 2002 revision).
- Adequate treatment at the Institute Rotary Cancer Hospital (IRCH) was considered when patients received a complete set of treatments as planned, at baseline, and at least three cycles of chemotherapy had been completed, except for those who had toxicity to chemotherapy and could not complete the planned treatment.
Response assessment after neoadjuvant chemotherapy
Response to neoadjuvant chemotherapy and the clinical size of the primary breast tumor and axillary nodes were determined prior to chemotherapy and prior to surgery
Clinical complete response
Disappearance of all known disease at primary sites and nodes.
Clinical partial response
At least a 50% reduction in bi-dimensional tumor size of all lesions added together, with no appearance of new lesions.
Clinical stable disease
If any composite lesion increased by lesser than 25% and no new lesion appeared.
Pathological complete response
If the mastectomy specimen did not reveal any histological evidence of invasive carcinoma in the breast or axilla.
Definitions outcome data used in the present study
Disease free survival
From the time of surgery to the last follow-up or development of recurrence or death.
Overall survival
From the date of diagnosis to the date of last follow up / death / lost to follow-up
Chemotherapy
FEC
Most frequently used chemotherapy regimen in the neoadjuvant setting
Doses
5 - FU- 600 mg/m2 iv (D1)
Epirubicin- 75 mg/m2 iv infusion (D1) over 60 minutes
Cyclophosphamide- 600 mg/m2 iv infusion (D1) over 30 minutes
Cycles repeated every three weeks for a total of six cycles
Statistical evaluation
For survival function, the Kaplan Meier method was used. The log-rank test was used for comparison between two survivals. The t-Test or Mann Whitney test was applied to compare DFS and OS (continuous variable) wherever applicable.
| » Results | | |
Outcome analysis was conducted on patients registered from January 1995 to December 2004, and follow-up was carried out till July 2009, with a median follow-up at 31 months (range 7 - 148 months). Out of a total of 2321 breast cancer cases, where complete staging workup was available, 609 (26.24%) patients had LABC. One hundred and twenty-eight (31.1%) patients received neoadjuvant chemotherapy. This is the analysis of those patients.
Median age at presentation was 48 years (Range = 22 - 85 years); 43.5% of our patients were premenopausal. Median duration of symptoms was five months (Range = 1 - 60 months) and the lump was the most common presenting feature. Skin involvement was observed in 63% of the patients.
One hundred and twenty-eight patients received neoadjuvant chemotherapy (NACT); this constituted 31.1% of the LABC patients. The overall clinical response rate of NACT was 84.4% with 13.3% CR and 71.1% PR; 7.8% of the patients achieved pathological CR (pCR) [Table 1]. The most frequently used chemotherapy regimen was FEC (77.3%) [Table 1]
Modified Radical Mastectomy (MRM) was performed on 91.4% of the patients. In the remaining patients, surgery could not be performed mainly because of progressive disease during chemotherapy and those patients remained inoperable. Infiltrating ductal carcinoma was the most common (95.1%) histological type.
The median number of identified axillary lymph nodes was 11 with a range from 1 to 29. The median number of positive axillary lymph nodes was two (range 0 - 20). This is obviously underestimated, due to prior chemotherapy. The estrogen receptor status was positive in 64% of the patients, and information on the Her2 neu status was incomplete.
Median DFS was 33 months and OS was 101 months, respectively [Figure 1] and [Figure 2], [Table 2]. The DFS and OS at five years were 41 and 58%, respectively [Table 2].  | Figure 1 :Kaplan Meier Survival curve for disease free survival of locally advanced breast cancer patients who received neo adjuvant chemotherapy.
Click here to view |  | Figure 2 :Kaplan Meier Survival curve for overall survival of locally advanced breast cancer patients who received neo adjuvant chemotherapy.
