Locally Advanced Breast Cancer
Locally Advanced Breast Cancer Background
Locally advanced breast cancer refers to Stage III disease. Stage III breast cancers encompasses non-metastatic breast cancers and includes those not generally considered operable. Stage III breast cancers encompass N2 disease (fixed or matted axillary lymph nodes or pathologically ≥ 4 LN with metastatic disease), N3 disease (clinically observed internal mammary nodes and ALN, I/L supraclavicular nodes, or infraclavicular nodes--Axillary Level III nodes, with or without Level I/II ALN or pathological confirmed metastases in ≥ 10 LN, or T4 disease involving skin, dermal lymphatics or chest wall or inflammatory breast cancer. Historically these diseases have not done well with surgical intervention. Stage IIB (T3N0 size > 5 cm) is sometimes included in locally advanced breast cancer categories. Inflammatory breast cancers (T4d) are included but M1 disease is not. In 1948 Haagensen & Stout published the "Grave signs of Locally Advanced Breast Cancer:
- Limited edema or peau d'orange skin
- Skin ulceration
- Fixation of tumor to chest wall
- Axillary lymph nodes ≥ 2.5 cm
- Fixed axillary lymph nodes
Diagnostic and Staging Studies
The normal work up and staging studies include a history and physical examination, CBC, LFT, ER/PR/Her2 receptor status, diagnostic imaging (mammogram, ultrasound, bone scan, CXR/CT as indicated, CT abdomen and pelvis. Pathlogic examination of axillary lymph nodes demonstrate that with T2 - T3 breast cancers (tumor size greater than 2 cm) there is a 30 % risk of pathologically positive axillary lymph nodes.
Patients with inflammatory breast cancer have twice the risk of death as those who have other locally advanced disease. Inflammatory breast cancer is a clinical diagnosis with a rapid onset (generally < 3 months), generalized induration, often without an associated mass, peau d'orange appearance and diffuse skin erythema affecting more than 2/3 of the breast. Nipple enlargement, retraction with warmth, and tenderness are common. Inflammatory breast cancer is pathologically characterized by dermal lymphatic involvement, but this is not required for diagnosis. It is a clinical diagnosis. Random biopsy of breast parenchyma may yield tumor cells.
Prognosis
Increasing number of positive lymph nodes and breast tumor size are the most important predictors for local and regional recurrence.
Staging
AJCC StagingTis | DCIS/LCIS/Isolated Paget's Disease |
T1mi | micro invasion ≤ 1 mm |
T1a | > 0.1 cm - 0.5 cm |
T1b | > 0.5 cm - 1 cm |
T1c | > 1 cm - 2 cm |
T2 | > 2 cm - 5 cm |
T3 | > 5 cm |
T4a | extension to chest wall excluding pectoralis muscle |
T4b | edema including peau d'orange or ulceration of skin of breast or satellite nodules confined to the same breast |
T4c | Both T4a and T4b |
T4d | Inflammatory breast cancer (clinical diagnosis) |
N1 | movable ipsilateral axillary LN |
N2a | Fixed ipsilateral axillary nodes |
N2b | Clinically apparent IM nodes absent clinically evident axillary nodes |
N3a | ipsilateral infraclavicular nodes |
N3b | ipsilateral IMN and ALN |
N3c | Ipsilateral supraclavicular nodes |
pN(i-) | Immunohistochemically negative |
pN(i+) | IHC positive; no cluster & gt; 0.2 mm -- isolated tumor cells |
pN0(mol-) | negative by PCR |
pN0(mol+) | postive by PCR |
pN1mi | all mets > 0.2 mm and < 2 mm |
pN1a | 1 - 3 ALN positive |
pN1b | IMN detected by sentinel lymph node dissection but not clinically apparent |
pN1c | 1 - 3 ALN positive and IM node detected by SLND but not clinically apparent |
pN2a | 4 - 9 ALN positive |
pN2b | clinically apparent IM nodes absent axillary LN mets |
pN3a | > 10 ALN positive |
pN3b | clinically apparent IM nodes with axillary LN mets or ≥ 3 ALN and IM node positive by SLN but not clinically apparent |
