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Chimioterapia neoadjuvantă cu Docetaxel, Epirubicină și Ciclofosfamidă în cancerul de sân

 Neoadjuvant chemotherapy with Docetaxel, Epirubicin and Cyclophosfamide in breast cancer

First published: 25 aprilie 2017

Editorial Group: MEDICHUB MEDIA

Abstract

Purpose. To establish the efficacy of neoadjuvant (NA) Docetaxel (DOC) with anthracycline-based therapy and to determine the toxicity of NA DOC associated with Epirubicin and Cyclophoasfamide in patients with breast cancer.
Patients and methods. Patients with breast cancer treated between January 2013 and December 2013 were taken into account for this study. There were included into the study 48 patients with breast cancer locally advanced, stages IIB, IIIA, IIIB, IIIC, treated in the Department of Medical Oncology I - IOB. None of the patients included were male. There were administered 6 cycles of TEC (Docetaxel 75 mg/m2 day 1, Epirubicin 75 mg/m2 day 1, Cyclophosphamide 500 mg/m2 day 1 at 21 days). Clinical tumor response was assessed at cycle 4. After 6 cycles patients who became operable went through surgical intervention. There were included patients regardless of immunohistochemistry tets - taking into accont that Trastuzumab was not reimbursed for neoadjuvant setting at that time.
Results. 48 patients were enrolled. All patients completed 6 cycles of TEC treatment. At 6 series, 33 patients had surgical interventions. The remaining 15 patients in the study group were as follows: 4 patients - stable disease, 6 patients - partial remission (RECIST> 30%) but have not converted to operability, 4 patients - progressive disease (even after 4 series only one patient had progressive disease), 3 of the patients with stationary disease have had subsequent progression, 1 patient refused surgical intervention. GM-CSF were administered prophylactic; it was done the prophylaxis of mucositis. Adverse reactions more commonly observed were: hematologic toxicity (neutropeniae, anemiae, and trombocitopeniae), hepatic toxicity, digestive toxicity - more frequent of grade 1 or 2, less frequent of grade 3-4. After 24 months, 25 from 48 patients developed local recurrence or distant metastases.
Conclusion. Neoadjuvant therapy type TEC (Docetaxel, Epirubicin, Ciclofosfamid) resulted in substantial improvement in responses to DOC. TEC is a series of chemotherapy relatively well tolerated with RR superior to other neoadjuvant chemotherapy regimes - according to literature, in locally advanced breast cancer cases, such as the study by Kuerer HM, Newman Smith TL et al. “Clinical course of breast cancer patients with pathologic complete axillary lymph node primary tumor and response to doxorubicin based neoadjuvant chemotherapy”, J Clin Oncol 1999; 17; 460-469, which showed a pathologic complete response at 20% of the ganglionic cases. Patients with Her 2 positive disease received adjuvant Trastuzumab; neoadjuvant administration of Trastuzumab was not reimbursed, HR positive disease received adjuvant hormonal treatments. Adjuvant radiotherapy was administered to patients according to international guidelines.

