Approximately 70% to 80% of patients with stage I or II invasive breast cancer are technically candidates for breast-conserving therapy (BCT).^1,² Six major randomized trials comparing mastectomy with BCT using modern radiotherapy techniques found no differences in disease-free or overall survival rates between the two approaches³^–⁸ (see web-only Table 61-1 available on the Expert Consult website), which were confirmed by a meta-analysis including additional studies.⁹

WEB-ONLY TABLE 61-1 Randomized Trials Comparing Mastectomy with Breast-Conserving Therapy

Many questions remain regarding optimal patient evaluation and selection for BCT, irradiation techniques and doses, factors affecting complications and cosmetic outcome, follow-up, and treatment of locoregional recurrences. Several texts discuss these topics in much greater depth.¹⁰^–¹³

Pretreatment Evaluation

Imaging

Mammography should always be performed before treatment, although it does not always accurately delineate the pathologic extent of disease. Magnetic resonance imaging (MRI) has substantial false-positive and false-negative rates.¹⁴ It may be most valuable for selected patient subgroups, such as patients with tumors larger than 2 cm, infiltrating lobular histologic characteristics, or positive axillary nodes.¹⁵ One small study found a lower risk of local failure in patients undergoing pretreatment MRI,¹⁶ but two larger studies with longer follow-up did not.^17,18

Postoperative mammograms rarely show residual calcifications in patients with uninvolved microscopic margins.¹⁹ In a series from Philadelphia, postoperative mammographic imaging made no difference to the recurrence rate for patients with ductal carcinoma in situ (DCIS).²⁰ Postoperative MRI has limited accuracy in assessing the presence or amount of residual disease.²¹

Pathologic Evaluation

The most common approach to microscopic margin assessment is surgical removal of a single specimen, which the pathologist rolls in India ink and sequentially sections (as one would slice a loaf of bread) perpendicular to its long axis. Some pathologists “shave” each face of a specimen; the margin is considered involved when tumor is seen in one of the shaved margin slides. These approaches may have quite different clinical implications.^22,²³ Some surgeons take additional “cavity” specimens after removing the main specimen²⁴; their value is uncertain. The role of intraoperative margin assessment is also uncertain.²⁵

Multidisciplinary Review

One quarter to half of prior community hospital radiologic and pathologic interpretations may be changed on review by specialists.^26,²⁷ Management strategies also often differ substantially between physicians and institutions. Hence, it is preferable to have a multidisciplinary review of cases before treatment plans are finalized.

Surgical Techniques

Breast-Conserving Surgery

Technical aspects of breast surgery are discussed in depth elsewhere.^10,^12,¹³ Studies differ on whether wider gross tissue resection margins reduce local failure rates.^28,²⁹ Patients with large cancers or lesions in areas where resection can cause substantial breast distortion may benefit from “oncoplastic” excision.^30,³¹ Reduction mammoplasty has been used prior to radiation therapy for patients with very large breasts with excellent results.³²

Axillary Dissection

The axillary nodes were divided by Berg ³³ into three anatomic “levels”: level I, lateral and inferior to the border of the pectoralis minor muscle; level II, under the pectoralis minor muscle; and level III (also called the infraclavicular nodes), medial and superior to the border of the pectoralis minor muscle. Randomized trials found no differences in axillary failure or survival rates between “limited” dissection (removal of level I or level I and II nodes only) and “complete” dissection (removal of level I, II, and III nodes), but limited dissection caused less morbidity.³⁴^–³⁶

Axillary failures are rare in patients treated with dissection whether nodes are involved or not.^33,³⁷ Failure rates are higher in patients treated with inadequate surgery or in patients with eight or more positive nodes.³⁸

Sentinel Node Biopsy

Sentinel node biopsy (SNB) uses injection of a radionuclide tracer or vital dye (or both) in the breast to guide the surgeon in determining which nodes to remove.³⁹ Immediate and long-term complications are substantially lower for SNB compared with level I or II axillary dissection.⁴⁰^–⁴² False-negative rates of SNB are 0% to 12%, but the risk of axillary failure after negative SNB is very small.⁴³^–⁴⁶ Treatment of patients with involved sentinel nodes is controversial and is discussed below. There were no differences in distant failure rates in two published randomized trials comparing axillary dissection and SNB.^47,⁴⁸ Results from many other trials are pending.

Breast-Conserving Surgery with Radiation Therapy

The effectiveness and toxicities of BCT in individual situations are affected by patient status, clinical and pathologic factors, and treatment parameters.

Patient Status

Pregnancy

Unterminated pregnancy is an absolute contraindication to breast irradiation because of the possible teratogenic and carcinogenic effects on the fetus of scattered radiation.⁴⁹

Prior Treatment with Radiation Therapy

Although most physicians recommend mastectomy,⁵⁰ there were no unusual acute or chronic sequelae among 12 women treated with conservative surgery and radiation therapy at the University of Pittsburgh 10 to 29 years after irradiation for Hodgkin’s disease or non-Hodgkin’s lymphoma,⁵¹ 37 patients treated in Milan,⁵² or 2 patients treated in Ottawa, Canada.⁵³ However, one of two such patients treated at Stanford University developed severe soft tissue necrosis.⁵⁴ A few such patients have been successfully treated with partial-breast irradiation, albeit with short follow-up.^55,⁵⁶

Rheumatologic Disorders

The effect of rheumatologic disorders on the risk of developing acute and chronic complications after radiation therapy has been controversial. Some investigators have considered the presence of these disorders a relative or absolute contraindication to the use of radiation therapy.¹ However, only three small studies have compared complication rates in patients with rheumatologic diseases with a matched “normal” population.^57,58,59 These studies found no clear evidence of increased risk (including the one study focusing on patients treated with BCT⁵⁸), except for patients with scleroderma. Therefore, the author believes that patients with other rheumatologic disorders can be treated safely but those with scleroderma and its variants should not receive radiation therapy if at all possible.

Breast Size

Women with large breasts have more acute skin reactions and long-term retraction and fibrosis than patients with smaller breasts. Results can be improved by using higher-energy photons,⁶⁰ 1.8-Gy daily fractions, and three-dimensional compensation. Treatment in the lateral decubitus or prone position may also be very helpful (see later discussion).

Prior Breast Augmentation

The risk of capsular fibrosis and other complications following irradiation of patients with prosthetically augmented breasts was 50% or higher in several series ^61,⁶² but very low in others.⁶³^–⁶⁵ Local failure rates have also varied between studies, from none⁶⁵ to 25%.⁶³ The small number of patients in these studies makes it difficult to assess how radiation therapy technique and pretreatment evaluation may affect such outcomes. Given the limitations of mammography in the augmented breast, MRI should be used to help assess the spread of tumor within the breast. If the lesion seems limited after such imaging and margin assessment, it seems reasonable to offer such patients BCT with irradiation. Three-dimensional treatment planning may then help reduce the risk of complications (see section on Acute and Chronic Complications).

Patient Age

Patients younger than 35 to 40 years at diagnosis have higher local recurrence rates than older patients for unclear reasons.⁶⁶ Despite this, mastectomy does not yield superior distant disease-free or breast cancer-specific survival rates.^67,68,69 One study found a 5-year actuarial local failure rate of only 3% among 38 patients with margins wider than 2 mm whose tumor did not contain an EIC.⁷⁰ In another series, there was no difference in the local failure rate between patients younger or older than age 45 years when margins were wider than 2 mm.⁷¹ In a study at the Beth Israel Deaconess Medical Center in Boston, the 8-year local failure rate for 54 patients age 40 years or younger with histologic grade 1 to 2 tumors was 7%, compared with 18% for 74 patients with grade 3 tumors.⁷² Systemic therapy also reduces local failure rates.^66,73

Older patients tolerate radiation therapy well and have excellent local control rates.^74,⁷⁵

Genetic Factors

Many studies found little or no difference in ipsilateral local failure rates between patients with BRCA1 or BRCA2 gene mutations and unaffected patients.76–78,79,80 Other studies have suggested that BRCA1 or BRCA2 mutation carriers have increased late local failure rates, likely resulting from the development of new primary cancers.⁸¹^–⁸⁴ Tamoxifen or oophorectomy may reduce rates of both ipsilateral local failure⁷⁹ and contralateral new primary cancers.^79,85 A recent study found equal distant failure rates for 160 BRCA1 and BRCA2 patients treated with BCT and 213 patients treated with mastectomy, with a mean follow-up of 10 years.⁸⁶ There is also no convincing evidence that contralateral prophylactic mastectomy improves the outcome.^80,^87,⁸⁸

Patients with rare genetic syndromes associated with impairment of radiation damage repair, such as ataxia telangiectasia, are at substantial risk of complications from radiation therapy.⁸⁹ However, patients heterozygous for BRCA1 or BRCA2 mutations do not seem to have increased toxicities.^79,90 Complication rates for patients with ATM heterozygosity were not increased in some studies,^91,⁹² but others suggested adverse results for patients with more than one ATM mutation⁹³ or those with particular single mutations.^94,⁹⁵ Patients with polymorphisms of multiple radiation repair genes may also be at increased risk of complications.^94,⁹⁶^–⁹⁹

Some patients with genetic defects of DNA repair may also be at increased risk of radiation carcinogenesis. In-field cancers have been reported to occur within a few years of radiation therapy in several patients with Li-Fraumeni syndrome.^100,¹⁰¹ Limited evidence suggests radiation therapy does not increase the risk of contralateral breast cancers in patients with ATM,^102,¹⁰³ BRCA1, or BRCA2 mutations, however.⁸⁶

Clinical Factors

Means of Detection

Local recurrence rates are similar for patients with palpable and nonpalpable cancers.¹⁰⁴ Patients with nipple discharge do not have higher local failure rates than other patients when resection margins are not involved.¹⁰⁵

Tumor Size and Location

Tumor size does not influence recurrence rates after BCT.⁷⁰ It is difficult, however, to achieve both acceptable cosmetic results and negative margins in most patients with tumors larger than 4 to 5 cm without using neoadjuvant chemotherapy (see Chapter 62).