pN3c | Ipsilateral supraclavicular LN |
M0 | no evidence of metastases |
M1 | Distant Mets |
M0(i+) | circulating tumor cells; no clinically apparent distant metastases |
Stage Grouping
T-stage | N0 | N1mi | N1 | N2 | N3 | M1 |
---|---|---|---|---|---|---|
T0 | 0 | IB | IIA | IIIA | IIIC | IV |
T1 | IA | IB | IIA | IIIA | IIIC | IV |
T2 | IIA | IIB | IIB | IIIA | IIIC | IV |
T3 | IIB | IIB | IIIA | IIIA | IIIC | IV |
T4 | IIIB | IIIB | IIIB | IIIB | IIIC | IV |
Treatment
If locally advanced breast cancers is considered inoperable, neoadjuvant chemotherapy may convert the disease to operable. Chemotherapy, should be used in the treatment of locally advanced breast cancer. If the cancer is operable, neoadjuvant or adjuvant chemotherapy is indicated. A modified radical mastectomy including Level I/II axillary lymph node dissection is definitive treatment. Post mastectomy radiation therapy is indicated in most circumstances. Hormonal therapy or herceptin as appropriate after defnitive systemic and local treatments are complete are used. Halstead mastectomies removes all breat parenchyma, a large region of breast skin, and pectoralis major and minor muscles and an axillary lymph node dissection, en bloc. This procedure is no longer used as a result of the outcome of the NSABP B06 study which shows equivalence of the modified radical mastectomy.
Modified radical mastectomy preserves the pectoralis muscles. More recently, total mastectomy (no axillary lymph node dissection) is used. Total and simple mastectomy removes the breast parenchyma and overlying skin, while preserving the axillary lymph nodes.
Lymph node dissections are used to determine staging and may influence treatment decisions post-operatively. Adequate node dissection has traditionally been considered a dissection of Level I-II axillary lymph nodes. These nodes are removed en bloc. If level III lymph nodes are clinically suspicious the node dissection is continued into the level III nodes (superior and medial to the pectoralis minor muscle).
Standard chemotherapy regimens include an anthracycline and taxane based regimen, usually adriamycin/cytoxan followed by taxol. Dose-dense chemotherapy is administered in 2 week cycles, rather than a standard regimen of every 3 weeks. The Intergroup C9741 trial compared 2005 node positive patients to AC x4 → T x 4 q3 weeks v. q2 weeks. DFS-4 years improved from 75% to 82% with the more frequent schedule. Overall survivlal also improved with the q2w schedule. Median followup was 36 months.
Radiation Therapy in the Post-Mastectomy Patient
Radiation therapy was discounted as being more toxic than beneficial in post mastectomy patients in the pre-modern series. All pre-modern historical studies demonstrated improved local control but did not demonstrate survival benefit. A meta-analysis of 6 trials in the 1970s demonstrated a 1% - 10% decrease in survival with post mastectomy radiation therapy. A second meta-analysis in 1987 of 9 trials demonstrated no overall survival benefit with post-mastectomy radiation therapy at 10 years. An update by Cuzick in 1994 demonstrated postmastectomy radiation therapy was associated with an increase in cardiac mortality and slightly decreased breast cancer mortality. Chemotherapy was thought to be of added benefit thus leading to the decline in use of post mastectomy radiation therapy. Chemotherapy then in common use was CMF (cyclophosphamide, methotrexate, 5-fluorouracil). However, radiation therapy techniques changed dramatically with the advent of 3D conformal radiation therapy techniques based on CT imagng in the mid-1980s at Universit of Michigan, University of North Carolina and Medical University of South Carolina.
