Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer

0360-3016/92 $5.00 + .oO Copyright 0 1992 Pergamon Press Ltd.

Inr I Radirrrion Oncology Bwl Ph.v.5 Vol. 23. pp. 915-923 Pnnted in the U.S.A. All rights reserved.

??Clinical Original Contribution

LONG-TERM RADIATION COMPLICATIONS FOLLOWING CONSERVATIVE SURGERY (CS) AND RADIATION THERAPY (RT) IN PATIENTS WITH EARLY STAGE BREAST CANCER SUSAN M. PIERCE,M.D.,’ ABRAM RECHT,M.D.,’ TATIANA I. LINGOS,M.D.,’ ANTHONY ABNER, M.D.,’ FRANK VICINI, M.D.,’ BARBARASILVER,B.A.,’ ANDREW HERZOG, M.D.* AND JAY R. HARRIS,M.D.’ ‘Joint Center for Radiation Therapy and Department of Radiation Oncology, Harvard Medical School, Boston, MA; and ‘Department of Neurology, Beth Israel Hospital, Boston, MA

Thefrequenpy of brachial plexopathy, rib fracture, tissue necrosis, pericarditis, and second non-breast malignancies occurring iI the treatment field among 1624 patients with early stage breast cancer treated with conservative surgery and radiation therapy at the Joint Center for Radiation Therapy between 1968 and 1985 is reported. The median follow-up time for survivors was 79 months (range S-233 months). Brachial plexopathy was related to the use of a third field, the use of chemotherapy and the total dose to the axilla. Brachial plexopathy developed in 20 of 1117 women (1.8%) who received supraclavicular irradiation with or without axilhuy irradiation. The median time to its occurrence was 10.5 months (range 1.5-77 mo), and the majority (80%) of cases completely resolved. Among patients treated with a three-field technique, the incidence of brachial plexopathy was 1.3% (13/991) in patients treated with a dose to the axilla of 5 50 Gy, compared with 5.6% (7/126) in women treated with an axilhuy dose of > 50 Gy. The incidence of brachial plexopathy was 4.5% (15/330) among patients receiving chemotherapy, compared with 0.6% (5/787) when chemotherapy was not used (p < 0.0001). Rib fracture was seen in 29 patients (1.8%), at a median time of 12 months following treatment (range l-57). In all cases, the rib fracture healed without intervention. The incidence of rib fracture was 2.2% (28/X300) among patients treated on a 4 MV linear accelerator, compared with 0.4% (l/276) for patients treated on a 6 or 8 MV machine (p = 0.05). Of patients treated on a 4 MV machine, 0.4% (l/279) developed a rib fracture when a whole breast dose of 45 Gy or less was given, 1.4% (10/725) after receiving between 45 and 50 Gy, and 5.7% (17/296) following 50 Gy or higher. Tissue necrosis requiring surgical correction developed in three patients (0.18%) 22,25, and 114 months after treatment. Presumed pericarditis (requiring hospitalization) was seen in 0.4% of women (3/831) who received radiation therapy to the left breast 2, 2, and 11 months after the start of treatment. Three women (0.18%) developed sarcomas in the treatment field at 72,107, and 110 months, for a lo-year actuarial rate of 0.8%. Two of these sarcomas developed in areas of probable match-line overlap. One patient (0.06%) developed an in-field basal cell carcinoma at 42 months. In conclusion, the risk of significant complications following conservative surgery and radiation therapy for early stage breast cancer is low. Small alterations in treatment, such as using a 6 MV machine and limiting the dose to the whole breast and axilla to 50 Gy or lower, may reduce their occurrence. Breast cancer, Conservative surgery, Radiation therapy, Chemotherapy, Complications, Brachial plexopathy, Rib fracture, Tissue necrosis, Radiation-induced second malignancies.

numbers, several years of follow-up and careful documentation. The reported incidence of severe complications following treatment with CS and RT has been 1% to 3% at institutions that use fractionation schemes and radiation technique consistent with current practice (10, 16, 22, 26, 36, 43, 46). This report details the incidence of brachial plexopathy, rib fracture, tissue necrosis, pericarditis, and second nonbreast infield malignancies occurring in patients with early stage breast cancer treated with CS and RT at this insti-

INTRODUCIION

Conservative surgery (CS) and radiation therapy (RT) have been used with increasing frequency in the treatment of early stage breast cancer over the past two decades. Improvements in radiation technique have evolved from observations of the acute effects of radiation on the breast and the subsequent cosmetic result, as well as analysis of local failure rates. However, the accurate definition of the risk of long-term complications requires large patient Presented in part at the 33rd Annual Meeting of the American Society for Therapeutic DC, November 199 1.

