Radiation Oncology Synopsis

Early Stage Invasive Breast Cancer Breast Cancer

General Breast Cancer Information

Breast cancer is the most commonly diagnosed cancer in women, followed by lung cancer and colorectal cancers. It is the second most common cause of death in women after lung cancer and ahead of number three colo-rectal cancers. There are about 180,000 invasive breast cancers and 65,000 non-invasive breast cancers per year with about 40,000 deaths. The median age at diagnosis is 61 years, and white women have the highest diagnosis rates, but black women have the highest mortality rates. About 12% (1 in 8 women) born in 2009 will be diagnosed with breast cancer in their lives if present trends continue. The incidence of breast cancer diagnosis is increasing, but mortality is decreasing.

Genetics

The most common genes associated with breast cancer are BRCA1 and BRCA2. These genes are associated with Ashkenazi Jewish ancestry with an incidence in this population of as many as 1:40. While both BRCA1 and BRCA2 are associated with a higher incidence of ovarian cancers, the risk is higher with BRCA1 (40-60% lifetime risk). BRCA2 carriers have a lifetime risk of 10%.

Family history and younger age shorten the doubling times of breast cancers. In these patients we recommend decreasing the screening intervals and starting screening earlier. Hormone replacement therapy is also associated with an increased risk of breast cancer with an increased relative risk of 1.7

The following factors increase the risk of breast cancer:

The following decrease the risk of breast cancer:

The risk of developing breast cancer in the contralateral breast of a patient with previously diagnosed breast cancer is about 1% per year for pre-menopausal women and about 1/2% per year in post-menopausal women. For the purposes of breast cancer discussions, menopause is defined as amenorrhrea due to

Screening Recommendations

Ordinarily in normal risk women (no particular risk factors, screening should commence at age 40-49 years, according to the ACR and the American Cancer Society. There has been recent controversy in the United States concerning this, related to new medical insurance laws. The U.S. Preventive Services Task Force no longer recommends a mammogram in this age group. The present (4/2011) recommendations of the ACR/ACS is that screening mammograms continue on a 1-2 year basis commencing at age 40. The original data for this recommendation comes from a study done by the Health Insurance Plan of New York which demonstrated that screening mammograms are useful in early detection of breast cancer and we are now finding out 40 years later, in reducing breast cancer mortality and morbidity.

For high risk women, the general recommendations are to start about 5 years earlier (mid-30s).

Special risk groups include women who have had radiation to the chest/thorax at ayoung age. Screening for these women should begin at 10 years after the radiation or at age 40 whichever is earlier. Cinical breast exams should be performed every 6-12 months. The risk of breast cancer in this population is higher.

MRI Screening

MRI screening is a relatively recent tool against breast cancer. There remains some controversy in its proper role. The ACS 2007 guidelines recommend screening with MRI for women who have lifetime risk of 20% - 25% or greater. This is based on a risk model published in 2004 and does not include women with dense breasts.

The NCCN guidelines in 2010 suggested the following uses were appropriate for screening MRI exams:

Types of Invasive Breast Cancer and Their Presentations

Favorable Histology Types

There are several histologic types associated with favorable prognosis. These cancers are associated with favorable outcomes:

Medullary cancer demonstrates a syncytial growth pattern of poorly differentiated tumor with a high mitotic rate. There is often a promient lymphoplasmacytic reaction involving at least 75% of the periphery and is present diffusely throughout the tumor. Medullary cancers are managed as invasive ductal cancers.

Phyllodes tumors are also favorable prognosis tumors with a wide range of biologic behaviors. They range from benign to malignant. Cystosarcoma Phylloodes tumors are rare tumors which exhibit a leaf like appearance, microscopically. Phyllodes tumors have both epithelial and stromal components. The stromal component has the potential for metastasis, with a 10% risk of lymph node involvement, thus requiring lymph node study. Surgery is the preferred treatment with radiation reserved for rare occurances of positive margins and large tumors (> 2 cm) treated with breast conservation surgery.

