CALGB 40101 - "Cyclophosphamide and Doxorubicin (CA x 4 Cycles) Versus Paclitaxel (4 Cycles) as Adjuvant Therapy for Breast Cancer in Women with 0-3 Positive Axillary Lymph Nodes:  A 2 X 2 Factorial Phase III Randomized Study "

Treatment Plan    (Supplied Drug:  None)

1)  RANDOMIZATION

(Administration of Filgrastim, Sargramostim, or Pegfilgrastim is recommended.  See protocol.)
Standard Chemo Arm (4 cycles)
Cyclophosphamide:  600mg/m2, IV per institutional guidelines, Day 1, q 14 days
Doxorubicin:  60mg/m2, IV bolus per institutional guidelines, Day 1, q 14 days
Single Agent Arm (4 cycles)
Paclitaxel:  175mg/m2, IV over 3 hrs, q 14 days

2)  XRT (if indicated)
Mandatory for lumpectomy pts. Pts who have undergone mastectomy may receive chest wall and nodal XRT.

3)  Tamoxifen
20mg, PO, QD, x 5 yrs is recommended if ER &/or PgR positive.  Trastuzumab allowed for pts whose tumors overexpress HER2.

NOTE:  Aromatase inhibitors may be substituted for Tamoxifen in post-menopausal women or administered after 2-5 yrs of Tamoxifen.

Eligibility

• Histol-confirmed invasive female breast carcinoma, w/0-3 positive axillary lymph nodes.

• Must have 0-3 positive axillary nodes.  Pts w/node-negative breast cancer must have sufficiently "high-risk" node-negative breast cancer to warrant chemo. (Generally, tumors >=1cm or ER or PgR receptor negative tumors of any size).   Ultimately, definition of "high-risk" determined by treating physician.  For pts w/1-3 positive axillary nodes, pt is eligible regardless of prim breast tumor characteristics, if tx deemed beneficial by treating physician.
  • Node-Negative Disease:  If pt had negative SN bx, no further axillary dissection is required, and pt is determined node-negative.  If axillary dissection w/o SN bx is performed, >6 axillary lymph nodes must be removed and analyzed and negative for pt to be determined node-negative.  Axillary nodes w/single cells or tumor clusters <0.2mm by H&E or IHC are considered node-negative.  Lymph nodes positive for PCR w/tumor cells or clusters <0.2mm are considered node-negative.  Any axillary lymph node w/tumor clusters >0.2mm will be considered positive.
  • 1-3 Positive Axillary Nodes:  If pt has SN bx and 1 of sentinel nodes is positive (tumor clusters >0.2mm), an axillary dissection must be performed.  Total of >6 axillary lymph nodes, including sentinel nodes + subsequent dissection, must be removed for pt to be eligible.  Of all lymph nodes removed from SN procedure and axillary dissection, 1-3 must be positive for pt to be eligible as node-positive pt.  If axillary dissection is done w/o SN procedure, >6 lymph nodes must be removed and 1-3 must be positive for pt to be considered node-positive and eligible.
• Determination of involvement of axillary nodes w/mets cancer will follow revised TNM staging system:  Axillary nodes w/single cells w/tumor clusters <0.2mm (by either H&E or IHC) will be considered negative axillary node.  Lymph nodes positive for PCR w/tumor cells/clusters <0.2mm will be considered negative axillary node.  Any axillary lymph node w/tumor clusters >0.2mm will be considered positive.
• Pts w/ER &/or PgR negative, positive, or unknown tumors are eligible. ER and PgR assays should be performed by immunohistochemical methods according to local institution's standard protocol.
• Pts with HER2 positive, negative, or unknown disease are eligible.  Pts whose tumors are HER2 positive by IHC 3+ staining or demonstrate gene amplification by FISH may receive Trastuzumab.
• Must be negative tumor margins for invasive cancer and DCIS in the case of mastectomy or lumpectomy. LCIS is acceptable at the margin.
• Multi-centric breast cancer allowed if all known disease is resected w/negative margins and 0-3 positive axillary nodes as defined in protocol.
• Must be registered w/i 84 days of last breast surgery (either modified radical mastectomy or lumpectomy).  For pts undergoing sentinel node sampling or axillary dissection, a simple mastectomy is acceptable.  Lumpectomy pts must receive RT per protocol.  If treated w/RT prior to chemo, pt should be registered after conclusion of RT, w/chemo beginning w/i 7 days of regist.  All prim breast and axillary node surgery must be completed prior to study enrollment. 
• No previous Trastuzumab, chemo, or hormonal therapy for this malignancy, except Tamoxifen as defined below.
• No previous anthracycline chemo for any disease.
• No locally advanced breast cancer, inflammatory breast cancer, or mets breast cancer. No involvement of dermal lymphatics on path, even if no clinical signs of inflammatory cancer.
• Bilateral, synchronous invasive breast disease is allowed if both primary tumors meet protocol criteria.  If pt has an invasive cancer on 1 side that meets eligibility criteria, & DCIS or LCIS on contralateral side, the pt is eligible. 
• Disease-free from prior malignancies >5 yrs, except curatively treated non-melanoma skin cancer or cervical carcinoma in situ.   Invasive breast cancer or DCIS are allowed if disease-free >5 yrs.  LCIS is allowed regardless of interval from dx.
• Age >=18.
• CTC perf status 0-1.
• No pregnant or nursing women.
• Concomitant exogenous hormone therapy including oral contraceptives, post-menopausal HRT, and Raloxifene must be stopped before pt is enrolled.
• May have received <=4 wks of Tamoxifen for this malignancy. Pts who received Tamoxifen or another SERM for prevention or for other indications are eligible. Tamoxifen or other SERMs must be discontinued pre-study enrollment.  Use of bisphosphonates for tx of osteoporosis is allowed.  No raloxifene after study enrollment.
• No active CHF. No MI <6 mos pre-regist.
• ANC >=1000/mm3; platelets >=100,000/mm3; creat <2.0mg/dl; bili <=1.5x IULN.
• May be enrolled on adjuv bisphosphonate studies.  May be enrolled concurrently or sequentially on 40101 and bisphosphonate trials.
• May be enrolled on adjuv hormonal studies approved by CALGB or CTSU such as SOFT and TEXT trials.  Hormonal therapy will begin as outlined in the specific hormonal trial.  The specified adjuv hormonal therapy will replace standard Tamoxifen or aromatase inhibitor recommended for after the conclusion of chemo.
• PRESTUDY REQUIREMENTS:
  • Hx & Progress Notes
  • PE
  • Pulse, BP
  • Ht, Wt, BSA
  • Perf Status
  • Pelvic exam w/cytology*
  • Eye exam (if receiving Tamoxifen)
  • EKG
  • MUGA/Echo
  • CBC/diff/platelets
  • Serum creat, BUN
  • Serum lytes
  • SGOT, SGPT, alk phos, bili
  • Whole blood for pharmacogenetics (optional companion - 5-10ml drawn prior to beginning study tx)
  • ER/PgR, HER2
  • CXR (PA & Lat)**
  • Bone scan** (only if clinical suspicion of positivity)
  • Mammogram**
    *  Recommended w/i 12 mos pre-study entry.
    ** If obtained as part of original dx, bx, and surgical tx need not be repeated. CXR is not required if chest CT was performed as part of pt's workup and showed no evidence of mets.
• Signed informed consent.