As a result, the criticisms of the prior meta-analysis were largely due to large fields, relatively low energy radiation generally using 60Co, and no correction for anatomy due to the lack of 3-d conformal imagery for treatment planning. Once this problem was solved with CT based highly conformal 3D treatment planning, the toxicity was greatly reduced.
The Danish 82b/c studies re-examined the role of radiation therapy in the post-mastectomy patient in 1999. 82b randomized 1705 premenopausal women to mastectomy → CMF x 8 cycles followed by randomization to radiation or no radiation. Patient criteria included:
- Positive axillary lymph nodes or
- tumor > 5 cm (T3) or
- skin or pectoralis fascia.
The results of the study were:
- OS-10 was 54% with postmastectomy radiation therapy and 45% without radiation therapy
- Crude cumulative local-regional recurrence was 32% without post-mastectomy radiation and 9% with PMRT.
- Survival benefit was seen in all patients (N0-N3)
The Danish 82c (postmenopausal) study included 1375 patients aged < 70 randomized to post-mastectomy tamoxifen for one year v. tamoxifen and post-mastectomy radiation therapy. The study included the same patient characteristics as the 82b study: postive axillary nodes or tumor > 3 cm or skin or pectoral fascia involvement.
82c demonstrated improved outcomes with the addition of radiation therapy. Post-mastectomy significantly improved local-regional control and reduced local relapse from 35% to 8%. Disease free survival was also improved from 24% (no radiation) to 35% (with post-mastectomy radiation therapy). Overall survival at 10 years likewise was improved with radiation from 34% to 45%. All of these results were statistically significant.
These studies have been criticized as having inadequate surgical node treatment with a median of only 7 lymph nodes dissected, suboptimal duration of tamoxifen at 1 year (v. 5 years presently recommended). However, Marie Overgaard did a re-analysis of the 82b/c data and excluded those patients with less than 12 nodes dissected with no change in study outcomes: Post mastectomy treatment in node positive patients improved overall survival at 10 years, improved disease free survival and improved local-regional control.
Studies
Chemotherapy Trials
Intergroup C9741 -- Adriamycin/Cytoxan → Taxol
This trial established the role of AC/T dose dense (Q2W) regimen of chemotherapy in locally advanced breast cancer. Disease free survival improved from 75% to 82% when dose dense regimens were used. Severe neutropenia was less frequent in the dose dense arm.
NSABP B18 Neoadjuvant Chemotherapy Study
This study was designed to assess preoperative AC for improvement in DFS and OS compared to post-operative AC. Secondary aims were to assess response to pre-op AC impact on survival and local relapse outcomes, as well as impact on rates of breast conserving surgery. All patients were operable at enrollment.
- All patients operable at enrollment
- Majority were T2 or smaller disease and were clinically node negative
- 16 year follow up to date (JCO 2008), showed no significant difference in OS or DFS.
- There is a trend toward better DFS and OS in women < 50 treated with neoadjuvant chemotherapy
- 27% conversion rate from mastectomy to breast conserving surgery
NSABP B27: Randomized to Pre-OP AC → T or Pre-Op AC and post-op Taxol
The addition of taxol did not improve survival but did improve pathologic complete response in the pre-op group.
In both NSABP B18 and B27, a pathologic complete response to chemotherapy was a harbinger of good outcomes.
CALGB 9344: Lymph Node Positive Patients: Taxol improves Disease Free Survival and Overall Survival
This study of 3121 patients with node positive brease cancer randomized patients to AC or AC followed by taxol improved both disease free survival and overall survival. A retrospective review of this study included 1500 patients in 2007 which found the benefit of Taxol appeared to be in HER2/neu positive patients and not HER2/neu Negative/ER Positive patients.
ECOG E1199 Study of dose regimens with AC and Taxol Chemotherapy
This was a 4 arm study of 4950 patients randomized as follows:
- AC q3w x 4 cycles → Taxol q3w x 4 cycles
- AC q3w x 4 cycles → Taxol qw x 12 cycles
- AC q3w x 4 cycles → Taxotere q3w x 4 cycles
- AC q3w x 4 cycles → Taxotere qw x 12 cycles
The study demonstrated that weekly taxol improved disease free survival (HR 1.27) and overall survival (HR 1.32) in all patients including ER+/H2N negative patients.