A few studies suggest that patients with medial tumors have higher local recurrence rates,^106,¹⁰⁷ but this has not been confirmed. Patients with subareolar or periareolar lesions that do not directly extend to the nipple or areola have high local control rates following excision with negative margins without nipple-areolar resection.^108,¹⁰⁹ Even when nipple-areolar resection must be performed, the appearance and texture of the remaining breast are at least as good as these characteristics following reconstruction procedures, and sensation in the remaining breast mound is preserved. Local control rates also appear to be comparable to those achieved with mastectomy.¹¹⁰

Bilateral Breast Cancers

Patients with bilateral breast cancer (either synchronous or metachronous) can be treated successfully with BCT without an increased risk of complications,^111,¹¹² even when the ipsilateral internal mammary nodes (IMNs) were initially irradiated.¹¹³

Multiple Ipsilateral Primary Cancers

Few patients have more than one independent ipsilateral breast cancer at presentation. Only 6 of a consecutive series of 200 patients (3%) with palpable masses had two or more separate lesions on mammography in one series.¹¹⁴ Eight of 225 selected patients (4%) in another series had biopsy-proven additional cancers in a separate quadrant detected only on MRI.¹¹⁵ Only 3 of 183 mastectomy specimens (2%) in another study had multiple lesions without demonstrable continuity.¹¹⁶ The majority of apparently independent lesions in one recent study were clonal, indicating spread from a single site of origin.¹¹⁷ Local failure rates in patients with multiple ipsilateral primary tumors having negative margins are similar to those of patients with a single lesion.^112,¹¹⁸^–¹²²

Pathologic Factors

Margin Status

A “positive,” or “involved,” margin is defined as invasive cancer or DCIS present at an inked surface when a “bread-loafing technique” is used (i.e., sequential sections of the specimen are obtained as one would slice a loaf of bread) or as tumor found anywhere in “shaved” margin specimens. Patients with involved margins generally have higher failure rates than those with uninvolved margins. Involvement by either invasive cancer or DCIS has similar implications.123,124

In a study from the Joint Center for Radiation Therapy (JCRT) in Boston ¹²³ with a median follow-up time of 127 months, the crude 8-year local failure rate was 14% for 122 patients with “focal” margin involvement (defined as DCIS and invasive cancer across all examined slides that could be encompassed by three or fewer low-power microscopic fields) and 27% for 66 patients with “extensive” involvement. In a study from Marseille, France, the risk of local failure was 14% (10 of 70) for patients with a single positive margin, compared with 36% (17 of 47) for patients with multiple involved margins with a median follow-up of 72 months.¹²⁵

Many investigators have arbitrarily distinguished “negative” from “close” but uninvolved margins based on a minimum tumor-free margin width. However, only three published studies with long follow-up times have subdivided results according to sequential intervals ^71,^123,¹²⁶ (Table 61-1). They do not show consistent patterns between increasing margin width and lower local failure rates.

TABLE 61-1 Tumor-Free Margin Width and Risk of Local Failure Following Breast-Conserving Therapy with Radiation Therapy*

Margin width may still be important for certain patient subgroups, such as young patients. Chemotherapy and tamoxifen substantially reduce failure rates in patients with uninvolved margins as a whole,^127,¹²⁸ but this may be proportionally greater for patients with margins narrower than 1 to 2 mm.^123,129

One study found that the volume of disease near uninvolved margins affected the risk of local recurrence.¹²⁶ The number of excisions required to achieve uninvolved margins was not a risk factor for local failure in most,^130,¹³¹ but not all,¹³² series.

Other Histologic Features

An extensive intraductal component (EIC) is defined when two features are simultaneously present for infiltrating ductal carcinomas: (1) intraductal carcinoma that is a prominent portion of the area of the primary mass (in an earlier definition, 25% or more) and (2) intraductal carcinoma clearly extending beyond the infiltrating margin or present in grossly normal adjacent breast tissue.¹³³ Predominantly noninvasive tumors, with only focal areas of invasion, are also included in this category. (Some investigators have used other definitions, most of which probably describe the same entity.) Tumors with an EIC extend more widely through the breast than others.¹³⁴ The presence of an EIC was a major risk factor for local failure in studies in which microscopic margins were not routinely examined, but its impact is uncertain when margin status has been taken into account.^70,123,135

The presence of lymphovascular invasion has been an independent risk factor for local recurrence in most,¹³⁶^–¹³⁸ though not all,¹³⁹ studies.

Patients with infiltrating lobular carcinomas or mixed ductal and lobular features have recurrence rates comparable to those of patients with infiltrating ductal carcinomas.¹⁴⁰^–¹⁴³ Results for rarer histologic subtypes also seem similar.¹⁴³^–¹⁴⁷

Benign proliferative diseases do not appear to affect the risk of local failure.^148,¹⁴⁹ One study found a substantial risk of residual DCIS or invasive disease on reexcision when atypical ductal hyperplasia was at or near the margins, however.¹⁵⁰

Studies conflict on whether finding lobular carcinoma in situ (LCIS) does ¹⁵¹^–¹⁵³ or does not¹⁵⁴^–¹⁵⁶ increase local failure rates.

Biologic Markers of Tumor Behavior

Patients with tumors that express the estrogen receptor have modestly lower local recurrence rates than patients with estrogen receptor-negative tumors when systemic therapy is not used. For example, the 10-year local recurrence rate for patients with node-negative, estrogen receptor-positive tumors in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial was 11%, compared with 15.3% for patients with estrogen receptor-negative tumors in the companion B-13 trial.¹⁵⁷ Appropriate systemic therapy reduced this difference substantially (rates of 3.6% and 3.5%, respectively, in these trials).

The impact of c-ERBB-2/neu, or HER2, overexpression on the risk of local recurrence is uncertain.^158,¹⁵⁹ Several studies found similar local recurrence rates for patients with “triple-negative” cancers and patients with other combinations of estrogen receptor, progesterone receptor, and HER2,¹⁶⁰^–¹⁶³ but such patients had modestly higher local failure rates in several recent series.¹⁶⁴^–¹⁶⁶

The implications of gene expression profiles for local therapy are just beginning to be explored. The “wound signature score” discriminated between patients age 53 years or younger who had a high or low risk of recurrence in one study.¹⁶⁷ The 10-year local failure rate after BCT was low (4% to 5%) for patients age 50 years or older with node-negative, estrogen receptor-positive tumors, regardless of the score of the 21-gene Oncotype DX test (Genomic Health, Redwood City, California), but for younger patients with a low score, the risk was 12.5%, compared with 27.7% and 26.5% for patients with intermediate- and high-risk scores, respectively (Mamounas E, oral presentation, San Antonio Breast Cancer Symposium, December 2005).¹⁶⁸

Conclusions

The great majority of individuals with early-stage breast cancer are candidates for BCT. For a few patients, radiation therapy is absolutely or relatively contraindicated due to toxicity concerns. For some individuals, the anticipated cosmetic results may be so poor (because of the need for very extensive resection or small breast size) that mastectomy with immediate reconstruction may be a more appealing alternative. Margin status is likely the most important determinant of local control, but other factors interact with margin status and each other in complex and poorly understood ways. If margins of the initial excision are microscopically involved or equivocal, then a reexcision should be done. If the margins of the reexcision specimen are still involved microscopically, the patient should understand that she may be at higher risk of local recurrence, although this may be reduced somewhat by systemic therapy. Some patients are willing to accept increased risks of local recurrence and even systemic failure in order to avoid mastectomy. Treatment decisions must be guided by the values of the affected individual.

Breast-Conserving Surgery without Radiation Therapy

Web-only Table 61-2 summarizes the largest randomized trials comparing conservative surgery alone and conservative surgery with radiation therapy for relatively unselected patients.^5,¹⁶⁹^–¹⁷⁴ These trials had broad entry criteria and required only very small microscopically tumor-free margins. In the most recently published meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group, which included 7311 patients in these and similar trials, the risk of isolated local recurrence among patients not receiving radiation therapy was 32%, compared with 10.3% in those receiving radiation therapy.⁹ There was a statistically significant reduction in the 15-year breast cancer-specific mortality rate among patients randomized to irradiation, compared with the control arm (35.9% and 30.5% in the two arms, respectively; hazard ratio, 0.83). The overall mortality rate was also significantly reduced (40.5% and 35.2%, respectively). Of note, the absolute reduction in the breast cancer-specific mortality rate was greater for patients with positive axillary nodes than for those with negative nodes, reflecting the higher risk of local relapse without radiation therapy in the former group (Fig. 61-1).

Figure 61-1 Breast cancer-specific mortality rates in patients in trials comparing lumpectomy plus axillary dissection with or without radiotherapy. A, Patients with uninvolved axillary nodes. B, Patients with involved axillary nodes. BCS, breast-conserving surgery; LF, local failure; N−, uninvolved axillary nodes; N+, involved axillary nodes; RT, radiotherapy.

Adapted from Early Breast Cancer Trialists’ Collaborative Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival. An overview of the randomized trials, Lancet 366:2087-2106, 2005, Figure 2; with permission of the publisher.

