Breast Cancer: Radiotherapy & Adjuvant Systemic Modalities

Women’s Health & Education Center’s Contribution

Radiation therapy (RT) plays an important role in management of breast cancer. In all situations, RT must be delivered in a manner that will appropriately treat the target tissues and minimize risks to adjacent normal tissues. For patients desirous of breast-conserving therapy (BCT), lumpectomy plus breast RT is typically the preferred approach, because it provides long-term survival rates equivalent to that achieved with mastectomy. BCT with lumpectomy plus breast RT is appropriate for most women with ductal carcinoma in-situ. Radiotherapy has long played an important role in the management of patients with locally advanced disease. There is also growing recognition of the utility of post-mastectomy radiotherapy (PMRT). Adjuvant systemic therapy for breast cancer has been a primary focus of oncology research for more than 40 years. Breast cancer is an example of a disease that has substantially benefited from the cumulative effect of small incremental improvements involving all available therapeutic modalities, which can explain the recently observed decrease in breast cancer mortality in some countries.

The purpose of this document is to briefly describe the different techniques currently used to treat patients with breast cancer, as well as newer approached that may become more widely used in future. This chapter also briefly reviews our current understanding of the role of adjuvant systemic therapy in the management of breast cancer in the modern era.

Radiotherapy Techniques

In all situations, radiotherapy (RT) must be delivered in a manner that will appropriately treat the target tissues and minimize risks to adjacent normal tissues (1). The various techniques currently used are:

Interstitial Implantation:

It is also termed as brachytherapy refers to the placement of radioactive materials inside the patient’s tissues. These materials typically emit low-energy radiation such that only the limited volume of tissue in the immediate vicinity of the implant is treated. This technique can deliver localized treatment to the tumor bed following lumpectomy for either invasive cancer or carcinoma in-situ, or in some special situations it can be used to irradiate a modest portion of the chest wall. Implants have also been used to treat large portions of the breast to very high doses in patients who have not undergone tumor excision. Implants have usually been used in conjunction with external-beam treatment, although there is growing interest in treating selected patients with implants alone. Breast implants are typically temporary, that is, the radioactive sources are placed in the patient for a finite time and then removed. High-dose-rate (HDR) brachytherapy is becoming very popular. Dose per dose, normal tissue reactions are generally more severe with HDR than with low-dose-rate (LDR) implants. For this reason, HDR therapy is typically delivered in a fractionated manner (eg, giving multiple treatments spread over a several-day period) to mitigate its effect.

External-Beam Treatment:

It is also termed as teletherapy refers to delivery of radiation to a patient from a device located a distance outside the patient. It is the most common method to deliver therapeutic radiation. Two types of external-beam radiation are commonly used: photons and electrons. A variety of radioactive materials theoretically can be used for external-beam photon irradiation. In practice only cobalt-60 provides a photon beam of high enough energy to be clinically useful. A linear accelerators (LINACs) also can generate a therapeutic electron beam. Removing the tungsten target from the path of the electron beam does this. Radioactive isotopes may also emit electrons. However, their energy is typically too small, and thus their depth of penetration is limited to be useful in the management of breast cancer. By varying the energy of the photon or electron beam, one can vary the depth of penetration of these beams. Low-energy photons, such as those emitted from brachytherapy sources (eg, Ir¹⁹²) do not penetrate deeply.

Most patients receiving RT to the intact breast or chest wall are treated with tangential photon fields to limit exposure of the underlying lungs and heart. “Wedges” which are wedge-shaped pieces of metal, are typically used to attenuate the beam more in some areas than others so as to compensate from the changing slope and thickness of the breast or chest wall and thereby make the distribution of radiation dose more uniform. Before delivering RT, patients undergo treatment planning on a simulator. The simulator has the same geometry as the treatment machine but provides diagnostic quality fluoroscopy. This facilitates the iterative process of field design. More recently, techniques of CT simulation have been developed that allow internal anatomic information to be incorporated into a “three-dimensional” treatment planning process. There is substantial patient-to-patient variation in normal anatomy, which may result in over-treatment of critical normal tissues and/ or under-treatment of target tissues when planning is based on surface anatomy, as is done using traditional fluoroscopic simulators.

With conventional RT techniques, the dose to the contralateral breast is minimal (2). In the United States and most of Europe, the entire breast of chest wall receives a dose of 46 to 50 Gy delivered in 25 to 28 individual sessions, giving one fraction daily, 5 days per week with a dose of 1.8 to 2.0 Gy per fraction. This “protracted” fractionation schedule appears to reduce the risk of late normal tissue reactions. Some centers advocate a shorter treatment regimen with higher daily dose per fraction and a lower total radiation dose. Following lumpectomy an additional 10 to 15 Gy “boost dose” is often delivered to the tumor bed region because most failures are in this area. This is usually done with an external electron field.