Keywords
breast cancer, neoadjuvant treatment, prospective study

Rezumat

Scopul studiului. Stabilirea eficacității și toxicității terapiei neodjuvante cu Docetaxel, Epirubicin și Ciclofosfamidă administrată pacientelor cu cancerele mamare biopsiate.
Pacienți și metodă: Au fost incluse în analiză paciente cu cancer mamar tratate în cadrul Institutului Oncologic București în perioada ianuarie 2013 - decembrie 2013. Au fost analizate cazurile a 48 de paciente cu cancer mamar în stadiile IIB, IIIA, IIIB, IIIC tratate în Departamentul de Oncologie Medicală I. Nu a fost inclus nici un pacient de sex masculin. Au fost administrate 6 cicluri de tip TEC (Docetaxel 75 mg/m2 ziua 1, Epirubicin 75mg/m2 ziua 1, Ciclofosfamidă 500 mg/m2 ziua 1 la 21 de zile). Răspunsul tumoral a fost evaluat clinic la ciclul 4. După 6 cicluri de chimioterapie de tip TEC, pacientele care au devenit operabile au suferit intervenție chirurgicală. Au fost incluse paciente, indiferent de rezultatul testelor imunohistochimice - ținând cont de faptul că Trastuzumabul nu era rambursat pentru terapie neoadjuvantă în acel moment.
Rezultate. 48 de paciente au fost înrolate. Toate pacientele au finalizat 6 cicluri de tratament TEC administrat neoadjuvant (după biopsie și evaluare imagistică inițială pentru excluderea metastazelor). După 6 serii, 33 de paciente au suferit intervenții chirurgicale. Restul de 15 paciente din grupul de studiu au prezentat: boală stabilă 4 paciente, 6 paciente - remisiune parțială (RECIST>30%), dar nu s-au convertit la operabilitate, 4 paciente - boala progresivă, chiar și după 4 serii doar un pacient a avut boală progresivă, 3 dintre pacientele cu boală staționară au avut progresii ulterioare, o pacientă - a refuzat intervenția chirurgicală. GM-CSF au fost administrate profilactic, s-a efectuat profilaxia mucozitei. Reacțiile adverse mai frecvente observate au fost: toxicități hematologice (neutropenie, anemie, trombocitopenie), toxicitate hepatică, toxicitate digestivă - mai multe de gradul 1 sau 2, mai puține de grad 3-4. După 24 de luni, 25 din 48 de paciente au prezentat recurență locală sau metastaze la distanță.
Concluzie. Terapia neoadjuvantă de tip TEC a dus la o îmbunătățire substanțială a răspunsurilor la DOC. TEC este o serie de chimioterapie relativ bine tolerată, cu RR superioară altor regimuri de chimioterapie neoadjuvantă - așa cum reiese din literatura de specialitate, în cazul pacientelor cu cancer mamar avansat, cum ar fi studiul de la MD Anderson Cancer Center FAC neoadjuvant: Kuerer HM Newman Smith TL și colab. “Clinical course of breast cancer patients with pathologic complete axillary lymph node primary tumor and response to doxorubicin based neoadjuvant chemotherapy”. Pacientele cu boală Her2 pozitivă au primit adjuvant trastuzumab; administrarea neo-adjuvantă a trastuzumabului  nu a fost rambursată, pacientele cu boală HR pozitivă au primit tratamente hormonale adjuvante. Radioterapia adjuvantă a fost administrată pacientelor în conformitate cu ghidurile internaționale.

Introduction

Breast cancer is the most common malignancy in women and accounts for about 26% of all malignancies diagnosed annually, and it is the second cause of death in women after lung cancer. For women in the age group under 65 years, breast cancer remains the leading cause of cancer death. Although breast cancer prognosis has improved dramatically in the last 20 years, a significant number of patients will present the evolution of the disease and most of them will die of this malignancy. About 1% of breast cancers occur in men and 90% of them show positivity for oestrogen receptors(1).

The incidence has been increasing until 2002, as a consequence of mammography screening, although currently it shows a downward trend. Part of the decrease in incidence is due to decreased use of postmenopausal oestrogen substitution. Although the incidence is substantially higher for women over 50 years compared with women under 50 years,  about 23% of breast cancers are diagnosed in women under 50 years(2).

The major factor in obtaining favourable outcomes in breast cancer treatment are represented by the precocity of diagnosis and the establishing of a correct therapeutic conduct(3).

One of the goals of modern medicine is the individualized therapy for each patient. It is a challenge for both the treating oncologist and patient alike.

In women, breast cancer represents 26% of new cancer cases and 15% of deaths related to cancer, being the second leading cause after lung cancer.

Neoadjuvant chemotherapy improves the efficacy of comprehensive treatment on breast cancer by shrinking tumor mass, reducing tumor stage and enhancing chemo sensitivity(4). As neoadjuvant chemotherapy, addition of taxane to anthracylcine-based regimens produces significant treatment response in tumors(5,6). However, it remains unclear whether they can improve long-term treatment outcome. Herein, we described the efficacy and clinical implication of neoadjuvant chemotherapy on 48 breast cancer patients treated with TEC.

Objectives

Administration of neoadjuvant chemotherapy regimen as TEC can obtain semnificative complete response and partial remission both clinical and pathological, regardless of immunohistochemistry profile, with minimal adverse events - results superior to those presented in literature obtained with other chemotherapy regimens.

Patients and methods

Into the present study, a prospective study, conducted in the Department of Medical Oncology, Institute of Oncology Bucharest, we included patients with locally advanced breast cancer. Patients with locally advanced breast cancer are a heterogeneous group that includes TNM staging according to the seventh edition, 2009: T3 N1 M0, T0-3 N2-3 M0, and T4 N0-3 M0. Only patients with N1, 2 or 3 were selected (in Romania, Docetaxel was reimbursed for N positive cases).