WEB-ONLY TABLE 61-2 Randomized Trials Comparing Breast-Conserving Surgery Alone with Breast-Conserving Surgery and Radiation Therapy for Relatively Unselected Patients with Early-Stage Invasive Breast Cancer, with Median Follow-up Time Longer Than 5 Years*

Many investigators have tried to identify patient subgroups with an acceptably low risk of local recurrence following conservative surgery alone.¹⁷⁵ Age older than 65 years,¹⁷⁴ the absence of comedo or lobular features,¹⁶⁹ and low histologic grade¹⁷⁶ were associated with reduced failure rates in series not employing systemic therapy.

Several randomized trials (Table 61-2) and retrospective or prospective studies^186,¹⁸⁷ found low local failure rates in selected patients treated with conservative surgery and antihormonal therapy without irradiation. None of the randomized trials showed any differences in rates of distant metastases, breast cancer-specific mortality, or overall survival between the arms. Antihormonal therapy may be needed to obtain acceptably low failure rates even in such populations.^178,^188,¹⁸⁹

TABLE 61-2 Local Failure Rates in Randomized Trials Treating Selected Patients with Breast-Conserving Surgery and Antihormonal Therapy with or without Radiotherapy

There are few data on how specific factors or their combinations affect outcome with conservative surgery with antihormonal therapy. There was no difference in local failure rates between patients ages 50 to 60 years, 60 to 70 years, or older than 70 years with tumors 1 cm or smaller with negative axillary nodes in one study in London.¹⁹⁰ In the Ontario–British Columbia trial, at a median follow-up of 94 months the actuarial 8-year local recurrence rate for patients age 60 years or older with positive estrogen receptor or progesterone receptor was 7% for 237 patients with tumors 2 cm or smaller and 5% for 107 patients with tumors 1 cm or smaller treated with tamoxifen alone.¹⁸¹ In the Milan study, patients with infiltrating lobular carcinomas had a slightly higher local failure rate (12%, or 9 of 72 patients) compared with patients with infiltrating ductal histology (8%, or 18 of 231 patients).¹⁸⁶ In a retrospective study of patients older than 70 years treated in Nottingham, England, with a limited median follow-up of 37.5 months, the risks of local failure were 33% (4 of 12 patients) for margin widths less than 1 mm, 12% (2 of 17 patients) for margins of 1 to 5 mm, and 2% (1 of 54 patients) for margins wider than 5 mm.¹⁹¹

Even patients with low failure rates may sometimes prefer to reduce their risk of local failure yet further by being irradiated.^192,¹⁹³ The effect of radiation therapy on patients’ quality of life is brief and limited.¹⁹⁴ Therefore the decision to omit irradiation should be made by the patient and her physicians together, not unilaterally.

When to Use Nodal Irradiation

Axillary Irradiation

Some patients with clinically uninvolved (cN0) axillary nodes may have a low risk of regional nodal failure without specific axillary treatment ^181,^184,^186,¹⁹⁵ or with breast irradiation alone.^186,¹⁹⁶^–²⁰⁰ Axillary plus breast irradiation results in failure rates of 1% to 3%,^{199,201,202,203} very similar to those of axillary dissection. Axillary plus breast irradiation resulted in failure rates that were 1% to 2% lower than those of breast radiation therapy alone in two Italian trials.^204,²⁰⁵ Axillary radiation therapy is not as effective for patients with clinically suspicious (cN1) nodes,³³ who should undergo a level I or II dissection.

Axillary failure rates after dissection in patients with positive nodes are generally low if a minimum of 6 to 10 nodes are removed, unless there is extensive involvement.^38,²⁰⁶ Failure rates may be 7% to 10% or higher in unirradiated patients with eight or more positive nodes or T2 to T3 tumors and four or more positive nodes³⁸ or when a substantial proportion of the removed nodes is involved.²⁰⁷ Extracapsular tumor extension does not increase the risk of axillary failure.^206,²⁰⁸

Management of patients with positive nodes on SNB is very controversial.³⁷ The largest study of different approaches was conducted in the Netherlands.²⁰⁹ With a median follow-up of 56 months, the 5-year risk of axillary failure in patients with sentinel node metastases smaller than 0.2 mm was 1% among 396 patients who underwent completion axillary dissection, none of 54 patients treated with breast and axillary radiation therapy, and 2% among 345 patients receiving breast radiation therapy alone or (about one third of the cases) mastectomy without irradiation. For patients with sentinel node micrometastases (0.2 to 2 mm), respective failure rates were 1.1% of 793 patients, none of 94 patients, and 5% of 141 patients. Results from two randomized trials comparing different approaches are not yet available.

Supraclavicular Nodal Irradiation

Supraclavicular recurrences (which are often grouped with axillary apical or infraclavicular recurrences) occur in only a small percentage of patients with uninvolved nodes or 1 to 3 positive axillary nodes.^37,^38,^210,²¹¹ Supraclavicular nodal failures occurred in 7% to 10% or more of patients with four or more pathologically positive axillary nodes in older studies,^38,^206,^212,²¹³ but several recent studies found rates of only 3% to 5%.²¹⁴^–²¹⁶ Patients with a high proportion of recovered axillary nodes involved may also be at increased risk.²⁰⁷ Some studies suggest that lymphovascular invasion in the primary tumor may increase the risk in patients with negative or positive axillary nodes,^206,^210,²¹⁵ though others do not.^208,²¹¹ A study from Taiwan of 2658 consecutive patients found that high grade, four or more positive nodes, and positive nodes at axillary level II or III were associated with increased supraclavicular failure rates.²¹⁷

Internal Mammary Nodal Irradiation

Internal mammary node (IMN) metastases occur in 5% or less of patients with pathologically negative axillary nodes.^218,²¹⁹ Reported rates are 20% to 50% in patients with a positive dissection. Tumor size and the number of involved nodes likely influence this risk.³⁷ Results of the largest such study²²⁰ are shown in web-only Table 61-3, available on the Expert Consult website. The location of the primary tumor appears to have only a minor impact when tumor size and axillary nodal status have been taken into account.^220,²²¹

WEB-ONLY TABLE 61-3 Incidence of Internal Mammary Node Involvement in Relation to Axillary Node Involvement and Tumor Size (Fudan University, Shanghai, China, 1956 to 2003)

Tumor Size, No. Involved Axillary Nodes	No. Patients	Internal Mammary Nodes Involved (%)
T1, N0	204	2.9
T2, N0	493	4.9
T3, N0	187	4.8
T1, 1-3	57	10.5
T2, 1-3	244	20.5
T3, 1-3	97	19.6
T1, 4-6	9	33.3
T2, 4-6	89	31.5
T3, 4-6	41	19.5
T1, ≥7	12	25.0
T2, ≥7	143	42.0
T3, ≥7	103	42.7

Data from Huang O, Wang L, Shen K, et al: Breast cancer subpopulation with high risk of internal mammary lymph node metastasis. Analysis of 2,269 Chinese breast cancer patients treated with extended radical mastectomy. Breast Cancer Res Treat 107:379-387, 2008.

It is common to see drainage to the IMNs when lymphoscintigraphy is performed for SNB.²²¹ Only 10% to 25% of such “hot spots” are involved pathologically, however.²²²^–²²⁴

The value of treating the IMNs prophylactically has been controversial for decades.²²⁵ Clinical IMN recurrence is found in 1% or less of patients in nearly all studies and is rare even when the nodes are shown to be involved by biopsy.²²⁶ Retrospective studies have differed as to whether patients benefit from IMN irradiation.²²⁷^–²³⁰ Randomized trials have not shown improved outcome after specific IMN treatment with either surgery or radiation therapy.²³¹^–²³³ Two large trials conducted by the European Organization for Research and Treatment of Cancer (EORTC)²³⁴ and the National Cancer Institute of Canada are closed, but outcome data are not yet available.

Conclusions

The benefits of nodal treatment are likely to be small. Axillary or supraclavicular radiation therapy need not be given routinely following level I or II axillary dissection when no positive nodes are present or when one to three nodes are positive. Insufficient data are available to justify firm recommendations for nodal irradiation for patients with four or more positive nodes. A supraclavicular field will be adequate for most such individuals. A full axillary field may be useful for patients with very extensive nodal involvement or a more limited dissection, but the risks of arm edema must be carefully considered (see section on Arm Edema). The role of prophylactic IMN irradiation is very uncertain. Because such treatment increases the irradiated volumes of lung and/or heart, it is never mandatory in the author’s view.

Treatment Techniques

Patient Position and Immobilization

Patients are traditionally irradiated in the supine position, but the lateral decubitus ²³⁵ and prone positions^236,²³⁷ may be especially useful for patients with very large breasts (see web-only Fig. 61-1, available on the Expert Consult website). Treatment in the prone position results in anterior displacement of the heart,²³⁸ which can increase the irradiated heart volume for some patients.²³⁹ These positions also have the disadvantages of reducing the coverage of the chest wall and of not allowing the use of nodal irradiation. Some patients are unable to tolerate lying in these positions.²³⁷ One study also reported an increased risk of acute skin reactions when using the prone position.²⁴⁰

Web-Only Figure 61-1 Patient with large, pendulous breast treated in the prone position. A, Planning CT. B, Detailed isodose distribution; prescription dose was 5040 cGy.

Numerous immobilization techniques using specialized breast boards, custom-made foam cradles, and other techniques can reproduce the daily patient position to within 5 mm.²⁴¹^–²⁴³ There is no fully satisfactory way to immobilize the breast itself, especially a large breast, however. Netting is useful to move the breast tissue medially, and careful taping can help open skin folds.