Reprint requests to: Susan M. Pierce, M.D., Joint Center for Radiation Therapy, 50 Binney St., Boston, MA 02 115. Accepted for publication 9 March 1992.

Radiology and Oncology, Washington 91s

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tution. We have identified an association between these complications and certain treatment factors and suggest alterations in radiation technique which may reduce their occurrence. METHODS

AND MATERIAL

Between 1968 and 1985, 1624 women with Stage I or II breast cancer were treated with CS + RT at the Joint Center for Radiation Therapy (JCRT). Patients with a previous history of malignancy (except non-invasive carcinoma of the cervix and non-melanoma skin cancer) or synchronous bilateral breast cancer were excluded from this study group. The median age at diagnosis was 5 1 years (range, 25-93). The median follow-up time for survivors was 79 months, with a range of 37-233 months (excluding the nine patients lost to follow-up). Surgery consisted of excisional biopsy, defined as gross removal of the tumor without regard to the microscopic margins of resection in 1593 patients (98%) while 3 1 patients (1.9%) had gross residual disease remaining in the breast after surgery. Axillary dissection was performed in 1193 women (73%) at the discretion of the surgeon, and usually was confined to removal of the level I and II lymph nodes. The remaining 43 1 women did not have an axillary dissection. The median age of the women who did not undergo an axillary dissection was 66 years (range. 2793 years), compared 48 years (range, 25-85) in women having an axillary dissection. External beam radiation therapy was given to the entire breast using either tangential fields alone (n = 507) or a three-field technique (n = 1117) as selected by the individual radiation oncologist. The posterior edges of the tangential fields are made coplanar. When used, the supraclavicular or supraclavicular/axillary field was usually angled slightly off the vertical (approximately 10 degrees) to avoid treating the spinal cord. A standard supraclavicular field extended from the sternal notch medially to the border between the distal third and proximal two thirds of the clavicle laterally. The lateral border of the supraclavicular/axillary field usually extended to include two thirds of the humeral head. Matching of the tangential field and this third field was done using the “hanging block” or “corner block” technique in the majority of cases (39, 45). A posterior or en face axillary boost was used in some women. A “hockey stick” directed at the internal mammary lymph nodes was rarely employed. The dose to the whole breast was 45-46 Gy in the majority of women, with a median dose of 46 Gy (range, 25.2-63 Gy), usually given in fractions of 1.8-2 Gy per day, 5 days per week. The whole breast dose was prescribed to a point on the central axis, measured 1 cm from the posterior border of the tangential fields. In more recent years, this point was moved to 1.5 cm from the posterior border on the central axis. A boost to the primary tumor bed was given by interstitial implantation in 905 women

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(56%) or external beam, the majority with electrons, in 595 women (37%). Thirty-eight patients (2%) had a combination boost treatment, and 86 women (5%) had no boost. The median total dose to the primary tumor site was 64.8 Gy (range 44-84 Gy), with 80% of women receiving between 60-70 Gy. The median dose to the supraclavicular field, usually prescribed at a depth of 3 cm, was 46 Gy (range, 19.850.4 Gy), with 96% of women receiving 44-50 Gy. The median dose to the supraclavicular/axillary field, usually prescribed at a depth of 5 cm, was 46 Gy (range, 6.2-75 Gy), with 95% of women receiving 44-55 Gy. Eighty percent of women were treated on a 4 MV linear accelerator. In the earlier years of this study, only women who were found to have a large separation (defined as 26 cm or greater measured along the medial to lateral plane of the posterior border) were treated on an 8 MV linear accelerator. In more recent years, 6 and 8 MV accelerators have been used almost exclusively. Adjuvant chemotherapy was given at the discretion of the medical oncologist to 379 women. This included cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), with or without vincristine or prednisone, in 276 women (72%); doxorubicin and cyclophosphamide in 15 women (4%); and a combination of doxorubicin and CMF-based regimens in 54 women ( 14%). The remaining 34 patients received other drugs. The sequencing of the chemotherapy with the RT has been previously described (28) and was not found to contribute significantly to the complications in this review. The first follow-up visit with the radiation oncologist was usually 3-4 weeks after the completion of RT, then every 3-4 months for the next l-2 years, and semiannually thereafter. The development of complications was recorded at the follow-up examinations. Detailed analyses of the complications radiation pneumonitis and arm edema have been previously published for this patient population (24, 28) and will be briefly reviewed in the discussion of this paper. Brachial plexopathy was defined as the development of new numbness, paresthesias, pain or weakness in the ipsilateral arm after RT. Women who were subsequently found to have an axillary recurrence were excluded from this group. Brachial plexopathy was scored as transient if the symptoms or signs completely resolved, or progressive if they increased in severity or did not resolve with time. Mild brachial plexopathy describes minimal interruption in daily function and severe represents marked impairment. Neurologic consultation and electromyograms (EMG) were obtained at the discretion of the radiation oncologist. Patients were recorded as having a rib fracture when chest wall pain, anatomically related to the rib cage, was present in the treatment field, with or without x-ray confirmation. Tissue necrosis was scored when it was severe enough to require surgical intervention. Patients were presumed to have pericarditis if they developed chest pain

