Acta Oncologica
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Radiation-Induced Brachial Plexus Neuropathy in Breast Cancer Patients N. K. Olsen, P. Pfeiffer, K. Mondrup & C. Rose To cite this article: N. K. Olsen, P. Pfeiffer, K. Mondrup & C. Rose (1990) Radiation-Induced Brachial Plexus Neuropathy in Breast Cancer Patients, Acta Oncologica, 29:7, 885-890, DOI: 10.3109/02841869009096384 To link to this article: http://dx.doi.org/10.3109/02841869009096384
Published online: 08 Jul 2009.
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Citing articles: 6 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20 Download by: [178.57.68.134]
Date: 13 September 2016, At: 01:47
Acia Oncologica 29 (1990) Fasc. 7
FROM THE DEPARTMENTS OF NEUROLOGY AND CLINICAL NEUROPHYSIOLOGY, AND ONCOLOGY R, ODENSE UNIVERSITY HOSPITAL, ODENSE, DENMARK.
RADIATION-INDUCED BRACHIAL PLEXUS NEUROPATHY IN BREAST CANCER PATIENTS N. K. OLSEN,P. PFEIFFER,K. MONDRUPand C. ROSE
Abstract The incidence and latency period of radiation-induced brachial plexopathy (RBP) were assessed in 79 breast cancer patients by a neurological follow-up examination at least 60 months (range 67- 130 months) after the primary treatment. All patients were treated primarily with simple mastectomy, axillary nodal sampling and radiotherapy (RT). Postoperatively, pre- and postmenopausal patients were randomly allocated chemotherapy or antiestrogen treatment. All patients were recurrence-free at time of examination. Clinically, 35% (25-47%) of the patients had RBP 19% ( 1 I-29%) had definite RBP, i s . were physically disabled, and 16% (9-26%) had probable RBP. Fifty percent (31-69%) had affection of the entire plexus, 18% (7-36%) of the upper trunk only, and 4% (1-18%) of the lower trunk. In 28% (14-48%) of cases assessment of a definite level was not possible. RBP was more common after radiotherapy and chemotherapy (42%) than after radiotherapy alone (26%) but the difference was not statistically significant (p = 0.10). The incidence of definite RBP was significantly higher in the younger age group (p = 0.02). This could be due to more extensive axillary surgery but also to the fact that chemotherapy was given to most premenopausal patients. In most patients with RBP the symptoms began during or immediately after radiotherapy, and were thus without significant latency. Chemotherapy might enhance the radiation-induced effect on nerve tissue, thus diminishing the latency period. Lymphedema was present in 22% (14-32%), especially in the older patients, and not associated with the development of RBP. In conclusion, the damaging effect of RT on peripheral nerve tissue was documented. Since no successful treatment is available, restricted use of RT to the brachial plexus is warranted, especially when administered concomitantly with cytotoxic therapy. Key words: Breast cancer, brachial plexopathy, postoperative radiotherapy, chemotherapy, lymphedema.
Neurological symptoms and signs from the upper limb may follow radiotherapy (RT) for breast cancer. This radiation-induced brachial plexopathy (RBP) may be difficult to distinguish from neoplastic infiltration of the brachial plexus (NBP) (1). Moreover, the two conditions
may coexist. The clinical description of RBP is hampered by the heterogeneity of the patient materials and great variation in radiation doses (2-5). In order to purge the description of RBP for these variables and attain more reliable figures of its characteristics, we conducted a follow-up neurological investigation of 79 patients who had received standardized postoperative RT for breast cancer in a single county in Denmark.
Material and Methods Since 1977, the Danish Breast Cancer Cooperative Group (DBCG) has conducted nationwide trials in early breast cancer (6-8). In the DBCG 77 protocols, patients with invasive breast cancer without evidence of distant metastases were treated primarily with total mastectomy plus axillary node sampling. All patients with axillary lymph node metastases, and/or primary tumor > 5 cm, and/or proven involvement of skin and/or deep invasion of the fascia had postoperative radiotherapy (7). Radiotherapy (RT) was administered using a standardized technique [8,9]. The aim of the radiotherapy was to deliver a dose sufficient to eradicate sub-clinical disease in regional lymph nodes and the chest wall, including the surgical scar. The treatment regimen aimed at a minimum CRE (cumulative radiation effect) at the target of 1345 ‘reu’ (8,9) with reference points at the midplane of the axilla and at the pleural surface below the anterior chest wall. A total dose of 36.60Gy in 12 fractions, with 2 fractions per week, was given in 40 days (range 37-49 days) in 77 patients. Two patients received one extra fraction (to a total of 39.60 Gy) because the treatment was
Accepted for publication 26 September 1989.