Respiratory excursion of the breast in different directions is 2 to 6 mm.²⁴⁴ Respiratory gating or breath-holding techniques during deep inspiration may reduce the amount of heart irradiated.^242,²⁴⁴^–²⁴⁸

The effects of daily setup variation and normal respiratory motions on the cumulative dose distribution within the breast or at the excision cavity are small.^244,^249,²⁵⁰ Respiratory motion may result in a substantial effect on the doses given to the IMNs, however.²⁴⁴

Whole-Breast Irradiation

Traditional “standard” tangential field borders, based on surface anatomy, are designed to include nearly the entire volume of the breast with adequate margin for daily setup error (Table 61-3). Fluoroscopic simulation has been largely replaced by computed tomography (CT) simulation; there is substantial interphysician variation in delineating the breast, however.^251,252,253 This may be reduced by the use of “standard” templates or atlases.^254,²⁵⁵ Because the risk of local recurrence is quite low for patients whose treatment planning has been based on surface anatomy, it is unlikely that such variations are of substantial clinical importance.

TABLE 61-3 Field Borders and Blocks

Tangents

Inferior: 1-cm margin inferiorly to the inframammary fold.

Superior: The margin of the breast is determined by palpation and will be given a 1-cm margin. When a three-field technique is used, the placement of the match line will depend on the location of the primary tumor as well as the breast tissue; ordinarily, the match line will be at the second intercostal space or the second rib (radiographically, usually at the inferior edge of the sternoclavicular junction).

Lateral: Include all breast tissue with a 1-cm margin; this usually places this border at the posterior axillary to midaxillary line.

Medial: At the midline in most patients. When the internal mammary nodes are to be included, then the medial border is best determined with the aid of lymphoscintigraphy or CT scanning; otherwise, the medial border is arbitrarily placed 3 cm across the midline. When the contralateral breast has been previously treated, or when both breasts are to be treated simultaneously, care should be taken to ensure that treatment fields do not overlap. A gap of 0.5 cm on skin between the medial borders of the two pairs of fields is adequate.

Anterior: 2-cm margin of light is given above the highest point of the breast.

Posterior: The deep edges of the tangents should be coincident; the medial and lateral borders determine their exact position.

Blocks: When the “corner-block” three-field technique is used, a block is drawn along the hanging wire that defines the match line at the superior border with the en face supraclavicular/axillary field. If a single-isocenter three-field technique or the primary collimators are used to match the superior border of the tangents to the nodal field, blocking is used to define the posterior field borders of the tangents. Heart blocks may be used if needed for some patients with left upper quadrant or central primary tumors.

Boost

Include the breast tissue from approximately the skin surface to the anterior chest wall, with 1 to 2 cm around the excision cavity, as the planning target volume.

Supraclavicular/Axillary Field

This field is angled approximately 5 to 10 degrees from the vertical toward the medial side to avoid treating the cervical spinal cord.

Borders

Inferior border: Determined by the match line with the tangential fields. With the JCRT technique, the central-axis plane is located here.

Superior border: Radiologically, usually the superiormost portion of the first rib. Except in unusual situations, it is preferable not to clear skin (or “flash”) in the supraclavicular region.

Lateral border: Usually two thirds of the medial-to-lateral distance through the humeral head. In some patients with very extensive axillary disease, it may be necessary to clear skin laterally.

Medial border: Set up to the center of the suprasternal notch (midline); then angle the gantry.

Blocks: The inferior border is defined by a block through the central axis. In most patients, the lateral third of the humeral head should be blocked; in some patients with very extensive axillary disease, this may not be possible.

Supraclavicular Field Same borders as the full axillary/supraclavicular field, except the lateral field border is at the coracoid process. En Face Axillary Boost (EAB) The couch, gantry, and collimator are angled to direct the beam from the axilla toward the supraclavicular nodes by aiming toward the suprasternal notch. The isocenter is placed at a point 3 to 4 cm lateral to the head of the clavicle, in the supraclavicular fossa. The field size will vary with the patient’s body size but will usually be on the order of 6 × 8 cm. The anterior border is set to run posteriorly to the anterior edge of the pectoralis major muscle, as determined visually and by palpation. The other borders are determined by the desired volume of treatment. Posterior Axillary Boost (PAB)

Inferior: Block the field to match the superior border of the tangential fields.

Superior: Parallel the clavicle.

Medial: 2 cm into the lung tissue medial to the chest wall.

Lateral: At the middle of the humeral head.

En Face Internal Mammary Field Use CT simulation to plan depth and width. Blocking is needed to avoid overlap with the tangential fields used to treat the breast and lateral chest wall.

Blocking or gantry rotation should be used to make the posterior field edges coplanar to reduce normal tissue exposure (Fig. 61-2). It may be acceptable to deviate from these field borders for selected patients (e.g., to move the medial entrance laterally in a patient with a lateral lesion to reduce heart and lung exposure).

Figure 61-2 Transverse view of tangential fields without nodal irradiation. Gantry rotation is used to make the posterior field edges coplanar. (Excision cavity outlined in red, with green circle representing a 2-cm circumferential expansion.)

Most patients are best treated with 6-MV photons. For patients with large breasts or medial-to-lateral separations (over 22 to 24 cm), it is preferable to use 10 = MV or higher energies alone or in combination with 6-MV photons to keep the maximum inhomogeneity less than 110%. Skin failures are rare, regardless of treatment energy,⁶⁰ so that a bolus or beam spoiler does not need to be used routinely.

The breast–chest wall volume varies substantially in shape and transverse dimensions from superiorly to inferiorly. Although physical wedges generally result in satisfactory dose homogeneity in the central-axis plane, there are often very large, intense “hot spots” in the more superior and inferior planes. Inverse-planned intensity-modulated radiation therapy (IMRT),^256,²⁵⁷ with or without treatment of regional lymph nodes,²⁵⁸^–²⁶⁴ results in much more homogeneous dose distributions throughout the entire treatment volume. Simple forward-planned IMRT techniques using only a few additional segments produce nearly identical results for the great majority of patients²⁶⁵^–²⁶⁸ (Fig. 61-3). Elimination of a physical medial wedge reduces scattered radiation exposure of the contralateral breast and other areas.^269,²⁷⁰ Using additional gantry angles may reduce the heart dose (see web-only Fig. 61-2, available on the Expert Consult website), albeit at the price of decreased coverage of the breast volume²⁷¹ or increased exposure of other normal tissues.^259,^263,^264,²⁷²

Figure 61-3 Dose distribution of tangential fields created using lung inhomogeneity corrections and forward planning, with additional medial and lateral segments added to improved homogeneity. The prescribed dose was 4500 cGy. Isodose color key: red, 30%; green, 50%; dark blue, 70%; yellow, 90%; magenta, 95%; light blue, 100%; white, 109%.

Web-Only Figure 61-2 Transverse dose distribution for a multiple-gantry angle intensity-modulated radiation therapy (IMRT) plan, used to reduce the heart dose. The prescribed dose was 5040 cGy in 28 fractions. Note how the 50% isodose line (2520 cGy) extends posteriorly, reflecting the use of a posterior field including the lateral portion of the breast.

Several randomized ^273,²⁷⁴ and retrospective and prospective studies²⁷⁵^–²⁷⁷ of three-dimensionally compensated breast radiation therapy found it reduces acute and chronic toxicities. Hence, CT simulation and three-dimensional treatment planning and compensation should be routinely used when possible.

Breast Boost Volume and Techniques

In most institutions, the breast boost clinical target volume is defined by adding 1- to 2-cm circumferential margins around the tumor bed, with the anterior boundary extending just below the skin and at the anterior chest wall or pectoralis major muscle. The volume of the excision cavity decreases after surgery, particularly within the first 1 to 2 months.278,279,280–282 There are no data showing whether local control or cosmetic results would be different if the boost were planned soon after surgery or just before it is to be given. The volume defined by CT is generally larger than that defined solely by surgical clips.^283,²⁸⁴ It can be difficult to delineate the extent of the cavity on CT scanning,²⁸⁵^–²⁸⁸ and there is no agreement on exactly what features should be included in the target volume. Variation between radiation oncologists in defining the lumpectomy site can be reduced by establishing common guidelines and training.²⁸⁹ Nonetheless, small differences in the size or placement of the boost volume seem unlikely to have a major impact on the risk of recurrence in patients receiving whole-breast irradiation.^290,²⁹¹

Local control and cosmetic results are similar with interstitial implantation, photons, or electrons 292,293 (see web-only Figs. 61-3 to 61-5, available on the Expert Consult website). Intraoperative photon and electron beams have also been used for this purpose.²⁹⁴^–²⁹⁷ Hence, the radiation oncologist appears free to use whatever technique is most convenient and available.

Web-Only Figure 61-3 Placement of stainless-steel needles through the breast for interstitial implant boost. Plastic tubes are inserted through the needles, which are then removed. Metal buttons are placed over the ends; after the radioactive material is inserted when the patient has returned to her room, these will be crimped to hold the implant securely in place. (The ends of the tubes have not yet been trimmed.)

Web-Only Figure 61-4 Three-field photon boost, using anterior, left lateral, and left posterior oblique fields. The excision cavity (shown in yellow color wash) was expanded by 2 cm to create the boost planning target volume (orange color wash), which was edited to come no closer than 5 mm to the skin surface and no deeper than the anterior chest wall or pectoralis muscle. A, Transverse view. B, Sagittal view. C, Coronal view. D, Left posterior oblique beam’s-eye view; 100% isodose surface in light blue.

Web-Only Figure 61-5 Electron boost planned on CT simulator. A, Transverse image of beam showing 2-cm expansion around the outlined excision cavity. B, Digitally reconstructed radiograph (DRR) of the electron field. C, Surface-rendered DRR showing the electron beam entry.

Supraclavicular and Axillary Nodal Irradiation

It is generally necessary to add a slightly obliqued anterior “third field” to treat the upper axillary and supraclavicular nodes, which are not adequately included in breast tangential fields.²⁹⁸^–³⁰¹ Both multiple-isocenter³⁰²^–³⁰⁶ and single-isocenter^307,³⁰⁸ approaches have been employed to match this field to the tangents. The former approaches use combinations of table, gantry, and collimator rotation and blocking to avoid “hot spots” resulting from field overlap or underdosing due to fields being too far apart (Fig. 61-4).