Post Mastectomy Radiation Therapy: Early RT studies (pre-1984)
Radiation therapy underwent a sea change in 1984-86 with the advent of 3D conformal CT based radiation therapy treatment planning and delivery. This change in technique enabled the delivery of radiation to at risk areas while sparing normal tissue. Post mastectomy radiation therapy was the standard of care for decades until sevearl trials were published in the 1970s showing improved local control but little or no survival benefit. Some of these studies showed worse outcomes with post-mastectomy radiation therapy. A series of meta-analyses of these trials demonstrated decreases in overall survival of between 1 and 10% (Stjernsward, Lancet 1974).
Cuzik's meta-analysis demonstrated no survival benefit with PMRT at 10 years (1987) and an update published in JCO in 1994 demonstrated slightly decreased breast cancer mortality, but increased cardiac mortality. With the advent of chemotherapy (CMF) and these studies, post-mastectomy radiation therapy was used less.
More modern studies have not shown the same results. Many of these studies included substantial numbers of patient treated with 60Co and without the aide of 3D conformal CT based treatment planning. There was significant heterogeneity of surgical techniques and older radiation therapy techniques were associated with increased cardio-toxicity. In addition, there was a lack of systemic (chemotherapy) treatments in many of these patients, suggesting that sub-clinical systemic disease was not well controlled.
PMRT: More recent Trials
Danish 82b/82c Trials -- DBCG 82b Pre-menopausal Trial
The Danish 82b published in 1997 (Overgaard, NEJM 1997, Lancet 1999) randomized 1708 women to mastecomy and adjuvant CMF chemotherapy x 8 cycles ± post mastectomy radiation therapy. Inclusion criteria were node positive patients, tumors > 5 cm, or skin or fascia involvement. Os10 was 54% with post-mastectomy radiation therapy and 45% without PMRT. Crude local/regional recurrence rates were 32% with surgery alone and 9% with PMRT. The survival benefit was seen for all patients (N0-N3).
82b has been criticized for the use of CMF chemotherapy, inadequate treatment of the axilla, having an average of 7 nodes removed, excess local failure in the axilla of 44% in the CMF arm.
Danish 82c Post menopausal Post Mastectomy Radiation Therapy Study (Overgaard)
This study is the post-menopausal equivalent of the pre-menopausal 82b study. This trial randomized 1375 post menopausal women with similar characteristics to that of 82b except the women were post-menopausal, but age < 70 and included tamoxifen for 1 year.
Again this trial demonstrated post-mastectomy radiation therapy significantly improved local recurrence rates (35% without RT, 8% with RT. Disease free survival also improved 24% without PMRT and 36% with PMRT. Finally overall survival was improved by the addition of PMRT to 45% from 34%.
Surgical and chemotherapeutic treatments were the same. This study is subject to the same criticisms: inadequate node dissection (average of 7), sub-optimal duration of hormone therapy (tamoxifen).
In both 82b/c the surgery was total mastectomy plus axillary lymph node dissection, with a median of 7 lymph nodes removed. 15% had 0-3 nodes, 75% less than 9 nodes which is significantly less than in US centers where > 10 LN is considered an adequate node dissection.
Post mastectomy radiation in the 82b trials was delivered after 1 cycle of CMS at 3-5 weeks post-operatively. For 82c, radiation was delivered 2-4 weeks post-operatively. Radiation doses were 48-50 Gy to the entire chest at 2 Gy/fraction to the chest wall, anterior photon fields were used to cover the high axilla and supraclavicular nodes and an anterior electron field was used to cover the internal mammary nodes and chest wall. For large women, a posterior axillary boost was added to insure adequate nodal coverage.