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postponed due to a major skin reaction. The maximum doses varied according to different anterior-posterior diameter measured at the level of the central axilla, peak values ranged from 40.80 to 49.56 Gy (median 43.36 Gy). The patients were treated in individually shaped fixation casts with the ipsilateral arm fixed in 100- 120” abduction. The patients were irradiated with one anterior photon field (8 MV) against the supraclavicular/infraclavicular and axillary regions. The borders of the anterior field were the midline medially, clearing the shoulder superiorly, and clearing the axilla laterally. The distal border was the contralateral inframammary sulcus or at least 3 cm below the surgical scar. A bolus covered the surgical scar in the photon field with a margin of 4cm. Individually placed blocks were used to protect the larynx, the caput humeri, and the lung below the level of the second rib (9). The remaining part of the chest wall was treated through an anterior electron field (most often 12 MeV) shaped to fit the lung block in the photon field. Starting concurrently with RT, premenopausal patients were allocated at random to receive either no further therapy, C (cyclophosphamide monotherapy 130 mg/m2 administered orally days 1 to 14) or CMF (cyclophosphamide 80mg/m2 orally days 1 to 14, methotrexate 30mg/m2 intravenously days 1 and 8, and 5-fluorouracil 500 mg/m2 intravenously days 1 and 8). Cytotoxic therapy (CT) was repeated every 4 weeks. Postmenopausal patients received either no drug therapy or tamoxifen (30 mg daily). All medications were to be continued for 48 weeks. All operative and histopathological data were obtained from the DBCG database. After treatment all patients were followed at regular intervals by clinical examination and chest radiography. Other relevant investigations were performed if the patients were suspected for recurrent disease. To ensure that the neuropathy actually was induced by RT, only patients without evidence of local or distant recurrent disease at least 5 years after the primary operation were included in the present investigation. Furthermore, patients were excluded if plexus symptoms preceded RT, if they had symptoms or signs of root lesions or peripheral polyneuropathy, or if informed consent to the randomised trials was not given. The study was approved by the local Ethical Committee. The investigation was limited to patients aged 70 years or less at the time of examination. In this age group, 204 patients from the county of Funen, Denmark, had received postoperative RT between August 1977 and November 1982 at the Department of Oncology, Odense University Hospital. Of these, 104 patients had no sign or history of recurrent breast cancer. Fourteen patients were lost to follow-up. Of the remaining 90 patients, 79 satisfied the inclusion criteria. These 79 patients all had a thorough, neurological examination performed by one of the authors (NKO). All neurologic examinations were made between May 1988 and November 1988, after a median follow-up period of 94 months (range 67 to 130
months). After anamnestic information, a general neurological examination was performed with special attention to symptoms and signs from the upper limbs. The patients were evaluated for RBP according to the following criteria: 1) ‘Definite RBP’: Definite sensory disturbances, weakness, hypoactivity of muscle stretch reflexes and/or atrophy of muscles were present, and the patient was disabled in her daily life. 2) ‘Probable RBP: Mild sensory disturbances, slight weakness, slight hypoactivity of muscle stretch reflexes and/or slight atrophy of muscles, but without disability in daily life functions. 3) ‘No RBP’: Absence of neurological signs and symptoms. RBP was defined as upper plexopathy, when the segments C,-C, were involved, and as lower plexopathy, when the disorder was limited to the segments C8-Th,. It was considered universal if the affection included both levels. Lymphedema was defined as a difference of at least 2.0 cm between the circumference of the 2 arms measured 10 cm above the medial humeral epicondyle. The differences between groups were tested in the relevant contingency tables using Fisher’s exact test or x2- test. Two-sided p-values less than 0.05 were considered to be statistically significant. All median values are followed by range in parentheses. Relative risks and frequencies expressed in percentages are followed by 95% confidence limits (95% CL).
Results Neurologic follow-up examination was performed in 79 patients. The characteristics of these patients are seen in Table 1. At the time of RT, 58 patients were
Table 1 Characteristics of 79 patients with breast cancer examined for RBP (Range in parentheses)
Median age at time of RT (years) Median age at follow-up (years) Median follow-up interval (months) Menopausal status at the time of radiotherapy Premenopausal (n) Postmenopausal (n) Radiotherapy Total dose (Gy) Median peak values (Gy) Median number of fractions Median duration (days) CRE (reu) Adjuvant therapy (n) CMF Cyclophosphamide Tamoxifen No adjuvant treatment Median number of lymph nodes removed at operation Median size of primary tumor (mm) Median hemoglobin value (g/IOO ml)
47 55 94
(33-63) (41-70) (64-130)
58 21 36.60 43.36 12 40 1 345
( 36.60-39.60)
(40.80-49.56) (12-13) (37-49)
24 24 9 22 6 30 12
(0-17)
(10-80) (6.6- 14.7)
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RADIATION DAMAGE OF BRACHIAL PLEXUS
Table 2 Frequency and localization of RBP. Percentage and 95% C L in parentheses
Definite RBP
Probable RBP
Total
Total
15 ( 100%)
13 (loo%,)
28
Entire plexus
11
Upper trunk
(73%, 45-92%) 3 (2O%, 5-48%)
3 (23%, 6-53%)
Lower trunk Undefinable
1
(100%)
14 (SO%, 31-69%)
L
3
( l 5 % , 2-45%)
(l8Y0, 7-36%)
0
1
(7%, 1-31%)
(O%, O-24%)
(4%, 1-l8%)
0 (O%, 0-21%)
8 (62%, 32-86%)
8 (28%, 14-48%)
