Treatment of Complications After Breast-Conservation Therapy

August 1, 2003

Over the past 2 decades, breast-conservation therapy with lumpectomyand whole-breast radiotherapy has become a standard option for themajority of women with newly diagnosed breast cancer. Long-term localcontrol is achieved in approximately 85% of patients, and the therapy isgenerally well tolerated. There can, however, be long-term effects on thebreast and other nearby tissues that may range from asymptomaticfindings on examination to severe, debilitating problems. Infection, fatnecrosis, and severe musculoskeletal problems such as osteoradionecrosisor soft-tissue necrosis are uncommon, affecting less than 5% ofpatients. However, changes in range of motion, mild-to-moderate musculoskeletalpain, and arm and breast edema are much more common.As more women choose breast-conservation therapy for management oftheir breast cancer, physicians will encounter these problems, as well asin-breast tumor recurrence, with greater frequency. This review willfocus on the incidence, contributing factors, and management of thelate problems of infection, fat necrosis, musculoskeletal complications,and local recurrence following breast-conservation therapy.

ABSTRACT: Over the past 2 decades, breast-conservation therapy with lumpectomy and whole-breast radiotherapy has become a standard option for the majority of women with newly diagnosed breast cancer. Long-term local control is achieved in approximately 85% of patients, and the therapy is generally well tolerated. There can, however, be long-term effects on the breast and other nearby tissues that may range from asymptomatic findings on examination to severe, debilitating problems. Infection, fat necrosis, and severe musculoskeletal problems such as osteoradionecrosis or soft-tissue necrosis are uncommon, affecting less than 5% of patients. However, changes in range of motion, mild-to-moderate musculoskeletal pain, and arm and breast edema are much more common. As more women choose breast-conservation therapy for management of their breast cancer, physicians will encounter these problems, as well as in-breast tumor recurrence, with greater frequency. This review will focus on the incidence, contributing factors, and management of the late problems of infection, fat necrosis, musculoskeletal complications, and local recurrence following breast-conservation therapy.

Breast-conserving therapy with lumpectomy, axillary dissection, and radiotherapy, has been associated with a variety of side effects and complications. It is important to have a good understanding of the frequency and severity of treatment- related problems in order to adequately counsel patients about their treatment options. In addition, continual assessment of techniques and other factors that may influence the incidence of complications is necessary to develop safer treatment approaches. In general, the best way to manage a treatment-related problem is to avoid its occurrence. This is especially important in patients who undergo irradiation, because the options for treatment of late effects may be limited.

This review will focus on some of the less commonly discussed side effects and complications of breast-conserving surgery and radiotherapy for early-stage breast cancer such as infection, fat necrosis, musculoskeletal effects, and pain. In addition, the options for management of in-breast tumor recurrence will be reviewed.

Infection

The incidence of cellulitis or breast abscess after breast-conserving therapy is low, ranging from 1% to 5% in most case series, with an annual risk for the development of delayed cellulitis of 0.8%.[1-3] Patients may present with cellulitis or abscess in the perioperative period, or at any time before, during, or after radiation therapy.[2,4] The majority of cases present with pain, erythema, axillary swelling, and warmth in the involved breast, whereas a breast abscess or seroma may present as suspicious mammographic changes or a clinically palpable breast mass.[5] The median latency period for the development of delayed cellulitis is 3 to 5 months postradiotherapy, and it may even occur many years after the completion of therapy.[1-3,6,7]

Risk Factors

Although the clinical scenario in which delayed breast cellulitis commonly occurs points to a multifactorial etiology, specific risk factors have been evaluated. Brewer et al[1] performed a matched case-control study to statistically associate potential risk factors with the development of breast cellulitis in a cohort of patients treated with breast-conserving therapy. Their analysis of 17 cases revealed that arm lymphedema was the most prominent risk factor for the development of delayed breast cellulitis. Other trials have also identified the potential role of clinical or subclinical lymphedema of the breast secondary to alteration of vascular and lymphatic flow from surgery and radiotherapy as a potential predisposing factor for the development of breast infection.