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requiring in-patient investigation after receiving RT to the left breast. All time intervals were measured from the start of RT. Patients were not censored from this analysis at the time of recurrent breast cancer, but remained at risk for complications through the time of their last follow-up or their death. The Kaplan-Meier method was used to compute actuarial rates. The Fisher exact test was used to compare differences between crude proportions. All tests of statistical significance were two-tailed with a p-value of 0.05 or less considered significant. RESULTS

Brachial plexopathy Twenty of 1624 patients (1.2%) developed a brachial plexopathy. The median time to its appearance was 10.5 months (range 1S-77 months). The median age of women with brachial plexopathy was 44 years old (range, 36-65), which was younger than that of the entire group. Eighteen (90%) of these 20 women presented with numbness or paresthesias. This was in the ulnar nerve distribution in seven patients, the median nerve region in two women, the upper arm/axilla in three, and in six patients the distribution was not specified. Two patients presented with pain in the arm. Motor dysfunction was found in 10 women (50%), with a decrease in deep tendon reflexes noted in five patients, and three patients were found to have weakness of their hand grip. In 16 of the 20 patients (80%), brachial plexopathy was transient and mild, and resolved within 1 year. One woman had a transient but severe brachial plexopathy, which resolved over 2 years. Three women had progressive and severe involvement. Thus, severe brachial plexus impairment occurred in 4 of the 1624 women in the entire group (0.25%). Electromyography (EMG) and nerve conduction studies were performed in only six patients, including two patients with transient and mild involvement and in all four patients with severe brachial plexopathy. Slowing in brachial plexus nerve conduction velocity across the thoracic outlet segment was demonstrated in all five cases in which it was measured. The EMG ranged from normal

showing loss of functioning motor units. The loss of functioning motor units occurred either because of neural demyelination without axonal damage (i.e., decreased total number of motor units but normal unit morphology), or demyelination with axonal damage (i.e., evidence of acute denervation, in the form of fibrillations, and/or chronic denervation, in the form of decreased total number of motor units with units of increased size and polyphasia). In the first patient with transient and mild brachial plexopathy, slowing across the thoracic outlet was demonstrated for both the median and ulnar nerves. The EMG was normal. The second patient with transient and mild brachial plexopathy did not have brachial plexus conduction velocity measurements, but had low amplitude median and ulnar sensory evoked potentials, consistent with brachial plexus rather than radicular localization of her neurological lesion. Her EMG showed a mild increase in the average size of the motor units in C8 innervated intrinsic hand muscles, with fibrillations and fasciculations in the abductor pollicis brevis. The EMG was normal for C7 muscles. The patient with the transient and severe dysfunction had slow thoracic outlet segment conduction for both the median and ulnar nerves and a moderate decrease in the total number of motor units in C6,7, and 8 segments, without evidence of denervation or reinnervation. Follow-up nerve conduction studies returned to normal over 2 years, which correlated with her subjective and objective improvement. One woman with gradually progressive and severe clinical involvement demonstrated commensurate electrophysiological brachial plexus slowing across the thoracic outlet segment. The EMG was normal 1 year after her symptoms appeared and was not subsequently repeated. The remaining two patients with progressive and severe involvement had slowing in brachial plexus nerve conduction, but EMG data were not obtained. The technique of treatment (2-field vs 3-field), axillary dose, and use of chemotherapy were significantly associated with the development of brachial plexopathy, as shown in Table 1. Of the 1,117 patients treated with a three-field approach, 20 (1.8%) had a brachial plexopathy, compared to none of the 507 patients treated with tangents only (p = 0.0009). The remainder of the analysis was re-

to

Table 1. Incidence of brachial plexopathy in relation to radiation technique, dose, and chemotherapy No CT Technique Two-field Three-field Three-field technique Axillary dose 5 50Gy >50Gy

