SWOG S0221 - "Phase III Trial of Continuous Schedule AC + G Vs. Q 2 Week Schedule AC, Followed by Paclitaxel Given Either Every 2 Weeks or Weekly for 12 Weeks as Post-Operative Adjuvant Therapy in Node-Positive or High-Risk Node Negative Breast Cancer"

Treatment Plan    (Supplied Drug:  G-CSF.  Pegfilgrastim may be eligible for reimbursement.)

RANDOMIZATION

Arm 1 (q14days x 6)

Doxorubicin:  60mg/m2, IV bolus, Day 1

Cyclophosphamide:  600mg/m2, IV rapid infusion, Day 1

Pegfilgrastim:  6mg (regardless of BSA), SubQ, Day 2

Followed by (beginning 14 days following last cycle of Doxorubicin/Cyclophosphamide):

(Q14days x 6 - see protocol for pre-medication regimen)

Paclitaxel:  175mg/m2, IV over 3 hrs, Day 1

Pegfilgrastim:  6mg (regardless of BSA), SubQ, Day 2

Arm 2 (weekly x 15)

Doxorubicin:  24mg/m2, IV bolus, Day 1

Cyclophosphamide:  60mg/m2 (rounded to nearest 25mg dose), PO, QD

Filgrastim:  5mcg/kg, SQ, Days 2-7 (begin 24hrs after Doxorubicin)

Prophylactic Trimethoprim Sulfa:  1 DS-tablet, PO, BID, Days 4 & 5

Followed by (beginning 14 days following last cycle of Doxorubicin/Cyclophosphamide):

(Q14days x 6 - see protocol for pre-medication regimen)

Paclitaxel:  175mg/m2, IV over 3 hrs, Day 1

Pegfilgrastim:  6mg (regardless of BSA), SubQ, Day 2

Arm 3 (q14days x 6)

Doxorubicin:  60mg/m2, IV bolus, Day 1

Cyclophosphamide:  600mg/m2, IV rapid infusion, Day 1

Pegfilgrastim:  6mg (regardless of BSA), SubQ, Day 2

Followed by (beginning 14 days following last cycle of Doxorubicin/Cyclophosphamide):

(Weekly x 12 - see protocol for pre-medication regimen)

Paclitaxel:  80mg/m2, IV over 1 hr, Day 1

Arm 4 (weekly x 15)

Doxorubicin:  24mg/m2, IV bolus, Day 1

Cyclophosphamide:  60mg/m2 (rounded to nearest 25mg dose), PO, QD

Filgrastim:  5mcg/kg, SQ, Days 2-7 (begin 24hrs after Doxorubicin)

Prophylactic Trimethoprim Sulfa:  1 DS-tablet, PO, BID, Days 4 & 5

Followed by (beginning 14 days following last cycle of Doxorubicin/Cyclophosphamide):

(Weekly x 12 - see protocol for pre-medication regimen)

Paclitaxel:  80mg/m2, IV over 1 hr, Day 1

Arms 1-4:  Hormonal Therapy for ER+ or PR+ Pts after Completion of Chemo

(See protocol for additional info)

Eligibility

• Women or men w/histol-confirmed dx of operable Stg I, II, or III invasive breast cancer w/known estrogen or progesterone receptor status.  No T4 tumors.  NOTE:  Pts are encouraged to submit tissue for banking.

• Bilat synchronous breast cancer diagnosed w/i 1 mo of each other is allowed if the higher TNM stage prim tumor meets eligibility for this trial.

• Must be high-risk by >1 of following:

  • Tumor >2cm in greatest diameter (determined from path specimen).  Size = max diameter of entire lesion, including invasive and intraductal components.  With multi-focal tumors, use largest lesion w/invasive component.  If tumor is resected in pieces, pathologist must re-orient tumor fragments to determine size.  Pts whose nodal status is N0i+ (no cluster of tumor cells in any node >0.2mm) are considered node-neg & must have prim tumors >2cm in size or tumors >1cm w/high risk features as defined below.  Pts registered to NCI-funded national sentinel node studies (i.e, NSABP B-32) are eligible.  Node-negative pts on basis of SN procedure may be entered if <6 axillary nodes were removed; otherwise >6 axillary or intrammary nodes must be negative for pt to be considered node-neg.