Figure 61-4 Multiple isocenter three-field match technique. A, Anterior surface-rendered digital reconstructed radiograph showing the match between the supraclavicular field and the tangential fields. Note the inferior divergence of the tangential fields from each other. B, Coronal CT representation of intersections of the match between the supraclavicular field and tangential fields at the level of the isocenter of the tangents. Note the blocks on the medial (red) and lateral (blue) tangential fields, which define their posterior borders and a cervical spine block on the medial portion of the supraclavicular field.

The “supraclavicular field” (i.e., lateral border at the coracoid process or medial border of the humeral head) includes the level III nodes in most patients, as well as the true supraclavicular nodes more medially. The inferior border is generally placed at the inferior edge of the clavicular head, which ensures coverage of these nodes.³⁰⁹ The “full axillary field” (also called a supraclavicular/axillary field) extends the lateral border of the supraclavicular field to split the humeral head, therefore including more soft tissue laterally. When CT simulation is employed, the subclavian and axillary vessels are used as surrogates for the position of the axillary nodes, and the sternocleidomastoid, pectoralis minor and major, and anterior scalene muscles and the clavicle are used to define the boundaries of the infraclavicular and supraclavicular nodal regions.³¹⁰ The location of the superior border varies between institutions, from the top of the first rib radiographically, to the top of the shoulder, to the superior border of the thyroid cartilage. A block is usually placed along the transverse spinous pedicles to protect the spinal cord, larynx, and esophagus, but care must be taken because a recent study found that some supraclavicular recurrences were very close to the medial field border.³¹¹

Supraclavicular and full axillary field doses are traditionally prescribed to an arbitrary depth below the skin surface (3 cm and 5 cm, respectively) when two-dimensional treatment planning methods are used. However, the depth of the supraclavicular vessels varies substantially.310,312 The location of the axillary nodes also varies with arm position.³¹³ Hence, CT planning should be used to define this depth when possible (Fig. 61-5).

Figure 61-5 Dose distribution in a supraclavicular-axillary field, prescribed to 4500 cGy at a depth of 5 cm.

It is not clear how often a full axillary field should be used, particularly in patients undergoing a complete axillary dissection. For example, there were no axillary failures in patients with 10 or more positive nodes who received supraclavicular irradiation, whether the axilla was fully irradiated or not.³¹⁴

The value of giving an axillary boost is uncertain. Because the nodes are fairly anterior, the use of a posterior axillary boost does not appear optimal.³¹⁵ For individuals with very deep nodes or situations calling for doses above 45 to 50 Gy, however, it may be best to use opposed fields or three-dimensional conformal techniques to improve nodal coverage with acceptable inhomogeneity.^316,³¹⁷

Internal Mammary Nodal Irradiation

The majority of IMNs are found in the first three intercostal spaces between the posterior edge of the sternum and the parietal pleura, but some may be as low as the sixth intercostal space and some are located directly under the ribs.^318,³¹⁹ Half to three-quarters of the nodes are located medial to the internal mammary vessels in the upper two to three intercostal spaces, with most (but not all) nodes lateral to the vessels in the more inferior levels.³¹⁹ The internal mammary vessels are usually visible at the sternal-pleural junction.³²⁰ Their depth and location from the midline vary substantially between patients.³¹³ Therefore CT simulation should be used to plan IMN treatment. However, the maximum distances of the IMNs from the vessels have not been described, and, hence, the optimal expansions needed to define the clinical target volume are not known.

Anterior photon fields were commonly used to treat the IMNs in the past, but this increases the risk of late cardiac deaths.³²¹ Heart exposure can be limited by using electron- or mixed-beam direct internal mammary fields,³²²^–³²⁴ but this approach requires substantial care to achieve an acceptable junction with the tangential fields. The “partially wide tangent technique” includes the IMNs in the third interspace and above in tangential fields that ordinarily cross the midline, with the inferior portion of the fields blocked posteriorly to reduce the irradiated volumes of lung and heart³²⁵ (see web-only Fig. 61-6, available on the Expert Consult website). Such blocking may increase the risk of local failure for patients with inferiorly located tumors, however.³²⁶ Coverage of the IMNs may be improved and normal tissue doses reduced with the use of IMRT.³¹⁶

Web-Only Figure 61-6 Treatment plan including internal mammary nodes (IMNs). The internal mammary vessels were outlined and expanded by a 1-cm margin to define the IMN planning target volume (PTV) (green color wash). The prescribed dose to the IMN PTV and breast–chest wall PTV (magenta color wash) was 5040 cGy in 28 fractions. A, Transverse view of dose distribution. Note that the medial field border enters to the right of midline. (The breast excision site is shown by the yellow color wash and the breast boost PTV by the orange color wash.) B, Coronal dose distribution. C, Medial tangent beam’s-eye view; 100% isodose surface in blue. Note blocking of inferior interspaces using multileaf collimators.

Radiotherapy Dose and Schedule Parameters

Interval between Surgery and Start of Radiation Therapy

Local failure rates do not seem to be increased when radiation therapy is started up to 4 months after the last breast surgery.327–331,332 Prolonging the start of radiation therapy beyond this time, however, resulted in increased failure rates for patients with close margins (≤1 mm) in one randomized trial of the sequencing of chemotherapy and irradiation.^333,334 Unfortunately, the effect of the tumor-free margin width was not reported in other such randomized trials.³³⁵^–³³⁷

Whole-Breast Fractionation

Conventions for prescribing doses to the breast varied substantially from one institution to another in the “two-dimensional” era and only examined the central-axis plane, without the use of inhomogeneity corrections.^338,³³⁹ Nor is there yet agreement on this in the three-dimensional era. (Differences in prescribing doses for boost fields are even more substantial.) Hence, the data below on dose response must be interpreted with caution.

Most centers in the United States and Western Europe have traditionally given whole-breast doses of 45 to 50 Gy in 1.8- to 2-Gy daily fractions. Centers in the United Kingdom, Canada, and occasionally elsewhere routinely used schemes with higher daily fraction sizes (e.g., 40 Gy in 15 or 16 fractions) with excellent results.³⁴⁰^–³⁴⁴ Several randomized clinical trials have compared these and other fractionation schemes.^{345–347,348,349,350} Two are particularly important. A trial conducted from 1993 to 1996 in Ontario and Québec, Canada, included 1234 women with pathologically clear resection margins and negative axillary lymph nodes, who were randomly assigned to receive whole-breast irradiation of 50 Gy in 25 fractions or 42.5 Gy in 16 fractions.^347,348 A boost was not given. With a median follow-up of 144 months, the 10-year rates of local recurrence in the two arms were 6.7% and 6.2%, respectively. Seventy percent of patients in each arm had excellent or good global cosmetic outcomes, with no difference in complication rates. The “START B” trial, conducted in the United Kingdom between 1999 and 2002, compared 50 Gy in 25 fractions with 40 Gy in 15 fractions in 2215 patients.³⁴⁹ A boost of 10 Gy in five fractions was given in 43% of patients. With a median follow-up of 6 years, the 5-year actuarial local failure rates were 3.3% and 2.2% in the two arms, respectively. Cosmetic results were slightly better in the 40-Gy arm. There was no difference between the arms in the risk of symptomatic rib fractures, symptomatic lung fibrosis, or ischemic heart disease.

Even more hypofractionated schemes have been tried.³⁵¹^–³⁵⁶ A randomized study at the Hôpital Necker (Paris) compared giving 45 Gy in 25 fractions, delivered in 5 weeks, to 23 Gy delivered as 5 Gy on days 1 and 3 and 6.5 Gy on days 15 and 17.³⁵¹ With a minimum follow-up of 4 years, the locoregional recurrence rate in patients undergoing tumorectomy was 7% (4 of 56 patients) in the conventional fractionation arm, compared with 4% (2 of 45 patients) in the hypofractionation arm. The incidence of fibrosis and telangiectasias appeared greater in the hypofractionated group, although the severity of these was not described. The “FAST” trial, conducted from 2004 to 2007 in the United Kingdom, will help assess the place of such schemes.^357,³⁵⁸

Total Dose to the Primary Tumor Site and Overall Treatment Time

Four randomized trials compared whole-breast radiation therapy alone with whole-breast irradiation plus a boost for patients with uninvolved margins.³⁵⁹^–³⁶⁴ Absolute differences in local control rates were only 2% to 3% for their overall populations. The largest was conducted by the EORTC.^362,³⁶⁴ This trial, however, defined margin status only in relationship to the invasive component of the tumor, ignoring DCIS, which severely limits the applicability of its results. Results of a central pathology review including about one-third of the entered patients found that the boost benefited patients with margins wider than 2 mm (reducing the 10-year failure rate from approximately 14% to 7% when the distance to invasive disease was assessed and from about 17% to 5% when DCIS was assessed).³⁶⁵ The boost did not have a statistically significant impact in the combined group of patients with either close (≤2 mm) or positive margins (approximately 11% and 9%, respectively, when invasive disease was considered, and approximately 14% and 11% when DCIS was examined). However, results were not presented separately for patients with close and positive margins, or for all patients with uninvolved margins together, regardless of width. Researchers also found that a boost decreased local failure rates significantly for “high-risk” groups characterized by high-grade invasive cancers or age younger than 50 years, but the results were not described according to margin status and the use of the boost simultaneously.

Giving doses above 60 Gy to the tumor bed may be of greater benefit for patients whose specimen resection margins are positive or not evaluated. In the EORTC randomized trial, patients with margins involved by invasive cancer were randomly allocated to receive either 76 Gy or 60 Gy.³⁶⁶ The rates of local failure at 10 years were 17.5% and 10.8%, respectively. However, 13% of patients in the high-dose arm developed severe fibrosis in the boost region, compared with 3% of the control group.