Locally advanced breast cancer needs multimodal treatment: chemotherapy, surgery, radiotherapy, hormone therapy or targeted therapy associated with trastuzumab therapy(7,8).

Neoadjuvant chemotherapy treatment effect is the first therapeutic option in these situations, by providing:

1. Early treatment of micrometastases.

2. Conservative surgical treatment in selected situations.

3. Possibility of transforming raw breast tumors inope­rable per operable tumors.

4. The possibility to adapt the adjuvant treatment according to the response to treatment assessment of pathological neoadjuvant(9,10).

Standard neoadjuvant treatment for patients with breast cancer in inoperable locally advanced is - according to Dennis Casciato, Oncology, Manual of Clinical preoperative breast cancer therapy - represented by antracyclines and taxanes. In recent years, it was also approved the neoadjuvant tratuzumab(11,12).

In selected cases where patients with contraindications for chemotherapy ER positive, neoadjuvant hormonal therapy may be used(13).

For patients with HER2 positive tumors, neoadjuvant chemotherapy regimen that includes strastuzumab has a high rate of pathologic complete response (adjuvant/ neoadjuvant trastuzumab therapy in women with Her2 / new - overexpressing breast cancer: a systematic review: Madarnas Y, Cancer Treat Rev 34 - 2008).

The aim of the present study is to determine the response rate and toxicity of chemotherapy regime type TEC in locally advanced breast cancers, without contraindications to chemotherapy.

The treatment regimen that was administered:

  • Docetaxel 75 mg/m2 day 1
  • Epirubicin 75mg/m2 day 1
  • Cyclophosphamide 500 mg/m2 day, 1 to 21 days.

GM-CSF was administered prophylactically. Mucositis prophylaxis was made for all patients.

From January 2013 to December 2013, there were included in the study 48 breast cancer patients locally advanced, stages IIB, IIIA, IIIB, IIIC, treated in the Department of Medical Oncology I - IOB. None of the patients included were male.

All patients had biopsy and histopathology confirmed malignancy of tumour and immunohistochemical evaluation of ER, PR, CerbB2.

Results

According to stage, there were included: 5 patients with IIB stage, 5 patients with IIIA stage, 25 patients with IIIB stage, and 13 patients with IIIC stage (Figure 1).
Figure 1. Distribution according to stage

The average age of the group of examined patients was 46.7 years (28-66).

From the point of view of menopausal status, 18 patients were postmenopausal (Figure 2).
Figure 2. Distribution according

According to immunohistochemistry evaluation of ER, PR and CerbB2, there were 27 patients with HR positivity and Her 2 negativity (56.25%), 6 patients with HR and Her2 positivity (12.5%), 8 patients with HR negative and Her2 positivity (16.66%) and 7 patients with triple negative breast cancer (14.58%) - Figure 3.
Figure 3. Distribution according to immunohistochemistry testing

According to histopathology type of tumour, there were: 29 patients with invasive ductal carcinoma, 16 patients with invasive lobular carcinoma, 1 patient with medullary carcinoma, 2 patients with mucinous carcinoma; no tubular and papillary carcinoma were included.

Six series of chemotherapy TEC type were given to all patients. All finished neoadjuvant intended treatment.

After 4 cycles, patients were clinically evaluated: 32 patients had partial remission, 11 patients had clinical complete remission, 4 patients had stable disease and only one patient had progressive disease and desired to continue with the same treatment (Table 1, Figure 4).
Figure 4. Clinical evaluation
Clinical evaluation after 4 cycles

After 6 series, surgical interventions were made to patients who were converted to operability. Also, pathological evaluation was made for each.

At 6 series, 33 patients suffered surgical interventions.

The remaining 15 patients in the study group were presented as follows:

  • 4: stable disease;
  • 6: partial remission (RECIST>30%), but have not converted to operability;
  • 4: progressive disease; even after 4 series only one patient had progressive disease, 3 of the patients with stationary disease have had subsequent progression;
  • 1: refused surgical intervention.

Efficacy of the treatment

Pathological response

Of the 33 patients who underwent surgical interventions, 5 patients achieved pCR ypT0ypN0, 13 patients achieved pCR at lymph node ypN0 (28% of 48 patients), and the rest of operated patients (40%) had ganglionic invasion (Table 2).
Pathological respone

Results at 6 series type TEC are presented in Figure 5.
Figure 5. Results at 6 cycles
Results according to immunohistochemistry profile

Toxicity

Haematological toxicity is represented by neutropenia, anaemia and thrombocytopenia.