premenopausal and 2 1 were postmenopausal, median age was 47 years (33 to 63 years). Adjuvant systemic therapy consisted of CMF (24 patients), C (24 patients), tamoxifen (9 patients), and no adjuvant therapy (22 patients). As seen in Table 2, 15 patients (190/,, 11-29%) had definite RBP, i.e. were physically disabled. Thirteen (16%, 9-26%) had probable RBP without disability in daily life. Fifty-one patients (65%, 53-75%) had no RBP. It appears from Table 2, that 73% (45-92%) of all patients with definite RBP had affection of both upper and lower plexus, while the lesion was limited to the upper plexus in 20% (5-48%), and to the lower plexus in 7% (1-31%). In the 13 patients with probable RBP, 23% (6-53%) had affection of both upper and lower plexus whereas 15% (2-45%) had affection of the upper trunk only. In the remaining 62% (32-86%) of the patients the clinical presentation did not allow any definite statement of the affected level. Only one patient complained of vegetative disturbances, and Horner’s syndrome was not observed in any patient. The interval from the last fraction of radiotherapy to the first symptom of plexus disorder (latency) was based entirely on anamnestic information. Ten out of 15 patients with definite RBP stated that their symptoms started within a few weeks after radiotherapy, while 5 patients claimed latencies of 3 to 49 months. The mild or even absent symptoms in patients with probable RBP precluded reliable latency figures in this group. In both groups, patients had persistent symptoms of brachial plexopathy for 5 years or more with the exception of 1 patient who had symptoms for 18 months after a latency period of 48 months. Table 3 shows the correlation between CT and development of RBP. Forty-eight patients (62%) received CT. Higher incidence of RBP was found in patients treated with adjuvant CT. In the 15 patients with definite RBP, 12 patients received postoperative adjuvant CT in addition to RT, whereas 3 patients did not receive adjuvant CT. In the 13 patients with probable RBP, 8 patients received postoperative adjuvant CT. However, these tendencies failed to reach statistical significance (p = 0.10). The same tenden-
cies were found when patients receiving CMF were compared with patients who did not receive CT. RBP was found in 2 of 9 postmenopausal patients (22%, 3-60%) treated with adjuvant tamoxifen. Table 4 shows the correlation between RBP and median age at time of radiotherapy. In patients less than 48 years of age, 29% (17-45%) developed definite RBP, in contrast to patients 48 years of age or more where only 8% (2-21%) developed definite RBP ( p = 0.02). When similar analysis was made for patients with definite and probable
Table 3 Definite and probable RBP according to prior adjuvant chemotherapy. Percentage and 95% C L in parentheses
Chemotherapy
No chemotherapy
p-value
Definite RBP
12 (25%, 14-39%)
3 (lo%, 3-27%)
0.10
Probable RBP
8 ( l 7 % , 8-30%)
5 (l6%, 6-33%)
No RBP
28 (58%, 4 - 7 2 % )
23 (74%, 56-88%)
Total
48
31
(100%)
(100%)
Table 4 Definite and probable RBP according to age at time of RT. Percentage and 95% C L in parentheses Age
p-value
(years)
47
Definite RBP
12 (29%, 17-45%)
3 (8%, 2-21%)
Probable RBP
7 (I7%, 8-32%)
6 (l6%, 7-31%)
No RBP
22 (%%, 38-69%)
29 (76%, 6O-88%)
Total
41 (100%)
38
(loo%)
0.02
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N. K. OLSEN ET AL
Table 5 Definite and probable RBP according to number of lymph nodes removed at surgery. Percentage and 95% CL in parentheses
No. of nodes
Definite RBP
No RBP
31 (75%, 60-87%)
9 (24%, 12-40%) 9 (24%, 12-40%) 20 (52%, 36-69%)
Total
41 (100%)
38 (100%)
Probable RBP
6 (IS%, 6-29%) 4 (lo%, 3-23%)
p-value
0.05
Lymphedema was present in 22% (14-32%) of the patients. There was no preponderance of lymphedema in patients with RBP compared with patients without RBP (p=0.90). Table 6 shows the correlation between lymphedema and age at time of radiotherapy. The incidence of lymphedema was more frequent in the older age group (p c 0.01). We found no correlation between RBP and other factors such as peak values of RT (Table 7), tumor size, hemoglobin level at time of RT or number of tumor infiltrated lymph nodes. Discussion
RBP the difference just failed to reach statistical significance (p = 0.06). The median number of lymph nodes removed at axillary exploration was 6 and the risk of RBP was evaluated in relation to number of nodes found (Table 5). In the group of patients with 6 or less lymph nodes removed, 25% (13-40%) had definite or probable RBP. The risk of RBP was as high as 48% (31-6470) in patients having at least 7 lymph nodes removed (p = 0.05).
The present study examined the incidence of RBP in a total of 79 patients primarily operated for breast cancer with simple mastectomy and axillary sampling. All patients received postoperative radiotherapy in a standardized fashion at a single department. In this unselected group of patients, 35% (25-47%) were found to have definite (19Y0, 12-29%) or probable RBP (16%, 10-26%). The damaging effects of radiotherapy to the brachial plexus have been examined in other studies. Stoll & Andrews (10) found a 15% incidence in a group of breast cancer patients who received a minimum of 51 Gy
Table 6 Lymphedema according to age at time of RT. Percentage 95% CL in parentheses Age (years)
p-value ~~
,60
Lymphedema
1 (go/,, 1-41%)
11
No lymphedema
10 (91%, 59-99%)
5 (63%, 25-91%) 3 (37%, 9-75%)
Total
11 (100%)
co.0 (18%, 10-30%) 49 (82%, 70-90%)
8
60 (100%)
(100%)
Table 7 Definite and probable RBP according to peak values of RT. Percentage and 95% C L in parentheses
Peak values of RT (Gy)
Definite RBP Probable RBP No RBP Total
40.80-42.64
43.08-43.57
44.16-49.56
6 (18%, 7-35%) 4 (12%, 4-28%) 23 (7O%, 52-84%)
4 (22%, 7-47%) 3 (16%, 4-41%) 11 (61%, 36-82%)
(IS%, 7-36%) 6 (21%, 9-40%) 17 (61%, 41-78%)
33
18 (100%)
(100%)
(100%)
5
28
RADIATION DAMAGE OF BRACHIAL PLEXUS