There are very few data on how the time to complete radiation therapy affects the risk of local recurrence. A retrospective study from Istanbul, Turkey, suggested that treatment interruptions or breaks of 8 days or more significantly increased this risk in patients treated with whole-breast irradiation plus a boost, most of whom also received systemic therapy.³⁶⁷ If radiation therapy is interrupted for more than 2 weeks, one may consider increasing the total dose to the primary tumor site, although the value of this is unknown. Several studies have investigated “concurrent boost” techniques, in which IMRT is used to give a higher daily dose to the boost volume than to the remainder of the breast.^368,³⁶⁹ Such treatment appears to be well tolerated acutely, but long-term data on efficacy and complications are not yet available.

Nodal Irradiation Doses

Doses of 45 to 50 Gy result in a very low incidence of nodal failure in patients with clinically uninvolved nodes or involved nodes following axillary dissection.^33,³⁷⁰ It is uncertain when, if ever, higher doses should be used in patients without gross residual disease. There is also little evidence regarding the nature of the dose-response relationship for suspiciously enlarged nodes.

Conclusions

Whole-breast doses of approximately 45 to 50 Gy in 25 fractions or 40 to 42 Gy in 15 to 16 fractions appear to be equally effective and safe for most patients, though it is not known whether some subgroups would have better results with one scheme or another. A boost dose to the excision cavity and its environs increases the local control rate very modestly for patient populations as a whole. It is not certain which patient subgroups are most likely to benefit from a breast boost. When a boost is used, the total dose to the primary tumor site should be approximately 60 to 65 Gy for patients with uninvolved margins. Higher doses may be appropriate for patients with involved margins, but the risk of toxicity is increased.

Accelerated Partial-Breast Irradiation

As noted above, occult synchronous primary cancers are rare in patients with clinically unicentric cancers. Most residual tumor cells remaining after lumpectomy are located within a few centimeters of the excision cavity.^134,³⁷¹ Two thirds or more of local recurrences are at or near the site of the primary tumor, whether radiation therapy is used or not.³⁷² Hence, treatment of only a more limited volume surrounding the tumor might be as effective as whole-breast irradiation for many patients. In principle, this approach might reduce complications associated with whole-breast irradiation and allow treatment to be completed more quickly.³⁷³

Among the approaches described to date for giving accelerated partial-breast irradiation (APBI) are the following: (1) low-dose-rate or high-dose-rate interstitial implantation ³⁷⁴ (see web-only Fig. 61-7, available on the Expert Consult website); high-dose-rate brachytherapy using a balloon catheter with one or more source channels^375,³⁷⁶ (see web-only Fig. 61-8); permanent interstitial implantation of radioactive seeds³⁷⁷ (see web-only Fig. 61-9); single-fraction intraoperative irradiation using 50-kV photons³⁷⁸ (see web-only Fig. 61-10), high-energy electrons³⁷⁹ (see web-only Fig. 61-11) or brachytherapy³⁸⁰; and three-dimensional conformal external beam radiation therapy (EBRT) using photons,³⁸¹^–³⁸³ mixed photons and electrons³⁸⁴ (see web-only Fig. 61-12), or protons.^385,³⁸⁶

Web-Only Figure 61-7 Transverse CT image of a volume interstitial implant for partial-breast irradiation, with target volume (red color wash) and superimposed isodose distribution.

From Vicini FA, Arthur DW: Breast brachytherapy, North American experience. Semin Radiat Oncol 15:108-115, 2005, Figure 3; with permission of the publisher.

Web-Only Figure 61-8 Optimal placement of balloon brachytherapy device for partial-breast irradiation.

From Shah NM, Wazer DE: The MammoSite balloon brachytherapy catheter for accelerated partial breast irradiation, Semin Radiat Oncol 15:100-107, 2005, Figure 4; with permission of the publisher.

Web-Only Figure 61-9 Permanent palladium-103 (¹⁰³Pd) seed implant for partial-breast irradiation, with superimposed dose distribution.

From Pignol JP, Keller B, Rakovitch E, et al: First report of a permanent breast ¹⁰³Pd seed implant as adjuvant radiation treatment for early-stage breast cancer, Int J Radiat Oncol Biol Phys 64:176-181, 2006, Figure 3; with permission of the publisher.

Web-Only Figure 61-10 Intraoperative partial-breast irradiation using the 50-kV intrabeam system, with the x-ray source in the breast wound (inset).

Vaidya JS, Tobias JS, Baum M, et al: TARGeted intraoperative radiotherapy (TARGIT). An innovative approach to partial-breast irradiation, Semin Radiat Oncol 15:84-91, 2005, Figure 2; with permission of the publisher.

Web-Only Figure 61-11 Intraoperative electron applicator in position for single-dose partial-breast irradiation.

Orecchia R, Veronesi U: Intraoperative electrons, Semin Radiat Oncol 15:76-83, 2005, Figure 2; with permission of the publisher.

Web-Only Figure 61-12 Partial-breast irradiation using mixed photons and electrons; prescription dose, 4000 cGy. A, Transverse dose distribution. B, Sagittal dose distribution. C, Coronal dose distribution.

Randomized Trials Comparing Whole-Breast and Accelerated Partial-Breast Irradiation

Web-only Table 61-4 lists the randomized trials comparing partial-breast irradiation with conventional whole-breast irradiation. Three have been completed, with published results. Two of these, one conducted from 1982 to 1987 in Manchester, England, and one from 1986 to 1990 by the Yorkshire Breast Cancer Group in Leeds, England, did not assess microscopic margin status and used treatment techniques that make them of limited relevance to current practice.^388,³⁸⁹ The National Institute of Oncology in Budapest, Hungary, conducted a trial from 1998 to 2004 that included 258 patients.³⁹⁶ All except one patient had microscopic margins of 2 mm or wider. Patients in the whole-breast irradiation arm received 50 Gy in 25 fractions without a boost, whereas patients in the APBI arm received either high-dose-rate implantation (36.4 Gy in 7 fractions over 1.5 weeks) or (if technically unsuited for an implant) electrons (50 Gy in 25 fractions over 5 weeks). With a median follow-up of 68 months, the 5-year actuarial local failure rates in the two arms were 3% and 5%, respectively. The rates of late grade 2 to 3 complications were 23% and 25%, respectively, and rates of excellent or good cosmetic results were 63% and 78%, respectively.

WEB-ONLY TABLE 61-4 Randomized Trials of Whole-Breast versus Partial-Breast Irradiation

Results of Nonrandomized Studies and Correlates of Local Recurrence

The only studies of APBI with a median follow-up of 5 years or more have employed interstitial implantation or balloon brachytherapy (Table 61-4). Local failure rates in most of these studies have been comparable to those achieved with conventional whole-breast irradiation. However, several series have had much higher failure rates, likely resulting from different patient selection criteria and treatment techniques.

TABLE 61-4 Results of Selected Studies of Accelerated Partial-Breast Irradiation with Median Follow-up of 5 Years or Longer

Experience with other forms of APBI is much more limited. So far, local control rates seem comparable to those of series using interstitial implants or balloon brachytherapy.^373,^408,⁴⁰⁹

There are few data on how the outcome of APBI varies in relation to patient, tumor, or clinical factors. In the Manchester trial, recurrence rates were quite similar in the two arms for patients with infiltrating ductal carcinomas (11% and 15%, respectively, for whole-breast vs. limited-field therapy); for patients with infiltrating lobular tumors, however, respective recurrence rates were 8% and 34%.³⁸⁸ The rate of local failure was 3% (4 of 130) for women younger than age 50 years treated with balloon brachytherapy in a large registry study, compared with 2% (21 of 1319) of older patients, with a median follow-up of 38 months.⁴¹⁰ In a study from the University of Wisconsin with a median follow-up of 48.5 months, the risk of local failure was 2% in 183 patients in a “low-risk” group (≥50 years of age; node-negative, estrogen receptor-positive disease) and 4% in 90 patients with one or more “high-risk” criteria (≤50 years of age; estrogen receptor-negative disease, or one to three positive nodes).⁴¹¹ In the William Beaumont Hospital study, the risk of local failure was 36% (4 of 11) for patients with a tumor-free margin width of less than 2 mm, compared with 1% (1 of 77) for patients with margin widths of 2 to 10 mm or 1% (1 of 111) for those with margins of more than 10 mm.^412,413 In the Radiation Therapy Oncology Group (RTOG) 96-17 trial, the risk of local failure was 14% (4 of 29) among patients not receiving systemic therapy, compared with 3% (2 of 70) among those who did.⁴⁰⁵

Complications

The most common long-term complication of APBI is fat necrosis, which occurs in 10% to 30% or more of patients by 2 to 3 years after interstitial implantation or balloon brachytherapy in some,^403,^404,^406,⁴¹⁴ but not all,^410,⁴¹⁵ series. Most are asymptomatic. Fibrosis occurs in a similar proportion of patients. Severe pain is rare.⁴⁰⁶ A few patients have had such severe fibrosis or discomfort that they have required mastectomy.⁴⁰⁵ Other toxicities include skin thickening and telangiectasias. In most studies, cosmetic results are good or excellent in 80% to 90% or more of patients, though some studies have lower rates.⁴⁰³

Few serious long-term toxicities have been seen so far in studies using intraoperative electron radiotherapy.^379,⁴¹⁶ Toxicity rates in general appear lower in patients treated with external beam APBI than with brachytherapy, but experience is more limited.^409,^417,⁴¹⁸ Radiation pneumonitis has been reported following external beam APBI, which exposed large volumes of the ipsilateral lung to relatively low doses.⁴¹⁹

Patients receiving chemotherapy after brachytherapy appear to have increased late toxicity and poorer cosmetic results.⁴²⁰^–⁴²² These problems can be reduced by delaying the start of chemotherapy by 3 weeks or more.⁴²¹ A recent pilot study showed, however, that external beam partial-breast irradiation using once-daily fractionation could be safely given with concurrent dose-dense doxorubicin and cyclophosphamide.⁴²³

Conclusions

The optimal pretreatment evaluation, selection criteria, and technical parameters, including how to choose between the different methods for APBI, are not known. Several professional societies ^408,^424,⁴²⁵ and expert consensus panels⁴²⁶ have promulgated guidelines for the use of APBI outside formal protocols, which, however, do not agree on all specifics. At present, the author prefers to limit such treatment to patients age 50 years or older with estrogen receptor-positive, node-negative invasive cancers or DCIS measuring 2 cm or smaller, with microscopic margins of 2 mm or wider.