British Columbia Trial
The British Columbia Trial consisted of 318 pre-menopausal patients with positive axillary lymph nodes considered high risk. The trial characteristics and results were:
- Randomized to
- CMF chemotherapy x 6 - 12 months OR
- CMF chemotherapy → Radiation therapy
- Surgery followed with total mastectomy and ALND
- Radiation therapy consisted of a 5 field plan: Opposed tangets to chest wall, Anterior oblique supraclavicular fields, Posterior axillary boost and anterior photon fields for bilateral internal mammary nodes using Co-60 to a total dose of 37.5 Gy in 16 fractions.
The British Columbia Trial established at 20 year follow up that adjuvant radiation therapy improved local regional recurrence before distant metastasis recurrence, at 13% Local-regional recurrence v. 39% without radiation. It also showed better disease free survival at 48% with radiation as opposed to 31% without radiation and better overall survival at 47% with RT v. 37% without radiation.
Of note, the BC trial did not report exessive cardiac deaths, despite the use of en face photons to cover the bilateral internal mammary nodes. The trial has been criticised for having higher than expected local-regional failure compared with many more modern series. CMF chemotherapy was used.
Early Breast Cancer Trialist Cooperative Group Metaanalysis
The EBCTCG studied 78 randomized trials including 42,000 women. Key points:
- After breast conserving surgery Radiation reduced the risk of local recurrence from 26% to 7% and increased breast cancer mortality from 30.5% to 35.9%
- Post mastectomy and ALND patients given PMRT reduced 5 year local recurrence from 23% to 5% and improved 15 year breast cancer mortality from 54% to 60%.This was an improvement of 5.4% in the entire cohort.
- In patients with node negative disease, PMRT reduced the 5 year local recurrence rate from 6% to 2% (p=0.0002), but caused a 3.6% increase in breast cancer related mortality.
- Tamoxifen reduced teh LR rate by about 1/2 in patients with ER positive disease
- Radiation Therapy was associated with excess contralateral breast cancer, lung cancer, and cardiac mortality.
- Many older trials were included in the EBCTCG meta-analysis.
Whelan Meta-analysis for PMRT
The Whelan meta-analysis was published in 2000 in the JCO included 18 relatively recent trials between 1967 and 1999. This analysis included 6367 patients who had mastectomy and chemotherapy. Adjuvant radiation therapy was associated with reduced local-regional recurrence (Odds ratio 0.25), reduced recurrences (all recurrences) (OR 0.69), and reduced mortality (OR 0.89). The survival benefit was not significant when the Danish trials were excluded.
Gebski Meta-analysis for PMRT
The Gebski meta-analysis (JNCI 2006), analyzed 36 PMRT trials and stratified the trials according to the EQD 2 dose delivered, considering 40-60 Gy at 2 Gy/fraction, and the radiotherapy target tissue. Gebski looked at 17 series that fit that criteria and had 5 year follow up data. Adjuvant radiation therapy was associated with an absolute 2.9% increase in OS5 and an absolute increase of 6.4% OS10.
MDACC Retrospective Series Regarding PMRT with neoadjuvant Chemotherapy
There have been no prospective randomized clinical trials evaluating post-mastectomy radiation therapy in the setting of neoadjuvant chemotherapy. The MD Anderson retrospective review looked at this situation retrospectively.
In 1994, Huang analyzed the outcomes of 542 patients who were enrolled in clinical trials and were treated with neoadjuvant chemotherapy, mastectomy and radiation therapy. These patients were compared with 134 patients enrolled in the same trials who did not receive adjuvant radiation therapy.
Clinical stage, margins and hormone receptor status did not favor the radiation group. Cause specific survival was improved in the adjuvant radiation group with clinical Stage IIIB or supraclavicular node positive disease, clinical T4 tumors (chest wall or dermal/lymphatic-skin involvement), and pN2 (≥ 4 nodes positve). Local-regional recurrence improvement was also demonstrated for clinical Stage III brease cancer or supraclavicular node positive lymph nodes with a pathologic complete response to chemotherapy.