It is believed that lymphedema results in stasis within the lymphatic channels, serving as a medium for bacterial growth. Similarly, microvasculature injury or skin desquamation may play an etiologic role.[2,4,7] It is felt that in this anatomically altered setting, microtrauma to the breast may precipitate cellulitis. In addition, many reports have implicated posttreatment breast seroma and aspiration of seroma fluid with the development of cellulitis.[1,4]

Mertz et al[7] found that radiographically demonstrable fluid collections at the lumpectomy site were present in 75% of a small cohort of patients treated for cellulitis after breast-conserving therapy. This finding may point to the presence of these fluid collections as a predisposing factor for the development of later infections.

Treatment

As with a variety of other cellulitis syndromes, bacterial pathogens are often not recovered, and procedures such as aspiration of the leading edge of a lesion and blood cultures, in the absence of other systemic symptoms of infection, usually produce a low yield.[4,6] Hence, treatment is generally empiric, and choice of antibiotic treatment is influenced primarily by clinical presentation. The most frequently cultured organisms are Staphylococcus aureus or beta-hemolytic streptococci species.[4,6]

Initial treatment for mild cases consists of empiric therapy with oral antibiotics to cover normal skin flora. Penicillinase-resistant penicillins, including nafcillin and oxacillin, and first-generation cephalosporins, including cefazolin and cephalexin, are commonly selected.[6] If S aureus is suspected, a beta-lactamase-inhibiting penicillin such as amoxicillin/ clavulanate (Augmentin) or ampicillin/ sulbactam (Unasyn) may be used.[4] For persistent cases or for patients with leukocytosis and fever, hospital admission for a course of intravenous antibiotics may be warranted.[2]

FIGURE 1

Cosmetic Appearance of the Breast in a Patient Treated With Breast-Conserving Therapy

Although many patients will experience a relatively quick response to empiric therapy, clearance of breast changes may be gradual and may persist for extended periods (Figure 1).[6] Cultures of abscesses or seroma aspirates may be obtained prior to the initiation of therapy to facilitate later revision of therapy as needed for patients without a clinical response. The recommended period of treatment is usually 10 to 14 days.

Incision and drainage should be considered for persistent abscess after completion of therapy. For nontoxic patients who do not respond to antibiotic therapy, a 7- to 14-day trial of nonsteroidal anti-inflammatory agents or topical corticosteroids may be warranted to treat potential dermatitis.[6] Skin biopsy to rule out cancer recurrence should be considered in all patients who fail to respond to conservative therapy.[8]

In addition to antibiotics, other preventive techniques to decrease lymphedema may be employed, such as compression therapy, skin care, and exercise. Patients with axillary or breast seromas should be counseled on the signs, symptoms, and treatment of cellulitis because they may be at higher risk of developing the problem.

Fat Necrosis

Fat necrosis commonly presents as an indurated mass in the region of the lumpectomy scar, with overlying skin fixation, retraction, erythema, and tenderness. Some reports indicate an incidence of less than 1% on long-term follow-up of patients treated with standard breast radiotherapy.[9,10] Boyages and colleagues[11] found a 4.5% 5-year actuarial risk of fat necrosis or fibrosis requiring surgery. The rate of fat necrosis may be significantly higher in patients treated with certain regimens of high-dose rate brachytherapy alone rather than standard whole-breast external-beam irradiation. Wazer et al[12] found that 27% of 30 patients, who received irradiation twice daily at 340 cGy for 5 days to the lumpectomy cavity plus a 2-cm margin, developed symptomatic fat necrosis. In another report, 10% of patients treated with high-dose rate brachytherapy (372 cGy twice daily for 5 days) developed fat necrosis within 4 to 18 months.[13] The average time to onset of symptoms is approximately 12 months posttherapy. In most patients, the presentation of fat necrosis clinically mimics that of recurrent tumor. Mammographic evaluation is helpful in identifying the lesion if characteristic changes such as radiolucent oil cysts are present. However, fat necrosis may also appear on mammography as round opacities, dystrophic calcifications, and clustered pleomorphic calcifications.[14] Given the often confusing clinical presentation and inconclusive imaging, ultrasound-guided core biopsy should be performed in all patients, even those with a history of breast trauma predating the appearance of their lesion.[15] If local symptoms of discomfort persist, excision may be considered in selected patients.