Acute and Chronic Complications and Cosmetic Results

Acute Reactions and Their Management

Most patients will develop mild skin irritation or itching as radiation therapy progresses. Moisturizers can reduce these symptoms. Applying skin care products prior to irradiation does not appreciably increase the skin dose ⁴²⁷; hence, patients may use such products whenever and as often as needed. The value of prophylactic skin treatment is much less clear. Two randomized trials found that washing with soap and water reduces the severity of skin reactions, compared with not washing at all or using water alone,^428,⁴²⁹ but several trials showed no differences in reactions between patients using different skin care products when compared with each other or when no products were applied.⁴³⁰^–⁴³³ One double-blind trial suggested that a cream including hyaluronic acid was more effective in preventing severe skin reactions than one containing only the base of polyethylene glycol, glycerol, and sorbitol.⁴³⁴ Another trial found that applying a potent steroid cream from the beginning of treatment decreased the intensity of the acute skin reaction.⁴³⁵ There were no data on whether this caused long-term changes in the skin, however.

About 10% to 15% of patients treated with radiation therapy alone or sequential chemotherapy and radiation therapy will develop moist desquamation (usually in the axilla or inframammary fold) during or shortly after completion of irradiation ³³³; the rate may be 50% or higher for patients receiving concurrent chemoradiotherapy.⁴³⁶ Patients with only limited areas of moist desquamation can often continue radiation therapy without interruption. It may be desirable to temporarily switch from tangential fields to the boost field, rather than giving a complete treatment break. Treatment breaks of more than 1 week are rarely necessary. Reepithelialization need not be complete for treatment to resume. Skin care commonly used in this setting includes chlorhexidine gluconate or other antibacterial soaps to cleanse the area (also useful for patients developing folliculitis) and using nonadherent dressings to absorb drainage and maintain moisturization. In a randomized trial performed in Scotland, patients with moist desquamation took longer to heal when a hydrogel dressing was used than when a dry dressing was applied.⁴³³

Fatigue is very common during irradiation. It is generally mild and resolves within 2 months following completion of irradiation. A prospective study performed in Munich, Germany, did not find any factors correlated with its development or severity.⁴³⁷ A study in Newcastle, Australia, found that a higher baseline fatigue level and higher baseline neutrophil and red cell counts were predisposing factors.⁴³⁸

Myelosuppression of clinical significance is extremely unusual, and, hence, blood counts do not need to be routinely checked.

Postoperative cellulitis or abscess should be dealt with before radiation therapy is started if possible. If radiation therapy has started, antibiotics and/or surgical consultation should be initiated promptly, but it is probably not necessary to interrupt radiation therapy unless abscess drainage is required.

Subacute and Chronic Complications

Skin, Soft Tissue, and Bone Reactions

Patients may develop a skin “radiation recall” reaction when chemotherapy (particularly doxorubicin) is given following irradiation (Fig. 61-6). This is rare when chemotherapy begins more than 2 weeks after the completion of irradiation, however.⁴³⁶

Figure 61-6 Moist desquamation in electron boost field after completion of radiotherapy. Such reactions are uncomfortable but rarely become infected.

Breast abscess or cellulitis develops in 5% to 10% of patients at any time after surgery.^439,⁴⁴⁰ Cellulitis may be more frequent in patients with hematomas or seromas requiring drainage, in those in whom large volumes of breast tissue have been resected, or in those with arm edema.^441,⁴⁴² Sometimes cellulitis or abscess mimics an inflammatory-type recurrence,^439,⁴⁴³ although the presence of pain, possible systemic symptoms of infection, and the time course of development usually make the distinction clear.

Rarely, patients develop patches of white or yellowish well-circumscribed sclerosis and induration weeks to years following radiation therapy, sometimes preceded by erythema. The patches may be surrounded by a more highly pigmented, bruise-like area. This phenomenon has been termed postirradiation morphea or circumscribed scleroderma.^444,⁴⁴⁵

Fibrosis is common but generally mild. When severe, it can impair the cosmetic results.

Some individuals develop fat necrosis, which typically causes a painful or painless mass, sometimes accompanied by retraction or dimpling of the overlying skin.⁴⁴⁶ The skin may be thickened clinically and radiologically. Mammography usually reveals a spiculated, often poorly defined mass that may contain punctate or large, irregular calcifications. Cystic degeneration may eventually develop, resulting in a cavity that contains oily fluid or necrotic fat.

Patients commonly note intermittent transient breast pain, which can be sharp and shooting or dull and aching, lasting a few seconds or minutes, or rarely longer. Younger patients seem more likely to experience pain after BCT than older individuals.⁴⁴⁷ In a randomized trial in which patients were allocated to receive radiation therapy or not following conservative surgery, patients treated with radiation therapy had more breast discomfort initially, but with further follow-up the degree of discomfort became equal in both groups.⁴⁴⁸ Pain is generally mild or moderate, but in some patients it is sufficiently bothersome to require medication.⁴⁴⁷ Some patients with severe pain or fibrosis have responded to treatment with pentoxifylline, alone or in combination with vitamin E.^449,450

Soft tissue necrosis is quite rare and generally associated with outmoded irradiation techniques.⁴⁵¹

The incidence of rib fractures is related to the treatment energy and the total breast dose given.⁴⁵¹ Today, this risk should be less than 1%.⁴⁵²

Arm Edema and Shoulder and Arm Function

Arm edema may cause psychological and functional morbidity, as well as predisposition to the development of cellulitis. Lymphangiosarcoma (Stewart-Treves syndrome) due to arm edema is extremely rare.⁴⁵³

The great majority of cases of arm edema develop in the first 3 years after treatment.⁴⁵⁴ Symptomatic arm edema occurs in at most 5% to 10% of patients when either SNB, level I to II axillary dissection, or radiation therapy alone is employed; these cases are usually mild.^455,⁴⁵⁶ The incidence and severity of arm edema are substantially increased following a complete axillary dissection,³⁵ especially when full axillary irradiation is also given.⁴⁵⁷^–⁴⁵⁹ However, full axillary irradiation does not increase the risk of arm edema for patients having limited surgery.⁴⁵⁷^–⁴⁶⁰ Arm edema rates were not increased by supraclavicular irradiation, even when patients underwent complete axillary dissection, in most studies,⁴⁶¹^–⁴⁶⁴ though in others they were increased.^465,⁴⁶⁶ Several studies found that a posterior axillary boost increased the risk of arm edema.^464,⁴⁶⁶^–⁴⁶⁸

Few randomized trials have compared different approaches to the management of lymphedema.⁴⁶⁹ For example, a trial conducted in Edmonton, Alberta, Canada, found that manual lymphatic massage had no benefits in addition to compression bandaging, except perhaps in patients with mild lymphedema.⁴⁷⁰

Axillary irradiation may also cause changes in shoulder mobility and/or arm functioning.⁴⁷¹ Such changes are rare in patients treated with doses of 50 Gy or less in 1.8- to 2-Gy fractions. Physiotherapy immediately following axillary dissection improved shoulder functioning in a randomized trial performed in Nijmegen, the Netherlands,⁴⁷² though the role of such therapy at a later time or in patients with dysfunction due to radiation therapy has not been studied.

Neurologic Injuries

The most common neurologic complication due to axillary dissection is the intercostobrachial nerve syndrome, characterized by fairly constant paresthesias and dull, aching, or burning pain of the upper arm, shoulder, and axilla, and occasionally of the more anterior chest wall. This syndrome may be permanent, at least for the most severely affected individuals. Treatment tends to be ineffective, although occasional patients respond to nerve blocks or topical measures.^473,⁴⁷⁴ Motor injury resulting from axillary dissection is unusual because the thoracodorsal, long thoracic, and pectoral nerves can be exposed and protected.