CT = chemotherapy.

0% (O/458) 0.6% (S/787) -pPOoool-

CT

Total

0% (O/49) 4.5% (15/330)

0% (O/507) 1.8% (20/l 117)

only: 0.4% (3/724) 3.2% (2163) -p=NS

p = 0.05

p = 0.0002 -

3.7% (10/267) b 7.9% (5/63)

p = NS

1.3% (13/991) 5.6% (7/126) p = 0.004

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Table 2. Incidence of rib fracture in relation to machine energy and dose to the whole breast Whole breast dose 5 45 Gy > 45-< 50 Gy

4MV

6or8MV

0.4% (l/279)

0% (O/131) 0.8% (l/120)

> 50Gy Total

stricted to the patients treated with a three-field technique. The incidence of brachial plexopathy was significantly higher when the axillary dose of radiation therapy was greater than 50 Gy, compared to an axillary dose of 50 Gy or less (5.6% and 1.3%, respectively, p = 0.004). The use of chemotherapy was also associated with an increased rate ofbrachial plexopathy (4.5% for patients treated with adjuvant chemotherapy and 0.6% for patients treated with radiation alone, p < 0.0001). These factors appeared to be additive. For example, a higher incidence of brachial plexopathy was seen when both chemotherapy and a dose greater than 50 Gy were used (7.9%) than when a dose of greater than 50 Gy was used but no chemotherapy was given (3.2%), although this difference was not statistically significant. The timing of chemotherapy and RT (concurrent vs sequential) was not significantly associated with the development of brachial plexopathy. The axillary doses of the four women with severe impairment were 4800, 5100, 5200, and 5350 cGy, which are all higher than the median dose of 4750 cGy for the patients who had a mild brachial plexopathy. One woman with a severe brachial plexopathy received fractions of 2.5 Gy for part of her treatment. The interval to the development of brachial plexopathy was not different for those who had severe plexopathy than for those with mild symptoms. Two of the four patients with severe brachial plexopathy received chemotherapy. Factors that were not found to be significantly associated with the development of brachial plexopathy included the use of an axillary dissection, the number of lymph nodes recovered in the axillary dissection, fraction size ( 1.8 Gy vs 2 Gy), and treatment of the supraclavicular area alone as compared to the supraclavicular plus axillary region. Rib fracture

Twenty-nine of the 1624 patients (1.8%) developed a rib fracture, with a median time to its occurrence of 12 months (range, l-57 months). Radiographic confirmation of the fracture was obtained in 2 1 of the 29 women (73%), and the remaining patients had signs and symptoms consistent with a rib fracture. In 20 patients, plain x-ray revealed the fracture. Six patients had x-rays taken which did not reveal a rib fracture, and three patients did not have an x-ray. A bone scan was obtained in six women; four showed increased uptake corresponding to the x-ray abnormalities, one patient had negative x-rays and a pos-

0% (O/25) * 0.4% (l/276) ??

Total 0.2% (l/410) 1.3% (1 l/845) 5.3% (17/321) I .8% (29/l 576)