Paget's Disease is caused by malignant epithelial cells infiltrating the breast epidermis via the mammary duct epithelium. The clinical presentation is crusting, scaling, itchy skin on the nipple that can progress to ulceration and bleeding. More than 95% of Paget's Disease is associated with an underlying breast cancer. Rule of thumb: if there's Paget's then there's very likely breast cancer. 90% of cancers associated with Paget's are invasive ductal carcinomas and 10% are ductal carcinomas in situ.

Invasive lobular carcinomas involve 5% - 10% of invasive cancers. Up to 30% of ILCs are associated with metachronous and synchronous contra-lateral breast primaries.

Less favorable Histology Types

Micropapillary Breast Cancer has an unfavorable prognosis. This is a rare form of breast cancer which has a less favorable prognosis than invasive ductal or invasive lobular carcinoma.

Natural History and Patterns of Failure/Progression

The NSABP B04 study, a study examining extensiveness of surgery identified, on 25 year followup in 2002 (Fischer, NEJM) that 25% of women will fail distantly after 5 years and 50% fail in the contralateral breast. This study demonstrates the need for ongoing, long term follow-up. The NSABP B04 trial also demonstrated that among women with a clinically negative axilla, 40% were found to have axillary metastases at diagnosis. Of the women with a clinically negative axilla and were spared axillary node dissection, 20% eventually developed a clinically positive axilla.

Workup and Staging of Early Breast Cancer

Workup

Standard work up for breast cancers includes the usual history and physical. Particular elements of the workup should include:

Stage Grouping (for TNM details look here).

Staging notes: All Stage I tumors are node negative. pN1(i+/-) are defined based on finding isolated tumor cells on immunohistochemical staining. pN1(mic) are nodes with tumors that are IHC positive but > 0.2 mm but ≤ 2 mm or ≥ 200 cells.

Staging of Paget's disease is Tis(Paget's). This stage should only be used in the setting of exclusive Paget's Disease. If DCIS or LCIS is also present the staging is Tis(DCIS) or Tis(LCIS). Paget's is staged according to the underlying cancer, but a notation should be made that Paget's is present.

AJCC 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

Oncotype DX Assay

The Oncotype DX assay is an assay of 21 genes within a breast cancer tumor which estimate the risk of any recurrence for early stage ER positive and node negative breast cancer. The NSABP B20 Study suggested that the Oncotype DX assay may quantify the benefit of chemotherapy in these patients. The Oncotype DX assay categorizes disease on a scale based on the gene assay into low, intermediate or high risk of recurrence.

An ongoing trial, the TAILORx trial is a prospective study evaluating the role of Oncotype DX in breast cancer treatment decision making.

Tissue microarray classification system

There are 5 subtypes of tissue microarray classifications. They are:

Treatment of Early Breast Cancer

Early stage breast cancer is primarily settled by several early NSABP Trials: B04 compared Halstead Mastectomy with modified radical mastectomy and found that we could preserve chest wall musculature and consequent morbidity by using the modified radical mastectomy. The next trial, B06 established the equivalence of MRM and lumpectomy with radiation therapy, and the inferiority of lumpectomy alone. Veronese, tested larger wide local excisions (quadrantectomy) and found that radiation was still needed short of mastectomy. At present, the choices of treatment are:

The general sequence is breast surgery followed by chemotherapy (if needed) followed by radiation therapy. If the cells are ER positive then hormonal therapy in the form of tamoxifen or an aromatase inhibitor is added for five years. In addition, if HER2/neu overexpressed, herceptin is also added with appropriate cardiac workup due to the possibility of reversible cardiomyopathy.

Chemotherapy

Adjuvant chemotherapy is added for all tumors > 1 cm and T1b (0.5 - ≤ 1 cm) tumors that are ER negative or HER2/neu positive (3+ or FISH confirmed). Chemotherapy can be considered for T1b (and greater) tumors that are moderate to poorly differentiated (Grade 2 or 3) or have lymphovascular invasion. For disease ≥ T1c that is ER+ consider the Oncotype DX assay to determine if the risk score for the benefit of chemotherapy is sufficient to justify the use of chemotherapy. The benefits of chemotherapy in age 70 and older are uncertain.