(1 950 reu) at the plexus level, but a 73% incidence when 55 Gy (2 100 reu) was given. Notter et al. (1 1) found an incidence of 17% in breast cancer patients treated with at least 45 Gy in 8-10 fractions. Svensson et al. (12) assessed the RT-tolerance level of the brachial plexus using Kirk’s rewritten form of Ellis’ formula, by calculating the cumulative radiation effect, CRE. Applying this formula to several series of patients, they showed that the frequency of RBP increased very rapidly above a given CRE-value. They concluded that CRE-values should not exceed 1 900 reu in order to obtain a reasonably low risk for RBP. Svensson et al. (12) did not include the study by McDermott (13) in their overall assessment. McDermott examined 53 breast cancer patients who received a calculated dose of 39-45 Gy in 10-13 fractions (1 490-1 685 reu) at a depth of 5 cm. RBP was found in 24% of patients, an incidence higher than the above mentioned figures. Based on pooled data on radiation-induced lesions of the brachial plexus, Cohen & Svensson (14) constructed an isoeffect table for a wide range of treatment schedules. They concluded that the table provided a useful set of tolerance dosage limits for late effects in irradiated peripheral nerves. In our study we applied a CRE of only 1345reu and our incidence of RBP may therefore seem high in comparison with the other figures. However, Overgaard et a1 (9) stressed the shortcomings of dose adjustment according to the CRE concept in order to predict isoeffects in various normal tissues. Besides this there are contributing factors in our study which might explain the observed differences in incidence of RBP. A major difference between the studies in question was that a majority of the patients in our study received adjuvant chemotherapy as a part of treatment. Forty-eight patients (62%) had systemic adjuvant CT starting concomitantly with RT; these patients received 2 cycles of C or CMF during the radiotherapy course. The higher incidence of definite RBP (25%, 14-39%) in patients treated with CT might explain, at least some of, the relative large numbers of RBP. As in the development of lymphedema and other complications (1,8, 15), adjuvant CT might be a contributing factor in the development of RBP. However, this could not be proved from our material (p =0.10). Moreover, CT, when given in combination with RT, might have a superimposed deteriorating influence on peripheral nerve function. This is in accordance with Salner et al. (l), who found a significantly increased incidence of reversible brachial plexopathy in patients treated with adjuvant CT. In our study, the incidence of RBP was significantly higher in the younger age group (p = 0.02). This could be due to the fact that adjuvant CT was given to the younger patients. Another explanation might be the use of more extensive axillary surgery in these patients, as RBP was more frequent in patients having the larger number of
889
lymph nodes removed (p = 0.05). The effect of combined surgery, radiotherapy and/or cytotoxic therapy has not been studied in the development of RBP, but in the development of lymphedema 2 or 3 combined treatment modalities play a major role (15-17). Another contributing explanation for the high incidence of RBP in our patients might be that all had a complete neurological follow-up examination performed by one neurologist, who actually was looking for RBP. The latency period found in our material was shorter than in the materials of Kori et al. (2) and Thomas & Colby ( 5 ) showing average latencies of 3.5 years (3 months to 14 years) and 6 years ( 5 months to 20 years) respectively. However, Bagley et al. (4) concluded that when neurologic symptoms appear within one year after RT, the diagnosis is probably RBP. McDermott (13) found that 36% of patients complained of reversible pain or discomfort starting within a few weeks of radiotherapy. A similar discomfort in our patients might, retrospectively, be misregarded as RBP. Most patients in our material had diffuse affection of the brachial plexus. This observation is in accordance with Thomas & Colby ( 5 ) and with Stoll & Andrews (lo), who concluded that the level of the brachial lesion did not allow any distinction between NBP and RBP. Kori et al. (2), however, did observe such a distinction and concluded ‘that painless upper trunk lesion with lymphedema suggests radiation injury, and painful lower trunk lesion with Homer’s syndrome implies tumor infiltration’. Our study is restricted to patients clinically presumed to be without recurrent disease, and we can therefore not make any distinction between RBP and NBP. Homer’s syndrome was not observed in any patient in our material, consistent with Kori et al.’s (2) experience with RBP-patients. Another adverse effect of RT was the development of lymphedema. The frequency of lymphedema in our material (22%, 14-32%) agrees well with those found by others (17). Pezner et al. (18) found that an age of 60 years or more at diagnosis of breast cancer was the most important factor that could be related to lymphedema. In our study, the same preponderance was seen. As RBP seems to occur preferably in the younger patients and lymphedema in the older, the two events seem, at least in part, to occur independently and to display different etiology. A fast reacting sensitivity of nerve tissue, perhaps superimposed by adjuvant CT, was characteristic for our material. Contrary to this, lymphatics display a long-term reactivity. The damaging effect of RT on lymphatics, superimposed on the progressive loss of adequate lympho-venous anastomoses and vascular degeneration, which imperceptibly accompanies aging (18), has a long latency. These topics need further investigations. In conclusion, the damaging effects of RT on plexus brachialis in patients operated for primary breast cancer are documented. The indication for RT in such patients
890
N . K. OLSEN ET AL.
must be considered thoroughly. RT and CT should probably be administered sequentially and not concomitantly when indicated.
ACKNOWLEDGEMENT We thank the Danish Breast Cancer Group for placing the operative and histopathological data at our disposal. Request for reprints: Dr Niels Kjaer Olsen, Arne Poulsensvej 7, DK-7100 Vejle, Denmark.
REFERENCES 1. Salner AL, Botnick LE, Herzog AG, et al. Reversible brachial
2. 3. 4.
5.
6.
7.
