Clinical trial NCT01352091: Adjuvant AI Combined With Zoladex
Official title: A Randomized ,Open Label Study Comparing the Efficacy of Zoladex® Combined With Arimidex® for 3-2 Years After Selective Estrogen Receptor Modulators (SERMs) as an Adjuvant Therapy for 2-3 Years Versus Continuing Tamoxifen up to 5 Years for Premenopausal Early Breast Cancer Patients With Hormone Receptor Positive, Lymph Node Positive or Tumor≥ 4cm.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Breast Cancer
Keywords: breast cancer
adjuvant endocrine therapy
AI
Zoladex
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2011-05-11
Enrollment: 670
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The present study is a randomized open-label -phase III study that aims to compare the efficacy of Zoladex® combined with Aromidex® for 3-2 years after SERMs (tamoxifen and Fareston®) as an adjuvant therapy for 2-3 years with the efficacy of tamoxifen up to 5 years for premenopausal breast cancer women with hormone receptor positive, lymph node positive or tumor ≥4cm. According to St. Gallen's guideline, hormone receptor positive was defined as endocrine responsive and endocrine response uncertain categories (table 3-1), and only those with ER or PR expression undetectable were considered as HR negative. The pathological evaluation of axillary lymph node could be done by sentinel node biopsy (SNB) when axillary nodes were clinically impalpable accompanied with axillary lymph node dissection (ALND) or directly through ALND when axillary nodes appeared to be positive in clinical examination. Based on the operating standard of local medical institution, identifying the numbers of lymph nodes to do the pathological evaluation and to do the dissection of I- or II-station nodes accurately.


Eligibility criteria: Inclusion Criteria:

1. All patients must have signed and dated an informed consent form
2. Patients must be female
3. Primary invasive breast cancer pathologically approved by core needle or open biopsy
4. Ipsilateral axillary or internal mammary nodes positive, or tumor size is equal to or larger than 4cm. Definition of nodes positive is according to the staging system of AJCC 6th edition (American Joint Cancer Commission) for breast carcinoma. The micrometastasis must be at least 0.2mm
5. Patients must have undergone standard surgery for primary breast cancer as shown in the following:

   * a standard radical mastectomy or modified mastectomy
   * standard breast conservation surgery (BCS), which is lumpectomy or qaudrantectomy accompany with axillary dissection, and the surgical margins of the resected specimen must be negative. BCS must be followed by standardized adjuvant radiotherapy to the partial conserved breast (delivered after adjuvant chemotherapy completed)
   * Treatment for confirmed breast cancer including the surgery modality listed above, loco-regional radiotherapy after lumpectomy, adjuvant radiotherapy to the chest wall and/or internal mammary nodes and/or supraclavicular lymph nodes, adjuvant chemotherapy
6. adjuvant endocrine therapy of TAM or Fareston must be started within 6 weeks when adjuvant chemotherapy or radiotherapy was finished
7. The date of randomization must be processed after taking TAM or Fareston for 2 or more than 2 years, but not more than 3 years of time
8. Patients taking neo-chemotherapy are eligible, and lymph node status could be identified during surgery before neo-adjuvant chemotherapy or after neo-adjuvant chemotherapy. The definition of lymph node positive is:

   * evaluation of lymph node status before neo-adjuvant chemotherapy must include pathological axillary nodes, internal mammary nodes (pN2b option) or supraclavicular nodes (pN3c option) involved. Micro-metastasis (i.e.≥0.2mm, pN1-pN3c) can be identified by the following method: fine needle aspiration (FNA) or sentinel node biopsy (SNB) or sampling/ total procedure of axillary dissection
   * patients with no nodes positive after neo-adjuvant chemotherapy, lymph node positive must be evaluated during surgery. Its definition was the either of following:

     * According the clinical practice guidelines of the local cancer center, it is acceptable when positive nodes was identified by SNB or axillary dissection
     * There is pathological evidence in lymph nodes positive (pN1-pN3c) during breast surgery after neo-adjuvant chemotherapy
9. Patients diagnosed as occult breast cancer clinically are found to pathologically have primary invasive carcinoma or DCIS with micro-invasive lesion in ipsilateral breast, and primary lesion or axillary node metastasis express ER and/or PR positive
10. Patients with synchronous bilateral cancers are eligible on the condition that If one side is IDC and the other side is DCIS, the IDC side should be of the ER and/or PR positive phenotype and IF two sides are both IDC, they must be ER and/or PR positive phenotype at the same time
11. Hormone receptor positive (≥＋) is defined as detecting ER or PR expression at any time is eligible. The situation of only PR positive and ER negative is eligible, too
12. According to the standard operation principles for clinical practice of local cancer center, patients must be randomized within 4 weeks after definitive physical examination, imaging examination and laboratory testing show no evidence of recurrence or metastasis
13. Based on the study objective, all patients are required to be premenopausal as defined by

    * menstruating actively
    * less than 6 months since last menstrual period (LMP), or patients younger than 40 years of age who became amenorrheic not more than 1 year if the serum free E2、FSH and LH level was premenopausal (according to the reference value of local center).
    * had previous hysterectomy with one or both ovaries left intact are eligible if the serum free E2、FSH and LH level are premenopausal (according to the reference value of local center).
14. patients must have an ECOG performance status of 0 or 1 (0-fully active, able to carry on all pre-disease performance without restriction, 1-restricted in physical strenuous actively but ambulatory)
15. leucocyte count must be ≥3.0\*10\^9/L and platelet count must be ≥100\*10\^9/L
16. AST/SGOT or ALT/AGPT must be \<3 times the ULN
17. serum creatinine must be \<2 times the ULN
18. patients can swallow pills
19. pregnancy testing is negative and are willing to do contraception during the treatment period

Exclusion Criteria:

1. patients with metastatic malignant tumor
2. previous history of asynchronous bilateral breast cancer
3. any previous malignancy in the past 5 years, except for those treated with curative intent, such as carcinoma in situ of the cervix, squamous carcinoma of the skin or basal cell carcinoma of the skin
4. any non-malignant systemic disease which interfere long time follow up
5. history of medical ovarian ablation therapy
6. history of AI therapy
7. severe live dysfunction, Child-Pugh is grade C
8. Occult breast cancer is found pathologically no IDC lesion or only DCIS without micro-invasive lesion in the ipsilateral breast
9. patients with Her-2 overexpression had used, or is using, or intending to use adjuvant trastuzumab
10. severe heart dysfunction, heart functional classification is above Class III Table 2 Child-Pugh score of hepatic cirrhosis

Primary outcomes:
measure: DFS
timeFrame: 5 Years
Secondary outcomes:
measure: OS
timeFrame: 5 years
measure: Time to distant metastasis
timeFrame: 5 years
measure: Bilateral secondary primary breast cancer morbidity
timeFrame: 5 years
measure: DDFS
timeFrame: 5 years
measure: Osteoporosis related events
timeFrame: 5 years
measure: Other adverse events
timeFrame: 5 years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: FUSCC
state: Shanghai
Study officials:
References:
citation: Li JW, Liu GY, Ji YJ, Yan X, Pang D, Jiang ZF, Chen DD, Zhang B, Xu BH, Shao ZM. Switching to anastrozole plus goserelin vs continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: preliminary results from a randomized trial. Cancer Manag Res. 2018 Dec 27;11:299-307. doi: 10.2147/CMAR.S183672. eCollection 2019.