Breast Cancer
Conditions
Keywords
Stage II and IIIA breast Cancer., Neoadjuvant chemotherapy., Weekly docetaxel.
Brief summary
Treatment consists of 4 AC cycles followed by 2 weekly docetaxel cycles (12 infusions). The pathological complete response rate obtained in previous studies is around 12%. The expected pathological complete response rate in this study is 25%. With an alpha error of 0.05 and a beta error of 0.2, and following Simon´s 2 phase test, 19 patients are needed initially. With 2 pathological complete responses, patient recruitment will continue until approximately 61 patients are recruited. Twelve pathological complete responses are needed to confirm the study hypothesis.
Detailed description
Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176). Adjuvant chemotherapy and radiotherapy were delivered according to the protocol of each participating center. Hormonal treatment was started after the last chemotherapy infusion in all patients with positive estrogen and/or progesterone receptor tumors and was continued for five years. Semiquantitative determination of three molecular markers was carried out by immunocytochemical methods. Tissue samples were taken prior to initiation of chemotherapy from the core of the primary tumors. Specimens were sent to a central laboratory for analysis of Topo II, survivin and p27.
Interventions
DRUGDoxorubicin
DRUGCyclophosphamide
DRUGDocetaxel
Sponsors
Sanofi
Spanish Breast Cancer Research Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent. * Patients with breast cancer stages II and IIIA, with histological diagnoses as per true-cut or open biopsy. * Negative extension study, including bilateral mammography, thoracic x-ray, computed tomography (CT)-scan or abdominal echography and bone scintigraphy. * Analysis of hormone receptor status in primary tumour. It is highly recommended to obtain a tumour tissue sample before start of treatment, and after definitive surgery. These samples will be analysed centrally by Spanish Breast Cancer Research Group (GEICAM). * Age \>= 18 and \<= 70 years old. * Performance status as per Karnofsky index \>= 80. * Minimum life expectancy of 6 months. * Electrocardiogram (EKG) 12 weeks before registration to the study. If abnormalities are suspected, cardiac function must be assessed by left ventricular ejection fraction (LVEF). * Haematology: neutrophils \>= 2.0 x10\^9/l; platelets \>= 100 x10\^9/l; hemoglobin \>=10 g/dl. * Hepatic function: total bilirubin \<= 1 x upper normal limit (UNL); Aspartate aminotransferase (AST) (SGOT) and and Alanine aminotransferase (ALT) (SGPT) \<= 2.5 x UNL; alkaline phosphatase \<= 5 x UNL. * Renal function: creatinine \<= 1.5 x UNL; creatinine clearance \>= 60 ml/min. * Patients able to comply with study requirements. * Negative pregnancy test. * Adequate contraceptive method during the study and up to 3 months after definitive surgery.
Exclusion criteria
* Previous systemic therapy for breast cancer treatment. * Previous treatments with anthracyclines or taxanes for any malignancy. * Previous radiotherapy for breast cancer. * Bilateral invasive breast cancer. * Pregnant or lactating women. * Previous motor or sensorial neurotoxicity grade \>=2. * Other serious pathologies: congestive heart failure or angina pectoris; history of myocardial infarction in the previous year; uncontrolled hypertension (HT) or high risk arrhythmias. * History of neurological or psychiatric impairment, precluding patients from providing free informed consent. * Active infection. * Active peptic ulcer; unstable diabetes mellitus. * History of previous or current malignancies other than breast cancer, except for basal skin carcinoma, cervical in situ carcinoma, other tumour diagnosed and treated more than 10 years before, ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). * Chronic treatment with corticoids unless the treatment started \> 6 months before registration to the study, and low doses are administered. * Substitutive hormonal therapy. This treatment must be interrupted before inclusion in the study. * Concomitant treatment with other investigational products or administration in the 30 previous days. * Males.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate | Up to 29 weeks | Pathological complete response was defined by the Miller & Payne criteria. pCR was defined as no invasive cells identifiable in breast sections at surgery. Response was measured by physical exam and breast imaging before surgery and was evaluated according to the World Health Organization (WHO) criteria. Pathological response after surgery, was based on the proportion of remaining tumor and postchemotherapy changes, evaluating separately the response in the breast and in the axilla lymph nodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response Rate (CRR) | Up to 29 weeks | CRR measured according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, where: * Complete Response (CR): disappearance of all target lesions * Partial Response (PR): \>=30% decrease in the sum of the longest diameter of target lesions * Progresive Disease (PD): \>=20% increase from smallest sum of longest diameter recorded since treatment started (best response). * Stable Disease (SD): Neither PD nor PR |
| Number of Participants With Over-expression of Topo II (>10% Cells With Nuclear Staining) | Up to 29 weeks | Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Over-expression of Topo II was defined as \>10% cells with nuclear staining. |
| Number of Participants With Over-expression of Survivin (>1% Cells With Nuclear Staining) | Up to 29 weeks | Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Tumors with more than 1% of cells with nuclear staining were considered to be over-expressing this protein. |