itive bone scan, and in one woman both studies were normal. Of the 2 1 patients with radiographic confirmation of a fracture, 11 women had involvement of the anterior rib cage (the medial chest wall and inframammary areas) and 10 had a fracture in the lateral chest wall along the anterior axillary line. The number of ribs involved were detailed in 16 patients, with the majority (94%) of these having more than one rib fractured. The fourth, fifth or sixth rib was involved in 88% of women. We evaluated rib fracture in relation to machine energy and radiation dose to the breast (Table 2). Its occurrence was greater for patients treated with a 4 MV machine energy (2.2%) than for those treated with a 6 or 8 MV machine (0.4%, p = 0.005). Among patients treated with 4 MV, the rate of rib fracture was correlated with the radiation dose given to the whole breast. Patients who received 45 Gy or less had a 0.4% incidence, patients who received more than 45 Gy but less than 50 Gy had a 1.4% incidence: and for women treated with 50 Gy or more, the rate was 5.7%. The difference between less than 50 Gy and 50 Gy or more whole breast dose was statistically significant (r, = 0.0001). Patients who received a whole breast dose of exactly 50 Gy had a significantly lower rib fracture rate (4.3%) than patients who received more than 50 Gy ( 14.6%, p = 0.02). We also assessed the contribution of chemotherapy to the development of a rib fracture (Table 3). With a whole breast dose of less than 50 Gy, the addition of chemotherapy was associated with an increased rate of rib fracture: 0.5% without chemotherapy and 2.3% with chemotherapy (p = 0.01). When 50 Gy or more was given to the whole breast, 4.7% of patients treated with radiation alone developed a rib fracture compared with 7.4% of patients who received adjuvant chemotherapy @ = NS). In all cases, the rib fracture healed without intervention. One patient had subsequent, multiple fractures in the treated area which all eventually healed. Table 3. Incidence of rib fracture in relation to chemotherapy and the dose to the whole breast Whole breast dose <50Gy 250Gy

no CT 0.5% (5/990) -p 4.7% (12/255) -p

CT = 0.01= NS-

2.3% (7/331) 7.4% (5/68)

Radiation complications in breast cancer 0 S. M. PIERCEet al.

Tissue necrosis Three patients (0.18%) developed tissue necrosis that required surgical resection 22, 25, and 114 months after treatment. All three patients were treated on a 4 MV linear accelerator without chemotherapy. In two women, the necrosis was located in the region of an interstital implant boost. Both patients had received a whole breast dose of 46 Gy in 23 fractions, followed by a two-plane iridium192 implant (delivering doses of 20.8 and 2 1 Gy). One of these two patients developed an ulcer at the nipple, which healed after surgical resection. The second woman developed a small ulcer 25 months after initial radiation. Biopsies and small resections lead to additional necrosis, and she eventually required a mastectomy and flap reconstruction. The third patient was treated with 50 Gy in 20 fractions to the entire breast, with an additional photon boost of 10 Gy in four fractions to the primary site. At 114 months, she developed osteoradionecrosis of the medial sternum and osteochondritis of the medial chest wall in the boost field. She required reconstruction of the involved area using a myocutaneous flap 20 months later. Pericarditis Three of 831 patients (0.4%) who received RT to the left breast developed chest pain requiring inpatient evaluation for presumed pericarditis 2,2, and 11 months after treatment began. None had received chemotherapy prior to the event. Measurement of the central lung distance (CLD) from the simulation or portal films, as described by Bornstein (6) was performed to determine if these patients had excessive volumes of lung and heart in their tangential treatment fields. One patient was treated to the entire breast using 1.8 Gy per day to 45 Gy. Simulation films showed a CLD of 2.5 cm, with 1.5 cm of the heart included in the tangential fields. She developed chest pain during the 2-week interval between external beam irradiation and the interstitial implant. Electrocardiogram (EKG) showed changes consistent with pericarditis, with marked changes involving the anterior wall of the heart. Evaluation included cardiac enzymes, thallium scan, and exercise tolerance test and all were normal. On follow-up examination 33 months after treatment, she was alive without breast cancer and without cardiac problems. The second patient was treated to the whole breast with 2 Gy per day to 46 Gy, followed by an electron boost to 62 Gy. The CLD on the simulator films was 2.5 cm and included 1 cm of heart in the field. She experienced the sudden onset of chest pain 2 weeks following the completion of radiation. The EKG ST segment in the inferior leads was elevated and cardiac enzymes showed a mild increase of creatinine phosphokinase to 124, with an MB isoenzyme fraction of 12%. Angiography showed a small area of apical hypokinesis consistent with a small myocardial infarction. Exercise tolerance test and echocardio-