Present Recommendations and Controversy: Post Mastectomy Radiation Therapy
At present, the ASCO guidelines recommend post-mastectomy radiation therapy in patients with ≥ 4 nodes positive, and is suggested for T3 (> 5 cm tumor size) with axillary lymphadenopathy or operable Stage III disease.
The NCCN guidelines carry this further. In addition to the ASCO recommendations, NCCN as of 2010 now strongly recommend PMRT in node positive patients based on Overgaard's re-analysis of the Danish 82b/c data, retrospectively reviewing patients with ≥ 8 LN dissected, which demonstrated a benefit to PMRT. In numerous studies involvement of 1-3 lymph nodes has been associated with an increased risk of local recurrence compared to node negative disease. Radiation therapy in older series has been associated with toxicity related mortality. Because of these older studies, there is some concern that radiation will lead to worse overall survival. However, more recent studies, including a British Columbia study (Ragaz, 2005), which examined 318 pre-menopausal women with high risk, including positive axillary lymph nodes, demonstrated at 20 year follow up adjuvant radiation therapy improved local-regional control before distant mets (13% recurrences with RT v. 39% without RT, improved Disease Free Survival at 48% with radiation v. 31%, and improved overall survival to 47% from 37%. This benefit was extended to those with 1 - 3 lymph nodes present, as well as those with > 4 nodes positive.
The British Columbia Trial enrolled 318 pre-menopausal high risk patients with positive Lymph nodes. These patients were randomized as follows:
- All patients received CMF chemotherapy x 6 - 12 months
- Patients were then randomized to no adjuvant radiation therapy orradiation therapy
- Radiation therapy was delivered using 60Co to 37.5 Gy in 16 fractions (2.34 Gy/fx) using a 5 field technique, which included an en face photon field to cover the bilateral internal mammary nodes.
Of note in this study: despite the fact that en face photons were used on the anterior chest wall, no excess cardiac deaths were reported in the study.
Arguments for treating with post-mastectomy radiation therapy in patients with 1-3 lymph nodes include the data from all three modern randomized controlled trials: Danish 82b, Danish 82c and British Columbia.
These studies all show significant overall survival benefit with post-mastectomy radiation therapy, even in sub-group analysis and even when that analysis was restricted to patients who had at least 8 axillary lymph nodes dissected.
Other Factors Influencing PMRT
Retrospective Studies from NSABP, IBCSG ande MDACC have suggested that other high risk factors be considered in offering post-mastectomy radiation therapy:
- Lymphovascular invasion
- high grade/poorly differentiated disease
- younger age
- Extra-capsular extension ≥ 2 mm
- Insufficient axillary lymph node dissection (ie ≤ 10 LN examined)
- > 20% of Lymph nodes positive
- larger tumor size (T2 or ≥ 4 com
- Close/positive margins
These factors produce Local Regional Recurrence rates (at 10 years) of greater than 15%. PMRT should be considered for these patients. Comprehensive chest wall and axillary lymph node irradiation is recommended for most patients who have high risk of local-regional recurrence that warrant post-mastectomy radiation therapy. The benefit of radiation therapy to local regional lymph nodes far outweighs the risk of added toxicity in most cases. MDACC considers chest wall radiation alone only for those patients with mastectomy and T3N0 disease or T1/T2N0 patients who are being treated for positive margins.
Internal Mammary Nodes: Radiation or Not? (EORTC 22922 will have the answers)
IM nodal irradiation is controversial. The 3 PMRT trials (82b/c/British Columbia) and a non-randomized Israeli study that IM irradiation may improve disseas free survival 73% to 52% and trended toward improved overall survival. Others argue that it is not necessary to include the IM nodes since internal mammary nodal dissection did not improve overall survival (Veronese) for these patients. Others argue that the majority of the IM nodes are included in the breast tangents. The EORTC 22922/10925 study is examining the role of IM node irradiation on local-regional control and survival. This study has completed accrual but has not yet been published.