| Number of Participants With Over-expression of p27 (>75% Cells With Nuclear Staining) | Up to 29 weeks | Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Sections were rated according to the percentage of tumor cells nuclei with positive staining (1 = \< 25%; 2 = between 25-75% and 3 = \> 75%). |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Doxorubicin + Cyclophosphamide Followed Docetaxel Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176). | 63 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 1 |
Baseline characteristics
| Characteristic | Doxorubicin + Cyclophosphamide Followed Docetaxel |
|---|---|
| Age, Continuous | 48.43 years |
| Disease stage (I, IIA, IIB y IIIA) I | 1 Participants |
| Disease stage (I, IIA, IIB y IIIA) IIA | 23 Participants |
| Disease stage (I, IIA, IIB y IIIA) IIB | 35 Participants |
| Disease stage (I, IIA, IIB y IIIA) IIIA | 4 Participants |
| Hormonal receptors (Estrogen Receptor [ER]+/ Progesterone Receptor [PR]+, ER+/PR-, ER-/PR+, ER-/PR-) ER-/PR- | 10 Participants |
| Hormonal receptors (Estrogen Receptor [ER]+/ Progesterone Receptor [PR]+, ER+/PR-, ER-/PR+, ER-/PR-) ER-/PR+ | 3 Participants |
| Hormonal receptors (Estrogen Receptor [ER]+/ Progesterone Receptor [PR]+, ER+/PR-, ER-/PR+, ER-/PR-) ER+/PR- | 18 Participants |
| Hormonal receptors (Estrogen Receptor [ER]+/ Progesterone Receptor [PR]+, ER+/PR-, ER-/PR+, ER-/PR-) ER+/PR+ | 32 Participants |
| Median Tumor size, cm | 4.8 cm |
| Menopausal status Postmenopausal | 28 Participants |
| Menopausal status Premenopausal | 35 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 63 Participants |
| Region of Enrollment Spain | 63 participants |
| Sex: Female, Male Female | 63 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 63 |
| other Total, other adverse events | 63 / 63 |
| serious Total, serious adverse events | 12 / 63 |
Outcome results
Primary
Pathological Complete Response (pCR) Rate
Pathological complete response was defined by the Miller & Payne criteria. pCR was defined as no invasive cells identifiable in breast sections at surgery. Response was measured by physical exam and breast imaging before surgery and was evaluated according to the World Health Organization (WHO) criteria. Pathological response after surgery, was based on the proportion of remaining tumor and postchemotherapy changes, evaluating separately the response in the breast and in the axilla lymph nodes.
Time frame: Up to 29 weeks
Population: 2 patients did not received surgery, 1 because of disease progression, and 1 due to inacceptable toxicity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Pathological Complete Response (pCR) Rate | 11 Participants |
Secondary
Clinical Response Rate (CRR)
CRR measured according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, where: * Complete Response (CR): disappearance of all target lesions * Partial Response (PR): \>=30% decrease in the sum of the longest diameter of target lesions * Progresive Disease (PD): \>=20% increase from smallest sum of longest diameter recorded since treatment started (best response). * Stable Disease (SD): Neither PD nor PR
Time frame: Up to 29 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Clinical Response Rate (CRR) | Complete response | 29 Participants |
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Clinical Response Rate (CRR) | Partial response | 28 Participants |
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Clinical Response Rate (CRR) | Stable Disease | 5 Participants |
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Clinical Response Rate (CRR) | Unknown | 1 Participants |
Secondary
Number of Participants With Over-expression of p27 (>75% Cells With Nuclear Staining)
Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Sections were rated according to the percentage of tumor cells nuclei with positive staining (1 = \< 25%; 2 = between 25-75% and 3 = \> 75%).
Time frame: Up to 29 weeks
Population: 20 patient tumor sample could not be evaluated
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Number of Participants With Over-expression of p27 (>75% Cells With Nuclear Staining) | < 75% | 24 Participants |
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Number of Participants With Over-expression of p27 (>75% Cells With Nuclear Staining) | > 75% | 17 Participants |
Secondary
Number of Participants With Over-expression of Survivin (>1% Cells With Nuclear Staining)
Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Tumors with more than 1% of cells with nuclear staining were considered to be over-expressing this protein.
Time frame: Up to 29 weeks
Population: 17 patient tumor sample could not be evaluated
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Number of Participants With Over-expression of Survivin (>1% Cells With Nuclear Staining) | > 1 % | 18 Participants |
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Number of Participants With Over-expression of Survivin (>1% Cells With Nuclear Staining) | < 1% | 26 Participants |
Secondary
Number of Participants With Over-expression of Topo II (>10% Cells With Nuclear Staining)
Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Over-expression of Topo II was defined as \>10% cells with nuclear staining.
Time frame: Up to 29 weeks
Population: 20 patient tumor sample could not be evaluated
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Number of Participants With Over-expression of Topo II (>10% Cells With Nuclear Staining) | > 10% | 20 Participants |
| Doxorubicin + Cyclophosphamide Followed Docetaxel | Number of Participants With Over-expression of Topo II (>10% Cells With Nuclear Staining) | < 10% | 21 Participants |