Clinical trial NCT00851110: Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors
Official title: A Prospective Randomized Feasibility and Phase II Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: High-Risk Breast Cancer
Keywords: high dose
breast cancer
adjuvant
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2009-02-25
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Objectives of the study:

This randomized multicenter phase II study compares the tolerability, toxicity and quality of life between two high-dose chemotherapy regimens based on cyclophosphamide, thiotepa and carboplatin.

Regimen A: full dose CTC. Regimen B: two courses of CTC (tCTC) with 33% dose reduction.

Primary endpoints are:

* Maximum degree of non-hematological toxicity.

Secondary endpoint:

* Total number of hospital days.
* Quality of life evaluations during and following high-dose chemotherapy (up to 1 year).
* Effect of therapeutic dose monitoring of CTC or tCTC.

Trial design:

This investigation is a multicenter prospective randomized phase II study. Patients eligible for the study will be identified after mastectomy or wide tumor excision with axillary clearance. Following randomization, all patients will receive four courses of cyclophosphamide, epirubicin and fluorouracil (FEC). Patients with early progressive disease at any time will be taken off study. The first chemotherapy course must be given as soon as possible after the surgical procedure, preferably within 3 weeks, but not later than 6 weeks since primary surgery. After the third or fourth FEC course G-CSF is administered and peripheral stem cells will be harvested. All radiation therapy (including radiation therapy administered as part of a breast conserving strategy) must be postponed until all chemotherapy has been concluded.

Questionnaires, comprising the Rotterdam Symptom Checklist (RSCL) and the Short-Form General Health Survey (SF-36) will be sent by mail before randomization, after chemotherapy, 3 months thereafter, further on every l/2 yr till at least 1 year follow-up as performed earlier. \[6, 28, 29\].

All patients will be randomized before the initiation of chemotherapy.

* The 'standard' treatment arm will include 4 courses of FEC followed by high-dose chemotherapy with a single course of full dose CTC followed by peripheral stem cell reinfusion. Subsequently, conventional external beam radiotherapy to the breast or chest wall and to the regional lymph node areas including the axilla and the parasternal area will be administered following guidelines of the individual center. Patients with hormone receptor positive disease will go on to receive 5 years of tamoxifen. Patients with receptor positive disease who have not entered menopause will be advised to undergo ovarian ablation as well.
* The 'experimental' treatment arm will be identical to the 'standard' one, except that the single course of CTC will be replaced by 2 courses of tCTC each followed by peripheral stem cell reinfusion.

Detailed description: High-dose chemotherapy with the alkylating agent combination CTC appears to add significantly to the efficacy of conventional dose chemotherapy in patients with high-risk breast cancer, provided that the HER-2/neu gene is not amplified in the tumor. As a high-dose chemotherapy regimen, CTC is associated with significant toxicity \[31,32\]. Although high-dose alkylating therapy seems to be effective, there is virtually nothing known about the dose-response curve for this combination (for a detailed discussion see the classical paper by E. Frei III \[32\]. If one assumes that the efficacy increase levels off with increasing dose, the efficacy of tCTC might be almost as great as that of CTC, but with considerably less toxicity. In addition, two closely spaced courses of tCTC might further increase the efficacy of the regimen. There are some suggestions that a double transplant may be more effective than a single one, in multiple myeloma and in Ewing sarcoma. A similar suggestion has also been made for breast cancer (study of Nitz et al ref 4, table 1).

Eligibility criteria: Inclusion criteria:

1. Modified radical mastectomy (or breast conserving surgery) and axillary clearance, histologically confirmed stage IIA, IIB or IIIA adenocarcinoma (excluding supraclavicular lymph nodes) of the breast, with 4 or more involved axillary lymph nodes. Presence of tumor cells near or in the resection margins at microscopic examination is acceptable
2. The primary tumor must be immunohistochemically negative for HER-2/neu expression. An immunohistochemistry score of 1+ is also acceptable. A score of 3+ is not acceptable. A score of 2+ is only acceptable if a FISH analysis (or equivalent) has clearly shown that there is no HER-2/neu gene-amplification
3. No prior chemotherapy or radiotherapy
4. No evidence of distant metastases
5. Age \< 50 years
6. Performance status (ECOG-ZUBROD) 0 or 1;
7. Normal bone marrow function, WBC \> 4.0 x 109/l, platelets \> 100 x 109/l;
8. Adequate renal function (creatinine clearance \> 60 ml/min.);
9. Adequate hepatic function (serum bilirubin \< 25 umol/l);
10. Study treatment must begin within 6 weeks of surgery;
11. No other malignancy except adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin;
12. No significant prior or concomitant disorder that might interfere with adherence to the intensive treatment regimen, including but not limited to a history of angina, myocardial infarction or heart failure, severe lung function impairment, peptic ulcer disease, etc.;
13. Availability for follow-up.

Primary outcomes:
measure: Maximum degree of non-hematological toxicity.
Secondary outcomes:
measure: Total number of hospital days
measure: Quality of life evaluations during and following high-dose chemotherapy (up to 1 year)
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Free University Hospital
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Maastricht
country: Netherlands
facility: University Hospital Maastricht
city: Nijmegen
country: Netherlands
facility: University Medical Centre Nijmegen St. Radboud
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Daniel den Hoed Cancer Center
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
Study officials:
affiliation: University Medical Center Groningen
name: Elisabeth G.E. de Vries, MD, PhD
role: STUDY_DIRECTOR
affiliation: The Netherlands Cancer Institute
name: Sjoerd Rodenhuis, MD, PhD
role: STUDY_DIRECTOR
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