Musculoskeletal Effects of Breast-Conservation Therapy

Standard irradiation of the breast with tangential fields covers the anterolateral chest wall and a portion of the sternum. If the upper axilla or supraclavicular regions are treated, as in patients with multiple positive lymph nodes, the clavicle, portions of the scapula, and occasionally the medial third of the humeral head will also be within the treatment field. The effects of musculoskeletal tissue exposure to radiation include muscle and connective tissue fibrosis, osteitis or atrophy, and potentially even osteoradionecrosis. Changes in the bone and connective tissues may result in pain, decreased range of motion, or fracture. Other aspects of treatment, such as the type of axillary surgery performed, and patient factors such as age or comorbidities may also affect the development of musculoskeletal morbidity.

Range of Motion

TABLE 1

Methods Used to Assess Shoulder Range of Motion/Function

Shoulder mobility following breast-conserving therapy has been assessed in numerous investigations. The criteria used to report a decreased range of motion are not standardized, which leads to difficulties in comparing the incidence and severity of the problem among different studies (Table 1).[10,16-20] The frequency of symptoms will also vary based on the time of evaluation, subjective vs objective measurement tools, and the end points chosen. Furthermore, most of the studies do not indicate whether the patients were given any instruction in range-of-motion exercises or were referred to physical therapy or a rehabilitation service postoperatively or following symptom development.

All the patients in the study by Gerber et al[16] were put on a standardized rehabilitation program postoperatively, rather than waiting until problems appeared. They were instructed in methods of helping to reduce/prevent arm edema and were enrolled in an outpatient physical therapy program. Once they reached a predefined level of range of motion, the patients were discharged to a home maintenance program. The investigators found that the arm motion of women treated with lumpectomy, axillary dissection (including level III), and radiotherapy returned to the pretreatment baseline more rapidly than in patients treated with modified radical mastectomy (171.9 vs 194.8 days, respectively). They also measured time to achievement of functional range of motion and found that the mean number of days was greater for patients who underwent modified radical mastectomy (77.6 vs 66 days). No significant changes in range of motion occurred in either group after 1 year of follow-up. Unfortunately, it is not possible to determine whether the postoperative rehabilitation program used in these patients had a beneficial effect on the long-term rates of arm morbidity.

TABLE 2

Effects of Various Types of Treatment on Arm/Shoulder/Chest Symptoms

Table 2 summarizes the results of several recent studies evaluating arm morbidity, pain, and other posttreatment symptoms.[10,16-27] The incidence of mobility problems ranged from none at 3 years[17] to 49% over 5 years.[18] In the report from Tengrup et al,[18] 49% of patients subjectively had reduced range of motion, but only 20% were found to meet the author's objective criteria for decreased range of motion.

Arm Morbidity and Extent of Surgery

The extent of axillary surgery has been found to correlate with arm morbidity in numerous studies. Liljegren and Holmberg[21] found that the number of nodes in the axillary specimen (≥ 10) and a young age (< 65 years) correlated with a greater risk of arm morbidity. Studies by Lash and Silliman,[20] Meric et al,[10] and Mandelblatt et al[22] found greater arm problems among patients who underwent axillary dissection than among those managed without the surgery.

The use of sentinel node biopsy has resulted in a decrease in the risk of arm morbidity compared to level I and II axillary dissection.[23,24] Haid et al[20] used a summation score assessing subjective (strength, range of motion, edema, pain) and objective (abduction, arm volume, strength, sensitivity) criteria. Of a maximum of 100 points (no symptoms), the mean score for patients who underwent axillary dissection was 80.2 compared to 92.8 for patients treated with sentinel node biopsy. Although sentinel node biopsy procedures may also be associated with symptoms, limiting the extent of the axillary surgery should have a beneficial effect on arm and upper-body function. Avoiding the use of both axillary dissection and axillary irradiation unless necessary for tumor control should help to decrease the risk of arm morbidity.[10,28]

The management of arm mobility limitations generally includes stretching, range of motion exercises, and, for patients with significant symptoms, physical therapy. Postoperative physical therapy programs generally help patients regain mobility and decrease the subjective sensation of tightness in the axillary and shoulder areas.[16,25]

Our practice has been to advise women to continue their range-of-motion exercises during and after radiotherapy. Anti-inflammatory medications may be helpful, especially at the initiation of such an exercise program. Even with the decrease in axillary morbidity that occurs with the use of sentinel node biopsy, fibrosis of the chest wall musculature and soft tissues may predispose women to experience a sensation of tightness that can be minimized with a regular program of range-of-motion exercises.