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gram were normal, and repeat EKG two months later was normal. She died of recurrent breast cancer 21 months later. The third patient received 2.5 Gy per day to 45 Gy to the whole breast, with a external beam photon cone down to 60 Gy. The estimated CLD was 4 cm, with 4 cm of the heart in the tangential fields. This patient had asymptomatic EKG changes 1 month after RT, with moderate anterior wall ischemia and a decrease in T wave amplitude across the pericardium. Eleven months after treatment she presented with sharp left-sided chest wall pain with an associated rib fracture. A repeat EKG revealed progression of the previous findings, but vectorcardiogram showed no evidence of myocardial infarction. Second non-breast malignancies in the radiation treatment field

Three patients (0.18%) developed a sarcoma in the treatment field 72, 107, and 110 months after treatment, for a IO-year actuarial rate of 0.8%. All three patients were treated with a three-field technique, but two of the patients did not have an accurate geometric match between the tangential fields and the third treatment field. One patient received 50 Gy in 2 Gy fractions to the breast. The supraclavicular, axillary, and internal mammary lymph node regions were treated using a “hockey stick” technique to 46 Gy. At 50 months, liver metastasis was discovered and she received chemotherapy. At 72 months, a mass in the medial left chest wall was resected revealing a high grade malignant fibrous histiocytoma. This was located in the region of the matchline between the tangential fields and the hockey stick. The patient died of metastatic breast cancer 96 months after RT. The second patient received 48 Gy in 2 Gy fractions to the breast, and 46 Gy to the supraclavicular and axillary region. The hanging-block technique was used. She developed pain and swelling at the stemoclavicular joint at 95 months, and CT scan showed minimal erosion of the posterior cortex of the medial clavicular head. Aspiration of the clavicle was negative. She had persistent pain and swelling, and 1 year later destruction of the head of the clavicle with an associated expansile soft-tissue mass was found. A biopsy revealed fibrosarcoma and she was treated with resection and chemotherapy. Subsequently, she developed a local recurrence of the sarcoma and died 11 months after the sarcoma was diagnosed. The clavicle was within the supraclavicular/axillary field, located several centimeters from the matchline. The third patient received 47 Gy, half of which was delivered in 2.25 Gy fractions, to the breast, supraclavicular, and axillary regions. The three-field technique used did not achieve an optimal geometric match. At 110 months, she presented with a mass involving the interspace between the first and second rib. Biopsy revealed fibrosarcoma. She had a wide resection followed by flap reconstruction. She subsequently developed recurrent

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sarcoma in the neck, which was treated with a radical neck dissection, and a solitary lung metastasis which was also resected. Sixty-three months later, at the time of her last follow-up, she remained free of disease. One patient (0.06%) developed a basal cell carcinoma in the electron boost field 42 months after receiving a breast dose of 45 Gy and a boost dose of 16 Gy. This was treated with surgical resection.

DISCUSSION In this study, we have documented that the incidence of long-term complications for women with early stage breast cancer treated with CS and RT is low and is related to certain treatment factors. Brachial plexopathy occurred in 1.2% of the patients and was significantly related to the use of a three-field technique, a radiation dose to the brachial plexus greater than 50 Gy, and the use of chemotherapy. In the majority of women (80%) the brachial plexopathy was transient and mild, with complete resolution. Rib fracture was also unusual ( 1.8%) and was associated with higher doses to the whole breast, the use of a lower machine energy, and the combination of RT and CT. Tissue necrosis requiring surgical resection occurred in 0.18% of patients. Of the women receiving RT to the left breast, 0.4% developed presumed pericarditis requiring hospitalization. Second malignancies occurring in the treatment field included three sarcomas (with a IO-year actuarial rate of 0.8%) and one basal cell carcinoma. Brachial plexus injury following RT for breast cancer has been previously described (1, 2, 3,29, 30,42,48, 52). Some authors have required the finding of motor loss on physical examination for their definition of brachial plexopathy (3, 29, 30,48). In this series, however, one half of the patients did not have motor weakness on physical examination, but were classified as having had a brachial plexopathy. In the current report, the interval to the development of brachial plexopathy was 1.5 to 77 months, and an early or late onset did not predict for the severity of the injury. These findings are consistent with those reported by others (2, 3, 29, 30, 42, 52). Sensory changes consisting of numbness and paresthesias, which were present in 90% of the patients in this report, are also the most common presenting symptoms in other series (2, 3, 29, 30, 42, 48, 52). A consistent pattern of neurologic defects was not identified in this or other patient populations with brachial plexus injury (2, 30, 42, 48, 52). In this series, a small group of patients with brachial plexopathy underwent EMG. Their most consistent electrophysiological feature was slowing in nerve conduction velocity across the thoracic outlet segment with little evidence of axonal damage on EMG. Brachial plexus slowing was also a consistent finding by Harper (18) but not by Flaggman and Kelly (15). Lederman and Wilbourn (25) had a low incidence of slowing in their series, but found it more commonly when the plexopathy occurred