Therapy to the tumor-bed alone:

There is a growing interest in using brachytherapy alone to the lumpectomy site, without whole-breast external-beam irradiation, as definitive treatment for both invasive and non-invasive carcinoma. Such localized therapy can also be delivered with focused external-beam electron or photon techniques. The rationale for this approach is that most local recurrences are in the vicinity of the index lesion. Radiotherapy to the excision cavity, with several surrounding centimeters of normal breast tissue, should therefore in principle provide a high rate of tumor control. This approach however does not address microscopic multifocal disease and is technically challenging. The utility of this approach therefore is unclear because whole-breast RT remains useful even after quandrantectomy (2).

Intraoperative Radiation Therapy:

Devices have been developed to allow localized irradiation of the tumor bed, immediately following excision. Such “intraoperative RT” can be done using either low-energy photons or electrons. A trial using a miniaturized radiation source that can be introduced into the lumpectomy cavity, is being conducted in England.

Intensity-Modulated Radiation Therapy:

Traditional RT uses treatment fields that maintain a fairly uniform intensity of radiation dose in the two dimensions perpendicular to the direction of the beam. Newer hardware and software enable the radiation oncologist to adjust the two-dimensional intensity of the radiation beam, thus allowing the dose to be made purposely non-uniform. Such “intensity-modulated radiation therapy” (IMRT) may result in better conformation of the therapeutic dose to the target tissues. This may allow increased sparing of normal tissues and increased control of dose delivery to the target tissues, thus improving the therapeutic ratio of RT.

Prone Positioning and Respiratory Gating:

Patients undergoing RT for breast cancer are typically treated in the supine position. Delivering external RT to the patient in the prone position may improve the therapeutic ratio by moving the majority of the breast away from the underlying normal tissues. However, matching of such breast fields to the fields needed to treat the abutting supraclavicular and axillary regions may be challenging. Conventional RT is delivered virtually continuously throughout the respiratory cycle. It is possible to gate therapy such that, the machine is “on” only during a portion of the cycle, such as during deep inspiration. This approach might reduce the amount of lung and heart in the treatment fields without compromising treatment of the target tissues (3).

Radiotherapy without Surgery:

Patients with locally advanced breast cancers (LABCs) treated only with external-beam radiotherapy techniques (with or without systemic therapy) have loco-regional failure (LRF) rate of 30% or greater. LRF rates of 10% to 20% have been achieved using high-dose interstitial implantation (20 to 30 Gy) as a boost treatment following external-beam radiotherapy (45 to 50 Gy to the breast and regional lymph nodes). Because very large radiation doses must be given, such treatment may result in a 10% to 20% rate of moderate and severe complications (4). One approach, which has been especially popular in France, is to treat patients who have a complete (or near complete) clinical response to neoadjuvant therapy with radiotherapy alone; no breast surgery of any kind is performed. Local control rates among highly selected patients have been excellent in some series. One difficulty in selecting patients for this approach is the limited reliability of clinical and mammographic examination in detecting residual disease or estimating its volume and extent after neoadjuvant therapy. Small studies have found that magnetic resonance imaging (MRI) has high accuracy in this regard.

Both mastectomy (with immediate reconstruction if the patient so desires) and radiotherapy are usually needed to achieve optimal loco-regional control in patients with LABC. It is as yet unknown whether selected patients undergoing mastectomy after neoadjuvant chemotherapy have such a low risk of LRF that post-mastectomy radiotherapy (PMRT) could be omitted. It thus seems prudent at present to use PMRT routinely, even for patients with a pathologic complete response. Only a minority of patients with LABC are candidates for breast-conserving treatment after neoadjuvant therapy. It is unknown whether such patients would have a superior outcome if treated instead with mastectomy. Nonetheless, it seems reasonable to offer breast-conserving treatment to carefully selected patients. Results with approach are likely to be better with excision of tumor than when radiotherapy alone is used.

Radiotherapy and Ductal Carcinoma in-situ:

The rationale for treating patients with ductal carcinoma in situ (DCIS) with radiation therapy (RT) following conservative surgery (CS) is that RT can substantially reduces the incidence of tumor recurrence. The effectiveness of such treatment was hindered until recently by the limited available knowledge of the natural history of the disease of factors correlated with improved rates of tumor control. The cause-specific survival rates achieved with CS and RT have been reported to be 95% to 100%. This suggests that the long-term efficacy of this treatment approach is similar to that of mastectomy. Multiple retrospective studies and three prospective randomized trials have clearly established the long-term efficacy and role of CS and RT in the management of patients with DCIS. Data from multiple institutions support the value of thorough mammographic/ pathologic correlation and the need for careful attention to adequacy of excision in producing optimal long-term results; particularly for younger patients. Identification of clinical, pathologic and treatment related factors associated with a greater risk of local recurrence have helped define subsets of patients for whom CS and RT may be less appropriate than mastectomy. Current research goals include establishing which patients do not require RT after CS and the role of tamoxifen.