8.
plexopathy following radiation therapy for breast cancer. Cancer Treat Rep 1981; 65: 798-802. Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: 100 cases. Neurology 1981; 31: 45-50. Cascino TL, Kori S, Krol G, Foley KM. CT of the brachial plexus in patient with cancer. Neurology 1983; 33: 1553-7. Bagley FH, Walsh JW, Cady B, Salzman FA, Oberfield RA, Pazionos AG. Carcinomatous versus radiation-induced brachial plexus neuropathy in breast cancer. Cancer 1978; 41: 2154-7. Thomas JE, Colby MY. Radiation-induced or metastatic brachial plexopathy? A diagnostic dilemma. JAMA 1972; 222: 1392-5. Andersen KW, Mouridsen HT, Castberg T, et al. Organization of the Danish adjuvant trials in breast cancer. Dan Med Bull 1981; 28: 102-6. Mouridsen HT, Rose C, Brincker H, et al. Adjuvant systemic therapy in high risk breast cancer: The Danish breast cancer cooperative group’s trials of cyclophosphamide or CMF in premenopausal and tamoxifen in postmenopausal patients. Recent Results Cancer Res 1984; 96: 117-128. Overgaard M, Christensen JJ, Johansen H, et al. Postmastec-
tomy irradiation in high-risk breast cancer patients-Present status of the Danish Brzast Cancer Cooperative Group trials. Acta Oncol 1988; 27: 707-14. 9. Overgaard M, Bentzen SM, Juul Christensen J, Hjellund Madsen E. The value of NSD formula in equation of acute and late radiation complications in normal tissue following 2 and 5 fractions per week in breast cancer patients treated with postmastectomy irradiation. Radiother Oncol 1987; 9: 1- 12. 10. Stoll BA, Andrews JT. Radiation-induced peripheral neuropathy. Br Med J 1966; 11: 834-7. 1 1 . Notter G. Hallberg 0, Vikterlof KJ. Strahlenschaden am Plexus brachialis bei Patienten mit Mammakarzinom. Strahlenther 1970; 139: 538-43. 12. Svensson H, Westling P, Larsson LG. Radiation-induced lesions of the brachial plexus correlated to the dosetime-fraction schedule. Acta Radiol Ther Phys Biol 1975; 14: 228-38. 13. McDermott RS. Cobalt 60 beam therapy-Post-radiation effects in breast cancer patients. J Can Ass Radiol 1971; 22: 195-98. 14. Cohen L, Svensson H. Cell population kinetics and dose-time relationships for post-irradiation injury of the brachial plexus in man. Acta Radiol Oncol 1978; 17: 161-6. 15. Danoff BF, Goodman RL, Click JH, Haller DG, Pajak TF. The effect of adjuvant chemotherapy on cosmesis and complications in patients with breast cancer treated by definite irradiation. Int J Radiat Oncol Biol Phys 1983; 9: 1625-30. 16. Larson D, Weinstein M, Goldberg I, et al. Edema of the arm as a function of the extent of axillary surgery in patients with state 1-11 carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 1986; 12: 1575-82. 17. Ryttov N, Holm NV, Qvist N, Blicher-Toft M. Influence of adjuvant irradiation on the development of late arm lymphedema and impaired shoulder mobility after mastectomy for carcinoma of the breast. Acta Oncol. 1988; 27: 667-70. 18. Pezner RD, Patterson MP, Hill LR, et al. Arm lymphedema in patients treated conservatively for breast cancer. Relationship to patients’ age and axillary node dissection technique. Int J Radiat Oncol Biol Phys 1986; 12: 2079-83.
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Radiation-Induced Brachial Plexus Neuropathy in Breast Cancer Patients N. K. Olsen, P. Pfeiffer, K. Mondrup & C. Rose To cite this article: N. K. Olsen, P. Pfeiffer, K. Mondrup & C. Rose (1990) Radiation-Induced Brachial Plexus Neuropathy in Breast Cancer Patients, Acta Oncologica, 29:7, 885-890, DOI: 10.3109/02841869009096384 To link to this article: http://dx.doi.org/10.3109/02841869009096384
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 229
View related articles
Citing articles: 6 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20 Download by: [178.57.68.134]
Date: 13 September 2016, At: 01:47
Acia Oncologica 29 (1990) Fasc. 7
FROM THE DEPARTMENTS OF NEUROLOGY AND CLINICAL NEUROPHYSIOLOGY, AND ONCOLOGY R, ODENSE UNIVERSITY HOSPITAL, ODENSE, DENMARK.
RADIATION-INDUCED BRACHIAL PLEXUS NEUROPATHY IN BREAST CANCER PATIENTS N. K. OLSEN,P. PFEIFFER,K. MONDRUPand C. ROSE
Abstract The incidence and latency period of radiation-induced brachial plexopathy (RBP) were assessed in 79 breast cancer patients by a neurological follow-up examination at least 60 months (range 67- 130 months) after the primary treatment. All patients were treated primarily with simple mastectomy, axillary nodal sampling and radiotherapy (RT). Postoperatively, pre- and postmenopausal patients were randomly allocated chemotherapy or antiestrogen treatment. All patients were recurrence-free at time of examination. Clinically, 35% (25-47%) of the patients had RBP 19% ( 1 I-29%) had definite RBP, i s . were physically disabled, and 16% (9-26%) had probable RBP. Fifty percent (31-69%) had affection of the entire plexus, 18% (7-36%) of the upper trunk only, and 4% (1-18%) of the lower trunk. In 28% (14-48%) of cases assessment of a definite level was not possible. RBP was more common after radiotherapy and chemotherapy (42%) than after radiotherapy alone (26%) but the difference was not statistically significant (p = 0.10). The incidence of definite RBP was significantly higher in the younger age group (p = 0.02). This could be due to more extensive axillary surgery but also to the fact that chemotherapy was given to most premenopausal patients. In most patients with RBP the symptoms began during or immediately after radiotherapy, and were thus without significant latency. Chemotherapy might enhance the radiation-induced effect on nerve tissue, thus diminishing the latency period. Lymphedema was present in 22% (14-32%), especially in the older patients, and not associated with the development of RBP. In conclusion, the damaging effect of RT on peripheral nerve tissue was documented. Since no successful treatment is available, restricted use of RT to the brachial plexus is warranted, especially when administered concomitantly with cytotoxic therapy. Key words: Breast cancer, brachial plexopathy, postoperative radiotherapy, chemotherapy, lymphedema.