Chemotherapeutic Regimens

Generally, Adriamycin with cytoxan for for 6 cycles. AC is can be used alone in tumors > 1 cm which are node negative. There are standard and dose dense treatments. Standard treatment is every 3 weeks, and dose dense is every 2 weeks. Dose dense treatment has higher hematologic toxicity. Taxol is added to node positive patients and a recent study at University of Michigan demonstrated the advantage of adding Taxol to HER2/neu positive patients. Taxol is given in weekly doses for 12 weeks (dose dense). Generally doses are:

For HER2/neu positive tumors:

Because of synergistic cardiotoxicity of Adriamycin and Herceptin, Taxotere and carboplatin are preferred regimens in H2N positive disease.

Trastuzumab (Herceptin) is used in patients that are H2N+ (3+ IHC or FISH+) and who have tumors > 1 cm. T1a-b tumors that are node negative have a good prognosis even if trastuzumab is omitted, even in H2N overexpression. This cohort is not well studied. There is known reversible cardiomyopathy associated with trastuzumab which must be weighed against disease benefits before offering Trastuzumab.

Trastuzumab is administered after completion of Adriamycin phase of chemotherapy in standard AC → T and dose dense treatments. It can be administered with taxanes. Herceptin can be given concurrently with radiation therapy. It can also be given concurrently with 5FU or capecitabine and radiation therapy.

Endocrine Therapy

The NSABP B21 Study (Fisher, JCO 2002) looked at 1009 patients with tumors ≤ 1 cm post lumpectomy randomized to three arms:

• Tamoxifen alone @ 10 mg BID x 5 years: IBTR 16.5% CBTR 0.9%
• Radiation alone to 50 Gy IBTR 9.3% CBTR 4.2%
• Radiation to 50 Gy + tamoxifen IBTR 2.8% CBTR 3.0%

After 8 years of follow up the Ipsilateral Breast Tumor Recurrence was 16.5% with tamoxifen alone v. 9.3% with radiation alone v. 2.8% with Radiation and tamoxifen. No benefit was seen in ER neg. tumors.

Hormonal therapy is recommended in ER positive patients. There is a small byut significant benefit in the involved as well as the contralateral breast. For tumors < 1 cm which do not receive chemotherapy, endocrine therapy is indicated.

NCCN recommends endocrine therapy be given to premenopausal patients using tamoxifen 20 mg/day for five years. If the patient remains pre-menopausal, therapy is stopped. If she becomes post-menopausal aromatase inhibitors for five additional years are recommended.

If the patient is post-menopausal, then aromatase inhibitors for five years or tamoxifen for 2 - 3 years or 4.5 - 6 years followed by aromatase inhibitors for five additional years is recommended.

Tamoxifen for five years is given to any patient not treatable with aromatase inhibitors. Pre-menopausal status is a contra-indication for the use of aromatase inhibitors because the ovaries are still producing estrogen in high amounts.

The major side effects of tamoxifen include small increases in blood clots, strokes and uterine cancers as well as cataracts. Aromatase inhibitors increase bone mineral density loss and osteoporosis, as well as joint pain, stiffness and hpercholesterolemia. Bisphosphonates and statins are used to counteract these effects.

PMH/Canadian Trial (Fyles, NEJM 2004) on substitution of tamoxifen for Radiation. Princess Margaret Hospital studied 769 women, age ≥ 50 years with a median age of 68 years with T1 - T2 disease (size ≤ 5 cm) in node negative women. This study looked at omitting radiation therapy in women who had breast conserving treatments when Tamoxifen was added. In women aged 65 and older, either clinical evaluation or pathologic evaluation was sufficient and sentinel node biopsies were not performed. Lumpectomy to negative margins was performed and the patients were randomized to:

This trial demonstrated at 8 years of followup that radiation reduced the risk of local recurrence from 17.6% to 3.5%. It also showed that the risk of relapse was 2.6% in small (< 1 cm) tumors v. 0% for radiation therapy. For those patients age > 60 and tumors < 1 cm the risk was not statistically different, but this was an unplanned analysis with short interval follow up.