Pain

In addition to arm pain, patients may also experience breast pain and chest wall (rib cage) pain or tenderness following breast-conservation therapy. Tasmuth et al[26] found that chronic pain occurred less frequently (32%) in patients treated with modified radical mastectomy alone than in patients treated with breast-conserving surgery or mastectomy and radiotherapy (40% to 49%). No differences in pain scores were noted between the groups, with the mean score on a 10-point visual analog scale equal to 2.2 to 2.5. Only 4% of women who remained free of disease experienced progression of pain over time, compared to 27% of those who developed locally recurrent or metastatic disease.

In Tengrup's study,[18] 31% of patients continued to have some degree of pain 5 years after treatment. Gerber et al[16] found a significant increase in the incidence of chest wall tenderness after breast-conserving therapy compared to mastectomy at 1 and 2 years following treatment. Chest wall tenderness was detected in 58% of patients who received breast-conserving therapy. Rayan et al[27] did not find any significant differences in pain, physical function, breast symptoms, or global quality of life among women treated with breast-conserving surgery, with or without radiotherapy, over 12 months posttreatment. Moreover, analgesic use was uncommon, with no patients using chronic pain medication at 12 months.

In our experience, it is common for patients to have fleeting pain in the breast, especially at the sites of incision, in the first 6 months following surgery and radiotherapy. In addition, patients may have breast or chest wall tenderness-especially over the first 1 to 2 years posttreatment-that does not generally require regular use of pain medication. Nonsteroidal anti-inflammatory medication is offered to patients with more persistent discomfort.

Radiographic Changes in Bone

Exposure of bone to ionizing radiation may result in a variety of changes. Ewing[29] described the effects of radiation on bone with the term "radiation osteitis." He postulated that radiation changes were dose-related and ranged from temporary cessation of bone growth with recovery, periostitis, bone sclerosis with increased fragility, ischemic necrosis, and osteoradionecrosis with infection. Rubin and Casarett[30] thought that osteoradionecrosis resulted from a combination of damage from radiation, infection, and trauma. Howland et al[31] also believed that true necrosis required the presence of a secondary infection. For mature bone, the radiation dose that produces a 5% risk of necrosis or fracture at 5 years is generally considered to be 6,000 cGy.[32] Radiographic changes in bone include osteopenia (a mottled appearance with areas of increased density) and coarsened trabeculae. Stress fractures may occur and may show evidence of spontaneous healing.

In a series of patients treated before 1977, Langlands et al[33] reported evidence of severe osteitis in 13% and mild changes in 8%. Radiation injury to the ribs or clavicle was found in 7% of patients treated with a minimum dose of 4,500 cGy according to Shimanovskaya et al[34] and was seen in the shoulder girdle in 1% to 3% according to DeSantos et al.[35] Clarke et al[36] found 2 patients with asymptomatic rib fractures in a group of 76 patients treated with breast-conserving surgery and radiotherapy between 1973 and 1980. Of 294 patients treated at M. D. Anderson between 1990 and 1992, 1 was found to have fractures of two to three ribs at a median follow-up of 89 months.[10] The risk of severe bone damage in patients treated with modern techniques is low, but changes can evolve over many years, requiring long-term follow-up for accurate calculation of incidence.

Osteoradionecrosis will not generally heal spontaneously. In some situations, if the process is not progressive, conservative management with antibiotics and steroid medication may be appropriate. However, if the process is progressive and symptomatic, more aggressive treatment will generally be required. A variety of treatments have been used for osteoradionecrosis such as surgical debridement or resection of the involved area of bone and soft tissue with reconstruction, hyperbaric oxygen, and, more recently, pentoxifylline, with or without other medications. Most studies have focused on osteoradionecrosis of the mandible, but several recent reports focus on the management of chest wall osteoradionecrosis following radiotherapy for breast cancer.[37-42]

Surgical management often requires extensive resection of necrotic bone and soft-tissue reconstruction with tissue flaps. Transposition of the omentum and coverage with a split-thickness skin graft has been used successfully.[ 37,41,42] Hultman et al[41] reported a series of 60 patients who underwent thoracic reconstruction with omentum for a variety of conditions. Partial flap loss occurred in seven patients, with no total flap failures. Chest wall reconstruction with mesh and rotated latissimus dorsi myocutaneous flaps has also been found to be successful with no flap loss in five patients reported by Hines and Lee.[40]