Neurological symptoms and signs from the upper limb may follow radiotherapy (RT) for breast cancer. This radiation-induced brachial plexopathy (RBP) may be difficult to distinguish from neoplastic infiltration of the brachial plexus (NBP) (1). Moreover, the two conditions
may coexist. The clinical description of RBP is hampered by the heterogeneity of the patient materials and great variation in radiation doses (2-5). In order to purge the description of RBP for these variables and attain more reliable figures of its characteristics, we conducted a follow-up neurological investigation of 79 patients who had received standardized postoperative RT for breast cancer in a single county in Denmark.
Material and Methods Since 1977, the Danish Breast Cancer Cooperative Group (DBCG) has conducted nationwide trials in early breast cancer (6-8). In the DBCG 77 protocols, patients with invasive breast cancer without evidence of distant metastases were treated primarily with total mastectomy plus axillary node sampling. All patients with axillary lymph node metastases, and/or primary tumor > 5 cm, and/or proven involvement of skin and/or deep invasion of the fascia had postoperative radiotherapy (7). Radiotherapy (RT) was administered using a standardized technique [8,9]. The aim of the radiotherapy was to deliver a dose sufficient to eradicate sub-clinical disease in regional lymph nodes and the chest wall, including the surgical scar. The treatment regimen aimed at a minimum CRE (cumulative radiation effect) at the target of 1345 ‘reu’ (8,9) with reference points at the midplane of the axilla and at the pleural surface below the anterior chest wall. A total dose of 36.60Gy in 12 fractions, with 2 fractions per week, was given in 40 days (range 37-49 days) in 77 patients. Two patients received one extra fraction (to a total of 39.60 Gy) because the treatment was
Accepted for publication 26 September 1989.
885
886
N. K.OLSEN ET AL
postponed due to a major skin reaction. The maximum doses varied according to different anterior-posterior diameter measured at the level of the central axilla, peak values ranged from 40.80 to 49.56 Gy (median 43.36 Gy). The patients were treated in individually shaped fixation casts with the ipsilateral arm fixed in 100- 120” abduction. The patients were irradiated with one anterior photon field (8 MV) against the supraclavicular/infraclavicular and axillary regions. The borders of the anterior field were the midline medially, clearing the shoulder superiorly, and clearing the axilla laterally. The distal border was the contralateral inframammary sulcus or at least 3 cm below the surgical scar. A bolus covered the surgical scar in the photon field with a margin of 4cm. Individually placed blocks were used to protect the larynx, the caput humeri, and the lung below the level of the second rib (9). The remaining part of the chest wall was treated through an anterior electron field (most often 12 MeV) shaped to fit the lung block in the photon field. Starting concurrently with RT, premenopausal patients were allocated at random to receive either no further therapy, C (cyclophosphamide monotherapy 130 mg/m2 administered orally days 1 to 14) or CMF (cyclophosphamide 80mg/m2 orally days 1 to 14, methotrexate 30mg/m2 intravenously days 1 and 8, and 5-fluorouracil 500 mg/m2 intravenously days 1 and 8). Cytotoxic therapy (CT) was repeated every 4 weeks. Postmenopausal patients received either no drug therapy or tamoxifen (30 mg daily). All medications were to be continued for 48 weeks. All operative and histopathological data were obtained from the DBCG database. After treatment all patients were followed at regular intervals by clinical examination and chest radiography. Other relevant investigations were performed if the patients were suspected for recurrent disease. To ensure that the neuropathy actually was induced by RT, only patients without evidence of local or distant recurrent disease at least 5 years after the primary operation were included in the present investigation. Furthermore, patients were excluded if plexus symptoms preceded RT, if they had symptoms or signs of root lesions or peripheral polyneuropathy, or if informed consent to the randomised trials was not given. The study was approved by the local Ethical Committee. The investigation was limited to patients aged 70 years or less at the time of examination. In this age group, 204 patients from the county of Funen, Denmark, had received postoperative RT between August 1977 and November 1982 at the Department of Oncology, Odense University Hospital. Of these, 104 patients had no sign or history of recurrent breast cancer. Fourteen patients were lost to follow-up. Of the remaining 90 patients, 79 satisfied the inclusion criteria. These 79 patients all had a thorough, neurological examination performed by one of the authors (NKO). All neurologic examinations were made between May 1988 and November 1988, after a median follow-up period of 94 months (range 67 to 130
months). After anamnestic information, a general neurological examination was performed with special attention to symptoms and signs from the upper limbs. The patients were evaluated for RBP according to the following criteria: 1) ‘Definite RBP’: Definite sensory disturbances, weakness, hypoactivity of muscle stretch reflexes and/or atrophy of muscles were present, and the patient was disabled in her daily life. 2) ‘Probable RBP: Mild sensory disturbances, slight weakness, slight hypoactivity of muscle stretch reflexes and/or slight atrophy of muscles, but without disability in daily life functions. 3) ‘No RBP’: Absence of neurological signs and symptoms. RBP was defined as upper plexopathy, when the segments C,-C, were involved, and as lower plexopathy, when the disorder was limited to the segments C8-Th,. It was considered universal if the affection included both levels. Lymphedema was defined as a difference of at least 2.0 cm between the circumference of the 2 arms measured 10 cm above the medial humeral epicondyle. The differences between groups were tested in the relevant contingency tables using Fisher’s exact test or x2- test. Two-sided p-values less than 0.05 were considered to be statistically significant. All median values are followed by range in parentheses. Relative risks and frequencies expressed in percentages are followed by 95% confidence limits (95% CL).