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on the basis of radiation than on the basis of neoplasm. These other studies all showed more EMG evidence of axonal damage. This wide array of electrophysiological findings and apparent discrepancies among various investigational results (13, 15, 18, 25, 30) may reflect differences in the severity of plexus involvement, in particular, the degree of myelin versus axonal damage. The reversible course of brachial plexopathy for some women was first noted by Stoll (42). Reversible brachial plexopathy has also been previously reported from this institution (38) and was seen in 80% of the brachial plexopathy patients in the current series. Of note, we could not determine factors which would identify patients who would develop persistent and progressive brachial plexopathy. The radiation dose to the treatment area and the fractionation scheme have been associated with the risk of developing brachial plexopathy. Stoll (42) showed a reduction in the brachial plexopathy rate, from 73% to 15%, by decreasing the dose from 63 Gy to 57.75 Gy, and reducing the fraction size. Westling (52) showed a similar decrease in the rate of brachial plexopathy with dose modification. However, in these early reports patients were often treated with fractions of 4 Gy or higher. Using 3.4 Gy per fraction to a total dose of 5 1 Gy, Barr (2) reported a 2.4% incidence of brachial plexopathy. Basso-Ricci (3) found a 3.2% plex,us injury rate in patients given 2 Gy fractions to a total of 60 Gy, compared to 0% when the total dose was 49 Gy. Other publications from modern series find the incidence of brachial plexopathy following CS and RT to be less than 1% (10, 16, 43). Given the treatment policy within this institution, we could only assess the rate of brachial plexopathy in relation to fractions of 1.8 Gy to 2 Gy, and we found no significant difference between these two groups. However, patients receiving a total dose to the axilla greater than 50 Gy did have a significant increase in brachial plexus injury. We also found that brachial plexopathy was more frequent in patients who received chemotherapy, an association which has been noted by others (30). The combined use of chemotherapy and a third field to the supraclavicular/axillary area has also been associated with radiation pneumonitis (28). Given the demonstrated benefit of chemotherapy in breast cancer patients, it is important to assess the risks and benefits of adding the supraclavicular or axillary area to the tangential fields in patients selected for chemotherapy. We have recently assessed the risk of regional nodal failure in patients treated with CS and RT (37). Women with pathologically negative axillary lymph nodes had an axillary failure rate of 2% and a supraclavicular failure rate of 2% when radiation treatment was given to the breast alone. For patients with 1 to 3 positive axillary lymph nodes, the axillary failure rate was also 2%, and there were no supraclavicular failures after treatment to the breast alone. This low incidence of failure in the axilla after radiation of the breast alone in patients with 0 to 3 positive lymph nodes has been re-

Radiation complications in breast cancer 0 S. M. PIERCEet al.