Grade 3-4 neutropenia was observed in 5 patients (10.4%), and grade 1-2 in 9 patients (18.75%). Grade 3-4 anaemia that was treated with blood transfusions was observed in 6 patients (12.5%), grade 1-2 anaemia was observed in 10 patients (20.83%).

Grade 3-4 thrombocytopenia was observed in 3 patients (6.25%) and grade 1-2 in 5 patients (10.4%) (Figure 6).
Figure 6. Hematologic adverse reactions

Results obtained with hematologic toxicity were similar to those described in the medical literature(14).

Gastrointestinal toxicity that was determined into this study was represented by emesis and mucositis. Grade 3-4 emesis was observed in 4 patients (8.33%), and grade 1-2 emesis was observed in 14 patients (29.16%). Grade 3-4 mucositis was observed in 2 patients (4.16%), and grade 1-2 mucositis in 10 patients (20.83%) (Figure 7). Results obtained were similar to medical literature results with TEC treatment(15).
Figure 7. Gastrointestinal adverse reactions

Follow-up

Patients with Her2 positive disease received 12-month adjuvant Trastuzumab, and patients with HR positive disease received adjuvant hormonal therapy. Radiotherapy was administered in adjuvant setting according to guidelines. After 24 months, 25 out of 48 patients developed local recurrence or distant metastases.

TEC is a series of chemotherapy relatively well tolerated with RR superior to other neoadjuvant chemotherapy regimes - according to literature, in locally advanced breast cancer cases, such as the study by Kuerer HM, Newman Smith TL et al. Clinical course of breast cancer patients with pathologic complete axillary lymph node primary tumor and response to doxorubicin based neoadjuvant chemotherapy (J ClinOncol 1999; 17; 460-469) - pathologic complete response at 20% of the ganglionic cases.

Neoadjuvant treatment with taxanes is supported by the Trudeau M: Neoadjuvant Breast Cancer Disease Site Group - taxanes in the treatment of non-metastatic breast cancer. A systematic review. Cancer Treat. Rev. 31-2005.

Neoadjuvant chemotherapy with TEC regimens is an effective treatment for advanced breast cancers, and can prolong the long-term survival and disease-free survival after operation.

Obtained results were similar to those from literature, taking into account the fact that in the selected group of patients were included patients with Her 2 positive disease who did not receive Trastuzumab due to reimbursements constraints.

Discussion

Neoadjuvant treatment of breast cancer has become established as a safe and often effective therapeutic approach for larger primary and for locally advanced breast cancer. The neoadjuvant approach offers the advantages of downstaging the disease, potentially reducing the extent of surgery and in an era of individualization of therapy, testing the efficacy of therapy administered to patients.

We obtained good results taking into account the composition of the study population - with more patients in advanced stages, not administrating the Trastuzumab in neoadjuvant setting.

Although the administered Trastuzumab in adjuvant setting where appropriate, toxicity was acceptable, with lower grade 4 toxicities than expected. Therefore, we consider this type of cytotoxic regimen appropriate for use in neoadjuvant setting in proper cases. Her 2 positive cases require neoadjuvant administration of Trastuzumab and since it is already approved for this indication in Romania from the last year it should be used in all Her 2 positive breast cancer patients in neoadjuvant setting.

Bibliografie

1. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18 [J]. J Clin Oncol, 1997, 15(7):2483-2493.
2. Zhang B, Cai Y, Zhang Q, et al. Long-term results of preoperative chemotherapy for operable breast cancer [J]. ZhonghuaZhong Liu ZaZhi, 1997, 19(4):277-280. [in Chinese]
3. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27 [J]. J Clin Oncol, 2006, 24(13):2019-2027.
4. Liu K, Wang GB, Cheng B, et al. Clinical comparison of GC regimen (gemcitabine and cisplatin) versus FEC regimen (fluorouracil, epirubicin, and cyclophosphamide) as neoadjuvant chemotherapy for breast cancer [J]. Aizheng, 2007, 26(4):427-430. [in Chinese]
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10. Gunter von Minckwitz, SherkoKümmel, Petra Vogel, Claus Hanusch, for the German Breast Group- Intensified Neoadjuvant Chemotherapy in Early-Responding Breast Cancer: Phase III Randomized GeparTrio Study, Oxford Journals Medicine & Health JNCI J Natl Cancer Inst Volume 100, Issue 8, pp. 552-562.
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