  • Tumor >1cm in diameter & either:

    • ER-neg & PgR-neg OR

    • ER-pos or PgR-pos w/Genomic Health Recurrence Score >26

  • >1 axillary or intramammary nodes are involved by mets breast cancer.  If >1 node is involved, >6 axillary or intramammary nodes must have been examined histologically.  Pts with N0 (i+) disease are considered node negative.

• HER-2 positive tumors (3+ by immunohistochemical staining or amplified by fluorescence in-situ hybridization) is allowed.

• Must have either modified radical mastectomy or local excision of all tumors plus an axillary lymph node dissection or sentinel node resection pre-regist.  Final resection margins for prim tumor must be histologically negative for invasive cancer and DCIS.  Pts w/resection margins positive for LCIS are eligible.  Must have >6 axillary or intramammary nodes sampled, w/exception of pts who have SN procedure w/all sampled nodes being uninvolved by malignancy.

• Must be registered w/i 84 days from final surgical procedure to adequately treat prim tumor &/or axilla.

• No prior cytotoxic chemo for this breast cancer.  No prior chemo w/anthracycline, anthracenedione, or taxane for any condition.  Pts enrolled on this protocol may also be enrolled on SWOG S0230, IBCSG 24-02 (SOFT), or IBCSG 25-02 (TEXT).

• No prior RT for current malignancy, except for PBI following lumpectomy.  PBI completed >2 wks pre-regist.  Pts who have completed prior RT for DCIS are eligible if RT completed >2 wks pre-regist.  NOTE:  Pts who had segmental mastectomy or other breast sparing procedure will be treated w/RT according to standard procedure after completion of all chemo, unless treated w/PBI.  Participation in NSABP B-39 is allowed.  Pts who had modified radical mastectomy may receive regional RT after completion of all chemo, at treating physician's discretion.

• No CHF or active angina pectoris.  If hx of HTN or age >60, must have MUGA or echo w/i 42 days pre-regist w/LVEF% >ILLN.

• Serum creat & bili <IULN; alk phos <2x IULN; SGOT or SGPT <2x IULN; ANC >1200/µl; platelets >100,000/µl (all w/i 28 days pre-regist).

• Females of reproductive potential must have negative pregnancy test w/i 28 days pre-regist.  All pts of reproductive potential must use effective contraception during entire tx period.

• No other prior malignancy except adequately treated non-melanoma skin cancer, cervical cancer in situ, LCIS of breast, or other cancer disease-free >5 yrs.  Prior invasive breast cancer of DCIS is allowed if disease-free >5 yrs.

• Age >18.

• Zubrod perf status 0-2.

• No known HIV positive pts.

• Pts who consent to genetic polymorphism sample submission must submit a pre-tx sample of 17mL blood (one 10mL red top serum tube) for banking and 7mL purple top EDTA tube for DNA extractions.  Process per protocol.  Ship purple-top vacutainers on wet ice to:  Warren Davis, PhD; Breast Lab, DNA Analysis; Roswell Park Cancer Center; Buffalo, NY.  Ship frozen serum vials on dry ice to:  Kimberly Gonzales; Breast Serum Repository; CLASS Laboratory; Ann Arbor, MI.

• PRESTUDY REQUIREMENTS:

  • H&P, wt, perf status

  • Disease asmt

  • Antioxidant Questionnaire (w/pt's consent)

  • CBC/diff/platelets*

  • Serum creat*

  • Bili*

  • SGOT or SGPT*

  • Hormone receptor status

  • Alk phos*

  • Tissue specimen for banking*** (required to seek additional pt consent)

  • Serum specimen for banking# (required to seek additional pt consent) - Contact KCCOP for kit

  • Blood for analysis of genetic polymorphisms (encouraged)# - Contact KCCOP for kit

  • CXR**

  • MUGA, echo, or cardiac catherization (w/i 42 days pre-regist)

  • CT chest/abdomen**

  • Bone scan**

  *     Within 28 days pre-regist

  **   Recommended pre-study as good medical practice

  *** 1 block of prim tumor or punch of block + 25 unstained 5 micron sections on plus slides.  Ship on cold pack to SWOG Solid Tumor Tissue Bank (Lab #78).

  #    See protocol for collection information.  Ship on ice pack (Mon-Thurs) via overnight delivery to:  Warren Davis, PhD; SWOG Breast Lab - DNA Analysis (Lab #110).  If drawn on Friday, store till following week and then ship.

• Signed informed consent.