Intergroup Trial (Hughs NEJM 2004) studied 646 women age ≥ 70 with T1cN0 ER+ tumors randomized to tamoxifen alone or tamoxifen with radiation therapy after lumpectomy to clear margins. Node status was only assessed clinically and axillary dissection was discouraged. Radiation was given to 45 Gy to the whole breast with a 16 Gy boost to a total dose of 56 Gy. The initial local failure rate at 5 years was 4% (tamoxifen alone) v. 1% (radiation + tam.). At 8 years the local failure rate in the tamoxifen alone arm increased to 7% while the radiation arm remained stable at 1%. Thus, this study appears to give evidence that radiation remains beneficial, even in older women, provided a life expectancy is ≥ 8 years.

Radiation Therapy

Radiation therapy is indicated in the treatment of early breast cancer after breast conserving therapy. This result appears to hold true based on randomized controlled studies including the Intergroup/CALGB study of older women at 8 years follow up.

The timing of radiation therapy after surgery. Generally, radiation therapy can start any time after surgery as soon as the surgical wound healing is complete. This ranges from 2 to 4 weeks. There is some data in patients who receive chemotherapy that delays longer than 20 weeks may adversely affect outcomes. Most clinical trials mandated post-op radiation therapy start within 12 weeks of surgery. A British Columbia study published in the JCO in 2009 reported that delays beyond 20 weeks could have decreased disease free survival and increased breast cancer mortality rates. (Olivotto JCO, 2009).

Accelerated partial breast irradiation is the present subject of the NSABP B39 study. This study randomized women to whole breast radiation therapy v. accelerated partial breast radiation using either interstitial brachytherapy, mammosite brachytherapy or External beam radiation therapy. This is still investigational.

ASTRO has published guidelines on the eligibility for PBI per protocol off trial. Patients considered "suitable" for this treatement have the following characteristics:

Several retrospective studies have shown excellent local control in patients with short follow up. It must be emphasized that the CALGB/Intergroup external beam studies for whole breast radiation took 8 years of follow up to conclude that there is a benefit to radiation therapy in very low risk patients. Earlier analysis did not show benefits at 5 years.

Radiation doses off protocol for APBRT are for brachytherapy (interstitial or intracavitary) forms is 34 Gy in 10 fractions delivered BID (3.4 Gy/fraction). The target volume includes the tumor bed and a 1 cm margin for brachytherapy and a 1 - 1.5 cm for EBRT.

Post Mastectomy Radiation Therapy for early breast cancer. ASCO and the NCCN recommend post mastectomy radiation therapy in post mastectomy patients with node positive disease (≥ 4 nodes positive) and strongly recommend consideration of radiation therapy in 1 - 3 nodes positve as well. Post mastectomy radiation may not be needed if margins are clear (≥ 1 cm) but PMRT should be considered for patients with simple mastectomy and < 1 mm margins.

A Vancouver, British Columbia retrospective study suggested that PMRT may also benefit women with certain risk featuers such as poorly differentiated, no chemotherapy, lymphovascular space invasion or large (T2) tumors. In the presence of 2 -3 factors the Local-regional-recurrence risk is 21 - 23% if radiation therapy is omitted.

A Harvard study in 2005 reported similar factors predicted the risk of local-regional recurrence after mastecomy without PMRT: close margins, ≥ T2, permenopausal and LVI. Jagsi in this study reported the 10 year local regional recurrence rate was 80% in the chest wall.

Pregnancy

The management of breast cancer in the pregnant patient depends on the stage of the pregnancy and the patient's decisions related to her care. Adjuvant chemotherapy can be used except for the first trimester. Radiation or hormonal therapy can be added only after delivery. Chemotherapy used during pregnancy uses AC and 5FU.