Hyperbaric oxygen treatment has been used in the treatment of a variety of late radiation injuries,[43,44] because microvascular damage with subsequent tissue hypoxia is suspected to be a causative factor. Feldmeier et al[43] reported 23 cases of chest wall necrosis (8 soft tissue only, 15 bone and soft tissue) treated with hyperbaric oxygen. Of the 15 patients with bone and soft-tissue necrosis, 6 received hyperbaric oxygen treatment only without debridement, and all failed to heal; 8 patients received hyperbaric oxygen and aggressive debridement or flap reconstruction and went on to heal. One patient was found to have recurrent tumor on the chest wall, and the hyperbaric oxygen treatment was discontinued.

The majority of patients with only soft-tissue necrosis healed without requiring surgical debridement. Of 32 women with symptomatic late complications (pain, edema) from breast-conserving therapy, 7 became symptom-free following hyperbaric oxygen therapy according to Carl et al.[44] In their series, however, fibrosis and telangiectasia were not significantly improved. It appears that hyperbaric oxygen may have a beneficial effect on soft-tissue radiation injury but that surgical management, with or without hyperbaric oxygen, is necessary for most patients with osteoradionecrosis.

Recently, several reports have appeared describing improvement of radiation-induced fibrosis, soft-tissue necrosis, and other injury with the use of pentoxifylline and interferon-gamma-1b (Actimmune). A group of investigators from the University of Ulm has reported that interferon-gamma inhibits collagen production in dermal fibroblasts, which has been found to be increased in cutaneous radiation fibrosis and, therefore, may be useful in its treatment.[45,46] They found objective improvement of radiation fibrosis and healing of radiation ulcers and fistulae with the use of lowdose interferon-gamma in a group of eight patients[46] and in another group of five patients,[45] two of whom had cutaneous fibrosis following treatment for breast cancer. The investigators used a regimen of 100-mg interferon-gamma-1b injected subcutaneously three times a week for 6 months, then once a week for another 6 months.[45]

Pentoxifylline is a methylxanthine derivative that lowers blood viscosity, improves erythrocyte flexibility, and increases oxygen tension levels. Futran et al[47] reported on a series of 26 patients with late radiation injury (soft-tissue necrosis, fibrosis, and mucosal pain) who had been treated with oral pentoxifylline. Soft-tissue necrosis resolved completely in 75% of the patients, fibrosis improved in 67%, and mucosal pain resolved in all patients. Patients with soft-tissue necrosis who did not benefit from penytoxifylline therapy progressed to osteoradionecrosis. Delanian and colleagues[48] used a combination of penytoxifylline at 800 mg/d and vitamin E (tocopherol) at 1,000 IU/d in patients with radiation-induced fibrosis following treatment for head and neck and breast cancers. Treatment was continued for at least 6 months, and continuous clinical regression of all late effects was noted in all areas studied.

Delanian and Lefaix[38] also reported a case of a patient previously treated for breast cancer with osteoradionecrosis of the sternum and overlying soft-tissue necrosis, extensive fibrosis of the breast, brachial plexopathy, and lymphedema. The patient was treated with antibiotics, methylprednisolone, penytoxifylline, and tocopherol. After about 3 months, the oral bisphosphonate clodronate (investigational in the United States) was added to the regimen. Over approximately 3 years, the patient showed gradual healing of the necrosis, closure of a fistulous track, restoration of the bone defect in the sternum, and resolution of the fibrosis. The brachial plexopathy did not improve.

Pentoxifylline and tocopherol are generally well tolerated and should be considered for patients with late radiation soft-tissue and possibly bone injury in the absence of other standard means of medical management. Further studies of both pentoxifylline and interferon-gamma therapy appear to be warranted.

Influences on Cosmesis

A more common consequence of surgery and radiation-induced changes in the breast is the effect on cosmesis. The rationale for using breast-conserving therapy is not just to preserve breast tissue, but to preserve a cosmetically acceptable breast. A good cosmetic result is an important end point for both the physician and the patient when using a breast-conserving approach for the treatment of early-stage breast cancer. Many studies have analyzed the cosmetic outcome of breast-conserving therapy using both qualitative and quantitative measures.