Radiotherapy and Regional Nodes:

Patients with pathologically uninvolved axillary nodes following technically adequate axillary surgery are at low risk of regional nodal failure and should not receive specific nodal irradiation. Supraclavicular irradiation should be given to all patients with four or more positive axillary lymph nodes, given the substantial risk of failure in this area and the difficulty of controlling such recurrences. However, there is substantial controversy about whether supraclavicular irradiation should be used routinely for patients with one to three positive axillary nodes. There is no consensus on the value of prophylactic internal mammary nodal irradiation for patients with positive axillary nodes. Radiotherapy is effective in preventing axillary recurrence in patients with clinically uninvolved nodes. Hence, axillary irradiation is a reasonable alternative to dissection for such patients. The rate of serious complications resulting from current doses and techniques of axillary, supraclavicular, and internal mammary nodal irradiation is low.

Adjuvant Systemic Modalities

Breast cancer is an example of a disease that has substantially benefited from the cumulative effect of small incremental improvements involving all available therapeutic modalities, which can help explain the recently observed decrease in breast cancer mortality in some countries. More recently, a greater emphasis has been placed on the role of meta-analyses. Although both randomized clinical trials and meta-analyses are important tools to minimize the effects of bias on the observed results, even the latter can also be affected by the “play of chance”. These important developments have forced physicians caring for breast cancer patients to acquire a working knowledge of important biostatistics and methodology principles. Adjuvant systemic therapy includes endocrine manipulation, chemotherapy or both.

Who should not receive Adjuvant Systemic Therapy?

Decisions about whether to offer an individual woman adjuvant systemic therapy should balance her risk of relapse, the possible absolute benefit of therapy, and the importance of other comorbid conditions that may limit her survival or put her at an increased risk for adverse events associated with the treatment. Traditionally, women with early-stage breast cancer with a moderate to high risk of relapse have been offered adjuvant systemic therapy. Tumors from more than 50% of all women diagnosed as having breast cancer will express the estrogen receptor (ER) or progesterone receptor (PR). Although long in duration treatment with tamoxifen or other therapies that reduce estrogen content to the tumor cells is generally well tolerated and almost every woman with hormone receptor-positive invasive breast cancer will benefit from such treatment if contraindications do not exist. Although the risk of chemotherapy-related life-threatening events is small, there are many known and possibly unknown short- and long-term risks of chemotherapy. Based on usual prognostic factors, chemotherapy is recommended to most women with a node-negative breast cancer whose tumor size is at least 2 cm. Women with stage I breast cancer have an improved prognosis overall; however, up to 20% may suffer a recurrence. Thus other prognostic factors need to be considered in treatment factors of this early stage.

Preoperative Systemic Therapy:

Chemotherapy in women with early-stage breast cancer has traditionally been administered after definitive breast surgery. Based on the pathologic findings at the time of surgery (eg, the tumor size, nodal involvement, other characteristics such as grade and receptor status), clinicians can estimate the risk for recurrence and provide treatment recommendations to the patient. Primary chemotherapy (also designated preoperative chemotherapy or neoadjuvant chemotherapy) has traditionally been reserved for women with locally advanced breast cancer to enhance the likelihood of negative surgical margins or even breast preservation (5). Studies of the primary administration of chemotherapy in the locally advanced breast cancer setting have demonstrated that this treatment modality may provide other benefits. The administration of primary chemotherapy enhances the likelihood of breast conservation. Response to primary chemotherapy can be correlated with long-term outcomes such as disease-free-survival (DFS) and overall-survival (OS). Early eradication of micro-metastases may lead to improved DFS and OS either by decreasing the possibility of encountering drug resistance or by producing less favorable growth kinetics. Some have concerns that administration of primary therapy may be associated with the loss of standard prognostic factors such as tumor size or nodal involvement that are generally used to guide treatment recommendations.

Endocrine Therapy:

Primary therapy may also include endocrine agents. For decades primary therapy with tamoxifen has been used for older women with inoperable receptor-positive tumors. Endocrine therapy offers similar reduction in the annual odds of recurrence and death irrespective of age, menopausal status, tumor size or lymph node status and should be offered to virtually all patients with endocrine-responsive invasive disease. The National Institutes of Health (NIH) Consensus panel made the following recommendations regarding endocrine therapy (6).

1. The decision to recommend adjuvant hormonal therapy should be based on the presence of estrogen receptor (ER) or progesterone receptor (PR) as assessed with immuno-histochemical staining, and if insufficient tumor is available for testing, the hormone receptor status should be considered positive, especially in post-menopausal women.
2. The expression pattern of the HER2/neu gene should not influence the decision to recommend hormonal therapy.
3. Tamoxifen administration is not recommended for women with ER- and PR-negative invasive breast cancers.
4. Five-years of adjuvant tamoxifen therapy should be recommended for all women with hormone receptor-positive tumors, regardless of age, menopausal status, axillary lymph node status, tumor size, or use of adjuvant chemotherapy; possible exceptions include women with node-negative tumors smaller than 10 mm who wish to avoid the side effects of tamoxifen.
5. Ovarian ablation or suppression may be considered an alternative to chemotherapy in pre-menopausal women.