ported by others (5, 10, 14, 17, 23, 40). We were unable to assess the risk of regional nodal failure after treatment to the breast alone for patients with four or more positive lymph nodes, since the number of patients in this category was small. We also noted that regional nodal failures in areas which had not received RT could be controlled subsequently in approximately 50% of the patients. However, approximately one quarter of the patients who had a regional nodal failure and had not received RT during their initial treatment had persistent significant symptoms (37). Given the available information, our current policy is to use tangential fields alone in patients with 0 to 3 positive lymph nodes, particularly when adjuvant chemotherapy is used. For patients with four or more positive lymph nodes, it is reasonable to add a third field, but to restrict the dose using this field to 50 Gy or less. The development of rib fracture following breast irradiation has a reported incidence in the literature of 0% to 19% (4,8,9,27,3 1,33), with recent reports using modern radiation technique citing a 1% to 3% occurrence rate ( 16, 43). In the current series, rib fracture occurred in 1.8% of patients and was associated with the dose to the whole breast and the machine energy. Isodose distributions of breast irradiation show the presence of high dose areas or ‘hot spots’ (particularly when adjustments are made for differences in tissue density) at the medial, lateral, and inferior field margins (7). These locations correlate with the location of the rib fractures in this series. Solitary rib lesions on bone scan following breast irradiation have also been correlated with these ‘hot spots’ along the anterior and axillary plane of the tangential fields (50). A higher energy machine has been shown to decrease the size and magnitude of the hot spots (7) and is likely responsible for the lower incidence of rib fracture seen in patients treated on a 6 or 8 MV accelerator compared to patients treated on a 4 MV accelerator in this series. We and others have also demonstrated that doses to the whole breast exceeding 50 Gy are associated with an increased incidence of rib fracture, an increased rate of breast fibrosis, and a poorer cosmetic outcome (19, 3 1, 47). The association between an increased risk of rib fracture and the use of chemotherapy has also been found by others (9, 27). Using conventional fractionation, Danoff (9) reported no rib fractures in 19 women treated with RT alone on a 6 MV linear accelerator compared to a 4% occurrence rate for 27 patients who received RT and chemotherapy. Lichter (27) also reported an increased incidence in rib fracture with the combination of RT and chemotherapy compared to RT alone, 12% versus 4%, respectively. Based on these observations, we limit the dose to the whole breast to 45 to 46 Gy, and currently use a 6 MV energy machine for breast irradiation. There is little evidence to support an association between breast tangential irradiation and the development of clinically significant “pericarditis”. In this report, we noted cardiac events in three patients (0.4%) which occurred in association with left-sided tangential RT. For

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lack of a better description, these cardiac events have been termed pericarditis, although one of the three patients had findings consistent with a myocardial infarction and not pericardial inflammation. Other series using modern technique report either no pericarditis ( 10, 16) or an incidence of less than 1% (36). In this series, the central lung distance (CLD) was measured to determine if the volume of lung and heart in the treatment fields was excessive for these patients. It has been our policy to try to limit the CLD to 2.5 to 3.0 cm in our patients (28). Of note, one patient with pericarditis in this series had a CLD greater than 3.0 cm and showed a large amount of heart in the tangential fields. The association between RT and the subsequent development of a sarcoma in the treatment field has been recognized for decades (35, 51). This has been reported to occur in approximately 0.2% of patients following irradiation for breast cancer (12, 20, 34). Taghian (46) recently reported 11 sarcomas arising in 7620 women treated with RT to the supraclavicular-axillary area, breast, and internal mammary region. The minimum follow-up time was 1 year, but the median follow-up, exact RT technique and location of the sarcomas were not detailed. The cumulative incidence was 0.2% at 10 years, 0.43% at 20 years, and 0.78% at 30 years. The crude incidence of 0.18% for an in-field sarcoma in this series is similar to that reported by others. All three of the sarcomas that developed in this series occurred in women treated with a third radiation field to the axillary-supraclavicular area, and two of them appeared to be located in the region of the matchline. This suggests a relationship between the radiation technique (specifically, the potential overlapping of fields resulting in a high dose region) and the development of the second tumor. Radiation-induced sarcomas have been associated with high doses of radiation, both in vitro (2 1, 32,4 1,44) and in vivo ( 11,49). A careful matching technique of the axillary-supraclavicular field to the breast tangents has been used in this institution since the late 1970’s (39) and over more recent years, the trend has been away from the use of this third field. The impact of these changes on the likelihood of radiation-induced sarcoma will take several years to determine. The incidence of other complications, such as arm edema and radiation pneumonitis, following CS and RT in patients with early stage breast cancer have been previously published from this institution. Larson (24) found that the development of arm edema was related to the extent of the axillary surgery. Overall, there was a 13% incidence of arm edema in those patients having an axillary dissection and 4% in patients not having an axillary dissection. For patients having a full axillary dissection and axillary irradiation the incidence of edema was 36%, compared with 6% for patients having a limited axillary dissection and axillary irradiation. The incidence of radiation pneumonitis following CS and RT was reported by Lingos to be 1% (28). The development of radiation

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J. Radiation Oncology 0 Biology0 Physics

pneumonitis was associated with a three-field technique and chemotherapy, with an incidence of 3% for patients receiving both modalities, compared to 0.5% for all other patients. We conclude that long-term complications following RT for early stage breast cancer are uncommon and that

Volume 23, Number 5, 1992

certain treatment alterations may reduce their occurrence. Continued long-term follow-up and careful documentation of complications following RT is important for further improvement in the outcome of patients with early stage breast cancer treated with conservative surgery and radiation therapy.

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