In general, physicians have rated cosmesis as either excellent or good in 55% to 94% of patients, with a median follow-up of ≥ 3 years.[49-52] Qualitative analysis is often performed by a panel of observers who objectively evaluate predetermined cosmetic criteria based on a standardized scale. When such analyses are compared to similar data obtained from patient self-assessment questionnaires, many studies indicate low levels of concordance between the patients' and observers' ratings. Interestingly, patients often score the long-term result of their treated breast more favorably than do the panel observers, underscoring the inherent subjective bias and interobserver variability common in these types of evaluations.[50,53]

In an older series by Harris et al,[54] physicians rated the cosmetic result as good or excellent in 66% of patients following primary radiation therapy. In contrast, 81% of patients judged their own results to be good or excellent. This was likely due to differing criteria applied by patients and their physicians in judging the cosmetic outcome. Whereas physicians scored the physical effects of treatment on the breast alone, patients also took into account the psychological, social, and sexual advantages of breast preservation.[53,54] In general, more contemporary series using highly standardized assessment criteria report relatively higher physicianpatient concordance of cosmesis ratings (> 80%).[51]

Extending the Follow-up

In general, a minimum of 3 years of follow-up is required to assess cosmetic outcome adequately. Length of follow-up is especially important with respect to posttreatment changes that may appear early after treatment and improve over time, such as edema of the breast after adjuvant radiation therapy. Similarly, adequate follow-up is also important in order to assess changes in skin and subcutaneous tissue, such as retraction and telangiectasia, which occur over a more protracted period of time.

In their series of women followed after lumpectomy and radiation therapy at the Joint Center, Beadle et al[53] reported that breast edema decreased with length of follow-up. Minimal breast edema was noted in 32% and moderate edema in 3% of patients 6 months post-radiation therapy; with further follow-up, the edema declined slowly. By 5 years, 23% of women were reported to have minimal breast edema, and none were noted to have moderate edema. The reverse effect was seen for the development of telangiectasia; only 2% of patients had minimal telangiectasia at 6 months, but in subsequent followup, 27% of patients had minimal telangiectasia and 9% had moderate telangiectasia. Breast retraction peaked over the first 2 to 3 years after radiotherapy, with 2% of patients exhibiting moderate or severe retraction at 6 months, whereas at 30 and 60 months, the corresponding results were 12% and 9%, respectively.

Contributing Factors

FIGURE 2

Example of the Radiation Isodose Distribution in a Patient With a Large Breast

Cosmesis can be affected by numerous patient, tumor, and technical factors. Some factors that have been shown to have an adverse effect on cosmetic outcome in recent publications include large breast size,[50,52,55] excision volumes exceeding 50 to 100 cm3,[49,51,52,56] extent of axillary surgery,[51,56] postoperative infection or other complications,[ 19,52] and use of a boost to the lumpectomy bed following wholebreast treatment.[52,56] A total radiation dose of more than 5,000 cGy to the breast, greater dose inhomogeneity (Figure 2), and higher fraction sizes (especially to whole-breast volumes) have also been shown to have a negative impact on cosmesis and the risk of complications from radiotherapy.[51,55-57]

Management of In-Breast Tumor Recurrence

In-breast tumor recurrence following breast-conserving therapy and radiotherapy will occur in up to approximately 14% of patients at 20 years according to data from the National Surgical Adjuvant Breast and Bowel Project B-06 trial. Surgery alone resulted in a tumor recurrence rate of 39%.[58] Studies that were restricted to smaller primary tumors show even better results, with an 8-year recurrence rate of 16% after surgery plus tamoxifen, 9.3% after surgery plus radiotherapy, and 2.8% after surgery, radiotherapy, and tamoxifen reported by Fisher et al.[59] Veronesi et al reported a 10-year inbreast tumor recurrence rate of 5.8% with surgery plus radiotherapy and 23.5% with surgery alone.[60]

True Recurrence

In-breast tumor recurrence is often an isolated event, with no evidence of metastatic or regional recurrence found on restaging evaluation. The recurrence is generally classified as a true recurrence if it occurs in the region of the initial lumpectomy and has a similar histologic appearance. A new or second primary tumor is considered one that occurs distant from the original lumpectomy site or has a different histologic appearance.

