Neoadjuvant Chemotherapy

Three good things with Neoadj. Chemo:

  1. More BCT
  2. Assess clinical response instead of continuing a chemo which is not working ( in post-OP setting)
  3. Early end-point for clinical trials

In whom we can’t do the surgery as primary therapy:

  • Tumour greater than 5 cm (T3)
  • Fixation of the tumour to skin and/or chest wall (T4)
  • skin oedema (peau d'orange)
  • skin ulceration
  • satellite nodules and/or infiltration
  • large (>2.5 cm) or fixed/matted axillary LN (N2)
  • supraclavicular LN
  • arm oedema

These patients if are treated by mastectomy, > 50% will experience local disease recurrence and very few will survival 5 years or longer

Contraindications for Neoadjuvant Chemotherapy:

  • Multicentric carcinoma
  • extensive intraductal component
  • those who prefer mastectomy.

Patients most likely benefit (?)

  • ER negative
  • Unicentric
  • High grade

Does Neoadjuvant chemo improves survival?

NSABP B18 :

  • 1523 pts…. Operable…..
  • All received 4cycles of doxorubicin (A) and cyclophosphamide (C)
  • Arms:
    • BEFORE SURGERY
    • AFTER SURGERY
  • 9yrs OS and DFS identical
  • Response rate to neoadj: 79% ; CR: 13%
  • Also from this study we compare LR after BCT for those who were not candidate for BCT upfront comparing to those who were.
  • NSABP B18 LR: 15% in patients who required chemotherapy to undergo BCT vs 7% in those who were initially candidates for BCT.

EORTC

  • Confirmed no difference between Pre-Op vs Post-Op for OS and DFS
  • response rate: 49% ; complete response : 4%
  • fluorouracil, epirubicin and cyclophosphamide (FEC)
  • A meta-analysis of nine randomized trials of preoperative chemotherapy →no difference in OS but an elevated risk of locoregional recurrence
  • عوامل متعددی ممکن است منتج به افزایش عود موضعی در گروه نیواجاونت باشد. ازجمله تعدادی از بیمارانی با شیمی درمانی قبل به علت پاسخ کامل بالینی جراحی نگرفتند
  • inclusion of studies in the meta-analysis in which patients who had a clinical complete response did not have surgery.

a. The majority of patients with a clinical complete response do not have a pathologic CR (only 3-20%, with new chemo→ 34%)
b. Even in patients undergoing surgery an elevated risk of local recurrence has been observed.
c.
d. MARGINS: the volume of tissue resected is smaller than the volume originally occupied by the cancer. In this setting a negative margin may still be associated with a clinically significant residual tumor burden that is unlikely to be controlled by radiotherapy. Thus, an evaluation of both surgical margins and the extent of viable tumor elsewhere in the specimen is essential and may dictate resection of additional breast tissue even when margins are apparently tumor free. Percutaneous placement of marker clips within the primary tumor prior to the initiation of chemotherapy will provide a landmark for localization and excision should a clinical and radiographic complete response occur. The lack of a survival benefit for neoadjuvant therapy and the increased complexity in determining the appropriate extent of resection suggest that for women who are candidates for breast conservation at presentation, neoadjuvant therapy outside the context of a clinical trial offers little benefit.

NSABP B27

response rate : 91% ; CR: 19%

  • docetaxel (T) to AC.
  • Only 25% to 30% of patients who were not candidates for BCT at presentation were able to undergo the procedure after preoperative therapy.
  • Patchy nature of cancer after chemotherapy. The total number of viable tumor cells significantly decreases, but viable tumor remains scattered throughout the same volume of breast tissue ⇒ BCT not possible.
  • Rate of CR ( around 20% ) is IMPORTANT.
  • The question raised by this is doing sentinel node biopsy before chemo
    • If we do sentinel node biopsy after surgery → false negative sentinel node biopsy after neoadjuvant chemo ⇒ Which has implication on field size for XRT
    • If we do it before surgery
      • Disadvantages
        • The complete response will be less meaningful if the positive node is removed (that’s part of the disease!)
        • Delay of chemo particularly if it’s positive and an axillary dissection shall be done

In this trial : False NEG rate ( before chemo): 11%
Another meta-analysis

  • 1273 pts → sentinel node biopsy then axillary dissection then neoadj chemo.
  • False NEG rate : 12%
  • Results are similar to post chemo false neg

⇒ delaying sentinel lymph node surgery until after chemotherapy appears acceptable.

Patients with Human Epidermal Growth Factor Receptor-2 (HER-2) POSITIVE

  • Neoadj. Herceptin (trastuzumab) + chemotherapy → good complete response.
  • A randomized study (42 patients)
    • CR ↑: 26% to 65% By HERCEPTIN
    • A significant improvement in disease-free survival was also noted for trastuzumab
    • median follow-up of 36.1 months.
    • To date, no increase in cardiac dysfunction has been observed in the HERCEPTIN group.