Classic radiation therapy brachial plexopathy is a chronic, progressive syndrome the onset of which is highly variable, from as soon as 3 months to as long as 26 years after irradiation.⁴⁷⁵ Patients usually present with sensory and/or motor symptoms of the ipsilateral limb. Pain can occur but is generally less prominent, which helps in distinguishing the syndrome from neoplastic plexopathy. A second, rarer type of radiation plexopathy appears more rapidly than classic chronic plexopathy (median, 4.5 months) and usually resolves spontaneously.⁴⁷⁶ The incidence of brachial plexopathy is low (0% to 5%) in patients receiving doses at the plexus of 50 to 54 Gy in 1.8- to 2-Gy fractions or 40 to 45 Gy in 2.5- to 3-Gy fractions.⁴⁷⁷ In the JCRT experience, both the radiation therapy dose and the use of chemotherapy affected this risk.⁴⁵¹ Other studies using both nodal irradiation and chemotherapy had no patients who developed plexopathy, however.^333,⁴⁷⁸ There is no clearly effective treatment.⁴⁷⁷

The presence of an enhancing mass on MRI is the most helpful finding in distinguishing between radiation-induced and malignant brachial plexopathy, particularly in individuals with severe pain.⁴⁷⁹^–⁴⁸² Some patients with an indeterminate MRI may have abnormal uptake of ¹⁸F-fluorodeoxyglucose (FDG) on positron emission tomography (PET), indicating malignancy.⁴⁸³

Pulmonary Effects

Radiographic infiltrates and localized interstitial fibrosis are common in patients treated with radiation therapy.⁴⁸⁴ These generally stabilize by 12 months after treatment, although some may resolve and some continue to progress for as long as 5 years. Pulmonary function tests worsen soon after radiation therapy but then recover partially.⁴⁸⁵

Clinical radiation pneumonitis is characterized by nonproductive cough, fever, and nonspecific infiltrates on chest x-ray.⁴⁸⁴ It generally appears from 4 to 9 months after completion of radiation therapy. Rarely, radiation therapy appears to precipitate a more generalized syndrome called bronchiolitis obliterans with organizing pneumonia.^486,⁴⁸⁷ Prolonged courses of prednisone are often needed to treat symptoms when severe.

Clinical radiation pneumonitis is very rare in patients treated to the breast alone, whether chemotherapy is given or not.488,489,490 Pneumonitis occurs in about 5% or less of patients treated with a third nodal field when the average lung distance is 3 cm or less.⁴⁹⁰

There are conflicting data on whether the risk of pneumonitis is increased by chemotherapy (particularly when given concurrently with radiation therapy), which may be due to differences in details of such programs.⁴³⁶ Two studies found that tamoxifen increased the risk of radiologic pulmonary fibrosis following radiation therapy.^491,⁴⁹² In a series from the Fox Chase Cancer Center, however, tamoxifen did not affect the risk of clinical radiation pneumonitis.¹²⁹

Cardiovascular Complications

Radiation therapy may cause either acute or chronic heart damage.^493,⁴⁹⁴ Acute and subacute complications, such as pericarditis, are rare following breast radiation therapy.⁴⁵¹

Radionuclide cardiac imaging suggests that the development of perfusion abnormalities correlates with increasing irradiated cardiac volume.⁴⁹⁵ The presence of defects has not yet been shown to predict the long-term risk of clinical heart disease, however.⁴⁹⁶ Such toxicity appears to be mainly due to coronary artery disease and may have a latency period of 10 years or more. Long-term increased cardiac death rates were found by meta-analyses³²¹ and registry-based studies,^497,⁴⁹⁸ which included patients treated mainly with outmoded techniques of radiation therapy. Other registry studies did not find such an effect or found substantial effects only for patients irradiated before 1980.^499,⁵⁰⁰ For example, Giordano and colleagues⁴⁹⁹ found that, for 12,136 patients treated between 1985 and 1989, there was no significant difference in the 15-year cardiac mortality rates between patients treated to the left and right sides (5.8% and 5.2%, respectively). Several single-institution studies using modern irradiation techniques also did not show increased risks of cardiac morbidity and mortality at median follow-up times of 10 to 20 years.⁵⁰¹^–⁵⁰⁵ Some studies of patients treated after 1980, however, have found increased risks of cardiovascular mortality or morbidity.^506,⁵⁰⁷ A study from the University of Pennsylvania found that the 10-year actuarial cumulative incidence of cardiac mortality was 1.9% for left-sided patients and 1.5% for right-sided patients; at 15 years, rates were 4.4% and 2.9%, respectively, and at 20 years, 6.4% and 3.6%, respectively.⁵⁰⁶

Risk factors predisposing patients to cardiac complications of radiation therapy are not well understood. The University of Pennsylvania investigators found a statistically significant interaction between hypertension and left-breast irradiation in the development of coronary artery disease that increased over time. A study from Amsterdam and Rotterdam found that smoking was the only significant factor interactive with radiation therapy, however.⁵⁰⁸ Of note, excess cardiac events occurred in patients treated with postmastectomy irradiation (which generally included the IMNs) but not patients treated with BCT. The volume of heart irradiated in the tangential fields was not a risk factor, however, in another study from the Netherlands with a median follow-up time of 16 years.⁵⁰⁷

Most studies have not shown an increased risk of anthracycline cardiac toxicity in irradiated patients receiving commonly used doses.^452,⁵⁰⁹^–⁵¹² So far it does not appear that there is a deleterious interaction between radiation therapy and trastuzumab, but follow-up times have been short.^513,⁵¹⁴ It is also uncertain whether irradiating the IMNs will increase the risk of toxicity from trastuzumab.^515,⁵¹⁶

Giving prophylactic irradiation to the supraclavicular nodes does not appear to increase the risk of stroke.⁵¹⁷^–⁵¹⁹

Carcinogenesis

Patients age 45 years or younger at initial diagnosis appear to have a small increased risk of developing new contralateral primary cancers due to radiation therapy.520,521 In a study using the Connecticut Tumor Registry, the relative risk was 1.21 at a dose of 1 Gy (probably the minimum achievable with current techniques).⁵²⁰

Most cancers that develop within the radiation therapy fields are soft tissue sarcomas or angiosarcomas. These may appear as soon as 1 or 2 years after treatment but tend to occur after 8 to 10 years or longer.^522,⁵²³ The excess incidence of soft tissue sarcomas is 9 to 14 cases per 100,000 patient-years of observation.⁵²⁴^–⁵²⁷ In a series from the Institut Gustav-Roussy near Paris, the 10-year actuarial incidence was 0.2%, the 20-year incidence 0.43%, and the 30-year incidence 0.78%.⁵²⁵ The excess incidence of angiosarcomas in patients treated with BCT is 5 to 13 cases per 10,000 treated patients.^522,⁵²⁷^–⁵²⁹ Of interest, a registry study from Finland found the risk of angiosarcomas was increased in both irradiated and unirradiated breast cancer patients, compared with that expected.⁵³⁰

In one study, postmastectomy irradiation was associated with an estimated excess of seven to eight lung cancer cases per 10,000 women who survived more than 10 years from diagnosis.⁵³¹ Such cancers are almost entirely limited to current or former smokers.^532,⁵³³ More recent studies found no increased risk of lung cancer following BCT, perhaps because of the smaller volumes of lung treated.^534,⁵³⁵

Radiation-induced leukemia appears very rare in patients not receiving chemotherapy.⁴⁵² The risk of leukemia may be increased by radiation therapy by 0.3% to 0.5% in patients who receive standard-dose chemotherapy.^536,⁵³⁷

Cosmetic Results

The great majority of patients have acceptable cosmetic results.²⁹² Patients tend to have more favorable views of cosmetic outcome than do physicians.^538,⁵³⁹ Cosmetic results tend to decline for the first 3 years after treatment but then remain stable.

Cosmetic outcomes have improved over time due to changes in surgical and irradiation techniques (Fig. 61-7). However, results in different series are difficult to compare because there is no “standard” for describing cosmesis. Schemes for objectively measuring changes in breast size, shape, fibrosis, or contour have been devised,^540,⁵⁴¹ but these are not widely used. They also may not capture skin changes and other significant sequelae.

Figure 61-7 This patient was treated for right breast cancer in 1974 and left breast cancer in 1991; the photograph was taken 2 years after the last treatment. The right side was treated using a 4-MV linear accelerator to a dose of 46.8 Gy to the breast and regional nodes, followed by an electron boost. The left side was treated on a 6-MV accelerator, giving 45 Gy to the breast only followed by an electron boost. On the right, the patient has substantial fibrosis and retraction of the breast superiorly, a hyperpigmented and fibrotic ridge superiorly due to match-line overlap between the tangential and supraclavicular/axillary fields, and substantial telangiectasias in the electron-boost field. In contrast, the cosmetic result on the left is good, with an easily visible surgical scar in the upper outer quadrant but few other changes. In later follow-up (February 1997), telangiectasias began to appear in the left-sided electron boost field also (not shown).

Surgery appears to be the most important factor affecting cosmetic outcome.292,542 Greater breast size has been associated with increased retraction after BCT⁵⁴³^–⁵⁴⁵ (see web-only Fig. 61-7). This problem can be at least partially overcome, however, by the use of higher photon energies⁶⁰ and by placing the patient in the prone or lateral decubitus position. Doses to the entire breast much above 50 Gy in 2-Gy fractions seem to worsen results,⁵⁴⁶ as does the use of large fraction sizes when doses above 45 Gy are given.⁵⁴⁷ Giving a breast boost worsens results modestly,³⁶⁴ although in the EORTC trial the cosmetic results obtained with implantation and external beam boosts were comparable.⁵⁴² The use of a hockey-stick field or other techniques resulting in imperfectly matched field edges can cause substantial fibrosis and skin changes at areas of overlap (see web-only Fig. 61-13, available on the Expert Consult website).

Web-Only Figure 61-13 Example of a poor cosmetic result caused by excessive fibrosis and retraction in a patient with large breasts. Note also the hyperpigmented and fibrotic ridges seen at the medial and superior borders of the left breast due to overlap between a hockey-stick field and breast tangential fields.

Cosmetic results appear to be similar whether chemotherapy is given before or after radiation therapy.³³³ The cosmetic results in patients receiving concurrent chemotherapy and radiation therapy tend to be inferior to those with sequential regimens, although not all studies agree on this point.⁴³⁶ Overall cosmetic results were unaffected by tamoxifen.^129,⁵⁴⁸ In a study from the University of Pennsylvania, complication rates and cosmetic results were very similar whether tamoxifen was given concurrently or sequentially with irradiation, although breast edema was slightly more frequent in the former group (79% vs. 65%).⁵⁴⁹

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