In the first trimester, many recommend termination of pregancy. If a patient decides not to terminate the baby, a mastectomy should be considered with axillary staging. If chemotherapy is indicated, it should be held until the second trimester.

In the second and third trimesters breast conserving surgery or mastecomy can be considered. Neoadjuvant chemotherapy can be considred. Surgical management and chemotherapy in the pregnant patient is the same that is used in non-pregnant women except radiation therapy and hormonal therapy cannot be used until after delivery.

Toxicity of Treatment

Radiation therapy acute toxicities inlcude fatigue, radiation dermatitis, hyperpigmentation, pneumonitis.

Acute radiation dermatitis is more likely and if it occurs, more severe in the inframmary fold where the dose buildup physics dictates more radiation to the skin in that area and less skin sparing effect. Approximately 20 % - 30 % will experience skin breakdown, mostly in the IM fold or axillary sulcus. This can be minimized by careful immobilization and adjustment of the breast tissue. Hyperpigmentation occurs in nearly all cases and fades between six months and 1 year.

Radiation late toxicities include soft tissue fibrosis, lymphedema, telangiectasias, pulmonary fibrosis, cardiovascular disease and radiation induced second malignancy.

Lymphedema

Lymphedema occurs in about 15% of patients with comprehensive axillary lymph node dissection treated with post-operative radiation therapy. It occurs in approximately 5% of patients treated with sentinal node biopsy alone. The precise cause of lymphedema is unclear because data are confounded by tumor effect, surgery and radiation effects. Some retrospective studies suggest opposed tangent radiation therapy only is associatedwith a lower risk than anterior oblique supraclavicular fields or directed nodal irradiation.

Erickson published data on lymphedema risk and radiation in JNCI 2001. He reported the risk of lymphedema is low if the axilla is treated with radiation alone, sentinel node biopsy alone, or level I-II axillary dissection. A complete axillary dissection increases the rate to around 10%. Comprehensive nodal irradiation with axillary dissection increases the risk to > 15%.

Cardiovascular Injury

Older studies that pre-date the modern CT based conformal 3D treatment planning era suggest that radiation for left sided breast cancer is associated with a relative risk of 2 for cardiovascular related death, compared with right sided heart disease. This data has not been reproduced in women treated in the modern radiation therapy era.

Risk of Second Malignancy

The WECARE study published in 2008 for women < 40 receiving > 1 Gy to the contralateral breast had a relative risk of 3. This risk was not seen in women > 40. Sarcomas (primarily angiosarcomas within the treated field were < 1% (~10 cases/10,000) within 10 - 30 years.

Brachial Plexus Injury

Brachial plexopathy is hihgly dependent on the dose/fraction and the total dose administered. Hypofractionated doses of 2.2 - 4.6 Gy/fraction and total doses from 43.5 Gy - 60 Gy can increased bracheal plexus injury from 1.7% to 73%. The ordinary risk of brachial plexus injury is < 1%. The median time to onset of brachial plexus injury signs is 10 - 12 months, with a range of 1.5 - 77 months.

According to Joint Center data (Pierce, IJROBP 1992) if the dose is < 50 Gy the risk is < 1% without chemotherapy and 4.5% with chemotherapy. If the dose is above 50 Gy, the risk rises to 5.6% with chemotherapy and 1.3% if the dose is held to < 50 Gy.

Cosmesis

Approximately 20% - 30% have less than excellent cosmesis. This may be worse with altered fractionation schemes, but there is no clear and convincing data either way.

The EORTC boost trial looked at cosmesis and concluded that more fibrosis occured in boosted breasts. The cosmesis at 3 years was felt to be good to excellent in 86% without boost and 71% with a boost. the risk of fibrosis significantly increased with the maximum whole breast dose and concomitant chemotherapy and pos-operative breast edema/hematoma. Fibrosis was decreased with > 6 MV.

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