Huang et al[61] studied 126 patients with local tumor recurrence following breast-conserving therapy with radiotherapy and compared the outcomes according to whether the new tumor was considered a true recurrence or a new primary. They found that the time to development of the in-breast tumor recurrence was shorter in patients with a true recurrence than in those with a new primary (5.6 vs 7.3 years, respectively). Patients with new primaries were more likely to have a positive hormone-receptor status and less likely to have skin involvement than patients with true recurrences. Overall survival at 10 years was higher for patients with new primaries than for those with true recurrences (77% vs 46%).[61] Others have also noted an association between a poorer overall survival and a shorter interval to local tumor recurrence in the same quadrant.[62,63]

Treatment Strategies

The most common treatment for in-breast tumor recurrence following breast-conserving surgery and radiotherapy has been mastectomy; however, many women may prefer having the option of sparing the breast again, if feasible. Salvage therapy for patients treated without radiation initially has often included breast-conserving surgery followed by radiotherapy, as long as a reasonable cosmetic outcome can be achieved. Radiotherapy would generally be advised following salvage lumpectomy.

Surgery alone for in-breast tumor recurrence following surgery and radiotherapy was reported by Kurtz et al,[64] who treated 50 patients with salvage wide excision alone. The actuarial local control rate at 5 years was 62% and was influenced by the interval from primary treatment to tumor recurrence and margin status at the time of wide local excision. Fredriksson and colleagues[62] performed breast-conserving surgery for salvage of in-breast tumor recurrence in 45% of patients who had been treated initially with surgery alone. Of the patients initially treated with surgery plus radiotherapy, 26% had breast-conserving surgery for salvage. As in most studies of in-breast tumor recurrence, salvage treatment was individualized; therefore, treatment modalities cannot be compared directly.

TABLE 3

Treatment of Patients With In-Breast Tumor Recurrence

A few series reported in the literature have analyzed the use of repeat breast-conserving surgery and local radiotherapy with either brachytherapy or limited external-beam irradiation in patients previously treated with breast-conserving therapy plus radiotherapy (Table 3).[61-66] Deutsch[65] reported on his experience with external electron therapy in 39 women with in-breast tumor recurrence. Treatment consisted of gross total resection (5 of 39 with microscopic positive margins) followed by 5,000-cGy irradiation to the lumpectomy site. The 5-year estimated actuarial overall survival following retreatment was 78%. Of the 39 women, 8 (20.5%) developed second in-breast recurrences. Cosmesis was rated as good-to-excellent in 27 of 36 evaluable patients. In addition, the author stated that no long-term complications were noted, with a median follow-up of 51.5 months (range: 1-180 months).

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Ampicillin/sulbactam (Unasyn)
Amoxicillin/clavulanate
   (Augmentin)
Cefazolin
Cephalexin
Clodronate
Interferon-gamma-1b
   (Actimmune)
Methylprednisolone
Nafcillin
Oxacillin
Pentoxifylline

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Resch et al[66] reported on the use of pulsed-dose rate brachytherapy (8 with and 9 without low-dose external-beam irradiation) in 17 patients with in-breast tumor recurrence following prior breast-conserving therapy with standard radiotherapy. No local failures were noted in the nine patients treated with brachytherapy alone, but four of the eight women treated with the combination of external-beam irradiation and brachytherapy developed second recurrences. Of these 17 patients, 4 developed distant metastases at a median follow-up of 59 months (range: 20-84 months). Cosmesis was judged to be acceptable or better in 13 of the 17 patients.

Conclusions

Although mastectomy remains the standard recommendation for salvage therapy of in-breast tumor recurrence after initial breast-conserving surgery with radiotherapy, selected patients may again be eligible for breast-sparing treatment. Selection criteria are not well defined, but it is likely that small recurrences that are amenable to margin-negative resection with adequate remaining breast tissue would be most suitable for this type of approach. Knowledge gained from the increasing use of partial breast irradiation as initial therapy will be of use in refining the options for its use in salvage situations. Systemic therapy must also be individualized based on past treatment history and features of the recurrent tumor. Prospective studies are needed to define the optimal salvage treatments for in-breast recurrences.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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