Click here to view |
When survival analysis was performed with regard to NACT response, we observed that the responding group (CR + PR) had a median DFS of 44 ± 11 months in comparison to 13 ± 3 months in the non-responding group (SD + PD). This difference in DFS was statistically significant (p = 0.003) [Table 3], [Figure 3]. The median OS was 101 months in the responding group, however, the median had not been reached in the non-responding group. This difference in OS was also statistically significant (P = 0.03) [Table 4], [Figure 4]  | Table 3 :Mean and median DFS of NACT responding (CR + PR) and non-responding (SD + PD) patients and their comparisons
Click here to view |  | Table 4 :Mean and median OS of NACT responding (CR + PR) and non-responding (SD + PD) patients and their comparisons
Click here to view |  | Figure 3 :Kaplan Meier Survival curve for disease free survival of neoadjuvant chemotherapy responding and non-responding locally advanced breast cancer patients.
Click here to view |  | Figure 4 :Kaplan Meier Survival curve for overall survival of neoadjuvant chemotherapy responding and non-responding locally advanced breast cancer patients.
Click here to view |
| » Discussion | | |
There is paucity of data with respect to the actual prevalence of locally advanced breast cancer in India. There is also a paucity of information regarding the treatment outcome of our LABC patients.
The median age at presentation is 48 years (range 22 - 85 years); significantly lower than the western figures, but similar to other Indian figures. In an early breast cancer study in India the median age was 47 years as reported by Raina et al.[21] Segal et al. reported from North America that the median age of LABC patients was 57 years (Range = 28 - 88 years). [22] In Turkey, the median age of LABC patients was 47 years (range = 17 - 74 years). [23]
Premenopausal patients constituted 43.5% of all LABC cases in the present study. In the randomized study on operable LABC by Deo et al., premenopausal patients were 40 and 50% in two arms of the study. [24] Forty-eight percent of the cases were premenopausal in a study on LABC patients in Italy. [25] A study from North America reported that 38% of LABC patients were premenopausal. [22]
Sixty-four percent of the cases were Estrogen receptor (ER) positive. In an earlier study by Raina et al., on Indian patients, the ER positivity was 50.5%. [26] Redkar et al. reported 43.9% ER positivity in breast cancer patients by enzyme immunoassay. [27] Western studies reported ER positivity in 60 - 80% of the patients. The differences in ER status in Indian and Caucasian patients could be due to lower average age at presentation or racial differences.
Neoadjuvant chemotherapy was given in 31.1% of the cases and FEC was the most frequently used regimen (77.3%). Clinical CR was observed in 13.3% in the NACT group, with an overall response rate of (CR + PR) 84.4%. Pathological CR (pCR) was seen in 7.8% of the cases. An earlier Indian study showed an overall RR of 62% with 4% pCR. [24] A Study from Turkey reported an overall clinical response of 88% (CR 14.9% and PR 73%). [23] Hurley et al. reported 17% pCR in LABC patients with Docetaxel, Cisplatin, and Trastuzumab therapy. [28] In a study by Baldini et al., the pCR rate was 3.3% with standard CEF. [25] Kuerer et al. reported a pCR rate of 12% with four courses of FAC chemotherapy in the neoadjuvant setting [29] . Other studies reported a response rate of 60 - 93% including 10 - 20% CRs. A relatively lower pCR rate in the present study, in comparison to some other studies, was due to a majority of our patients receiving anthracycline-based chemotherapy in contrast to these studies, which used taxanes. [28]
In the present study, the neoadjuvant chemotherapy responding group (CR and PR) had significantly better survival than the non-responding group (SD and PD). Similar observation was also reported by others. Patients achieving CR had a five-year DFS and OS of 75 and 88%, respectively, with PR intermediate prognosis, with no response and very poor survival, in the study by Deo et al.[24] Patients were with pCR OS 100% and without pCR the OS was 83%, in four-year in the study by Hurley et al.[28] Eltahir et al. reported a five-year probability survival of 74% in patients who achieved CR with NACT and 36% in patients who achieved PR.[30]
In conclusion, LABC constitutes 26.24% (609) of all breast cancers during this 10-year period. This study analyzes the outcome of patients who received NACT in the largest number of LABC patients from a single center in India and our results are comparable with the results reported from other centers.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
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