Results Neurologic follow-up examination was performed in 79 patients. The characteristics of these patients are seen in Table 1. At the time of RT, 58 patients were
Table 1 Characteristics of 79 patients with breast cancer examined for RBP (Range in parentheses)
Median age at time of RT (years) Median age at follow-up (years) Median follow-up interval (months) Menopausal status at the time of radiotherapy Premenopausal (n) Postmenopausal (n) Radiotherapy Total dose (Gy) Median peak values (Gy) Median number of fractions Median duration (days) CRE (reu) Adjuvant therapy (n) CMF Cyclophosphamide Tamoxifen No adjuvant treatment Median number of lymph nodes removed at operation Median size of primary tumor (mm) Median hemoglobin value (g/IOO ml)
47 55 94
(33-63) (41-70) (64-130)
58 21 36.60 43.36 12 40 1 345
( 36.60-39.60)
(40.80-49.56) (12-13) (37-49)
24 24 9 22 6 30 12
(0-17)
(10-80) (6.6- 14.7)
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RADIATION DAMAGE OF BRACHIAL PLEXUS
Table 2 Frequency and localization of RBP. Percentage and 95% C L in parentheses
Definite RBP
Probable RBP
Total
Total
15 ( 100%)
13 (loo%,)
28
Entire plexus
11
Upper trunk
(73%, 45-92%) 3 (2O%, 5-48%)
3 (23%, 6-53%)
Lower trunk Undefinable
1
(100%)
14 (SO%, 31-69%)
L
3
( l 5 % , 2-45%)
(l8Y0, 7-36%)
0
1
(7%, 1-31%)
(O%, O-24%)
(4%, 1-l8%)
0 (O%, 0-21%)
8 (62%, 32-86%)
8 (28%, 14-48%)
premenopausal and 2 1 were postmenopausal, median age was 47 years (33 to 63 years). Adjuvant systemic therapy consisted of CMF (24 patients), C (24 patients), tamoxifen (9 patients), and no adjuvant therapy (22 patients). As seen in Table 2, 15 patients (190/,, 11-29%) had definite RBP, i.e. were physically disabled. Thirteen (16%, 9-26%) had probable RBP without disability in daily life. Fifty-one patients (65%, 53-75%) had no RBP. It appears from Table 2, that 73% (45-92%) of all patients with definite RBP had affection of both upper and lower plexus, while the lesion was limited to the upper plexus in 20% (5-48%), and to the lower plexus in 7% (1-31%). In the 13 patients with probable RBP, 23% (6-53%) had affection of both upper and lower plexus whereas 15% (2-45%) had affection of the upper trunk only. In the remaining 62% (32-86%) of the patients the clinical presentation did not allow any definite statement of the affected level. Only one patient complained of vegetative disturbances, and Horner’s syndrome was not observed in any patient. The interval from the last fraction of radiotherapy to the first symptom of plexus disorder (latency) was based entirely on anamnestic information. Ten out of 15 patients with definite RBP stated that their symptoms started within a few weeks after radiotherapy, while 5 patients claimed latencies of 3 to 49 months. The mild or even absent symptoms in patients with probable RBP precluded reliable latency figures in this group. In both groups, patients had persistent symptoms of brachial plexopathy for 5 years or more with the exception of 1 patient who had symptoms for 18 months after a latency period of 48 months. Table 3 shows the correlation between CT and development of RBP. Forty-eight patients (62%) received CT. Higher incidence of RBP was found in patients treated with adjuvant CT. In the 15 patients with definite RBP, 12 patients received postoperative adjuvant CT in addition to RT, whereas 3 patients did not receive adjuvant CT. In the 13 patients with probable RBP, 8 patients received postoperative adjuvant CT. However, these tendencies failed to reach statistical significance (p = 0.10). The same tenden-
cies were found when patients receiving CMF were compared with patients who did not receive CT. RBP was found in 2 of 9 postmenopausal patients (22%, 3-60%) treated with adjuvant tamoxifen. Table 4 shows the correlation between RBP and median age at time of radiotherapy. In patients less than 48 years of age, 29% (17-45%) developed definite RBP, in contrast to patients 48 years of age or more where only 8% (2-21%) developed definite RBP ( p = 0.02). When similar analysis was made for patients with definite and probable
Table 3 Definite and probable RBP according to prior adjuvant chemotherapy. Percentage and 95% C L in parentheses
Chemotherapy
No chemotherapy
p-value
Definite RBP
12 (25%, 14-39%)
3 (lo%, 3-27%)
0.10
Probable RBP
8 ( l 7 % , 8-30%)
5 (l6%, 6-33%)
No RBP
28 (58%, 4 - 7 2 % )
23 (74%, 56-88%)
Total
48
31
(100%)
(100%)
Table 4 Definite and probable RBP according to age at time of RT. Percentage and 95% C L in parentheses Age
p-value
(years)
47
Definite RBP
12 (29%, 17-45%)
3 (8%, 2-21%)
Probable RBP
7 (I7%, 8-32%)
6 (l6%, 7-31%)
No RBP
22 (%%, 38-69%)
29 (76%, 6O-88%)
Total
41 (100%)
38
(loo%)
0.02
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N. K. OLSEN ET AL
Table 5 Definite and probable RBP according to number of lymph nodes removed at surgery. Percentage and 95% CL in parentheses
No. of nodes
Definite RBP
No RBP
31 (75%, 60-87%)
9 (24%, 12-40%) 9 (24%, 12-40%) 20 (52%, 36-69%)
Total
41 (100%)
38 (100%)
Probable RBP
6 (IS%, 6-29%) 4 (lo%, 3-23%)
p-value
0.05
Lymphedema was present in 22% (14-32%) of the patients. There was no preponderance of lymphedema in patients with RBP compared with patients without RBP (p=0.90). Table 6 shows the correlation between lymphedema and age at time of radiotherapy. The incidence of lymphedema was more frequent in the older age group (p c 0.01). We found no correlation between RBP and other factors such as peak values of RT (Table 7), tumor size, hemoglobin level at time of RT or number of tumor infiltrated lymph nodes. Discussion
RBP the difference just failed to reach statistical significance (p = 0.06). The median number of lymph nodes removed at axillary exploration was 6 and the risk of RBP was evaluated in relation to number of nodes found (Table 5). In the group of patients with 6 or less lymph nodes removed, 25% (13-40%) had definite or probable RBP. The risk of RBP was as high as 48% (31-6470) in patients having at least 7 lymph nodes removed (p = 0.05).
The present study examined the incidence of RBP in a total of 79 patients primarily operated for breast cancer with simple mastectomy and axillary sampling. All patients received postoperative radiotherapy in a standardized fashion at a single department. In this unselected group of patients, 35% (25-47%) were found to have definite (19Y0, 12-29%) or probable RBP (16%, 10-26%). The damaging effects of radiotherapy to the brachial plexus have been examined in other studies. Stoll & Andrews (10) found a 15% incidence in a group of breast cancer patients who received a minimum of 51 Gy
Table 6 Lymphedema according to age at time of RT. Percentage 95% CL in parentheses Age (years)
p-value ~~
,60
Lymphedema
1 (go/,, 1-41%)
11
No lymphedema
10 (91%, 59-99%)
5 (63%, 25-91%) 3 (37%, 9-75%)
Total
11 (100%)
co.0 (18%, 10-30%) 49 (82%, 70-90%)
8
60 (100%)
(100%)
Table 7 Definite and probable RBP according to peak values of RT. Percentage and 95% C L in parentheses
Peak values of RT (Gy)
Definite RBP Probable RBP No RBP Total
40.80-42.64
43.08-43.57
44.16-49.56
6 (18%, 7-35%) 4 (12%, 4-28%) 23 (7O%, 52-84%)
4 (22%, 7-47%) 3 (16%, 4-41%) 11 (61%, 36-82%)
(IS%, 7-36%) 6 (21%, 9-40%) 17 (61%, 41-78%)
33
18 (100%)
(100%)
(100%)
5
28
RADIATION DAMAGE OF BRACHIAL PLEXUS
(1 950 reu) at the plexus level, but a 73% incidence when 55 Gy (2 100 reu) was given. Notter et al. (1 1) found an incidence of 17% in breast cancer patients treated with at least 45 Gy in 8-10 fractions. Svensson et al. (12) assessed the RT-tolerance level of the brachial plexus using Kirk’s rewritten form of Ellis’ formula, by calculating the cumulative radiation effect, CRE. Applying this formula to several series of patients, they showed that the frequency of RBP increased very rapidly above a given CRE-value. They concluded that CRE-values should not exceed 1 900 reu in order to obtain a reasonably low risk for RBP. Svensson et al. (12) did not include the study by McDermott (13) in their overall assessment. McDermott examined 53 breast cancer patients who received a calculated dose of 39-45 Gy in 10-13 fractions (1 490-1 685 reu) at a depth of 5 cm. RBP was found in 24% of patients, an incidence higher than the above mentioned figures. Based on pooled data on radiation-induced lesions of the brachial plexus, Cohen & Svensson (14) constructed an isoeffect table for a wide range of treatment schedules. They concluded that the table provided a useful set of tolerance dosage limits for late effects in irradiated peripheral nerves. In our study we applied a CRE of only 1345reu and our incidence of RBP may therefore seem high in comparison with the other figures. However, Overgaard et a1 (9) stressed the shortcomings of dose adjustment according to the CRE concept in order to predict isoeffects in various normal tissues. Besides this there are contributing factors in our study which might explain the observed differences in incidence of RBP. A major difference between the studies in question was that a majority of the patients in our study received adjuvant chemotherapy as a part of treatment. Forty-eight patients (62%) had systemic adjuvant CT starting concomitantly with RT; these patients received 2 cycles of C or CMF during the radiotherapy course. The higher incidence of definite RBP (25%, 14-39%) in patients treated with CT might explain, at least some of, the relative large numbers of RBP. As in the development of lymphedema and other complications (1,8, 15), adjuvant CT might be a contributing factor in the development of RBP. However, this could not be proved from our material (p =0.10). Moreover, CT, when given in combination with RT, might have a superimposed deteriorating influence on peripheral nerve function. This is in accordance with Salner et al. (l), who found a significantly increased incidence of reversible brachial plexopathy in patients treated with adjuvant CT. In our study, the incidence of RBP was significantly higher in the younger age group (p = 0.02). This could be due to the fact that adjuvant CT was given to the younger patients. Another explanation might be the use of more extensive axillary surgery in these patients, as RBP was more frequent in patients having the larger number of
889
lymph nodes removed (p = 0.05). The effect of combined surgery, radiotherapy and/or cytotoxic therapy has not been studied in the development of RBP, but in the development of lymphedema 2 or 3 combined treatment modalities play a major role (15-17). Another contributing explanation for the high incidence of RBP in our patients might be that all had a complete neurological follow-up examination performed by one neurologist, who actually was looking for RBP. The latency period found in our material was shorter than in the materials of Kori et al. (2) and Thomas & Colby ( 5 ) showing average latencies of 3.5 years (3 months to 14 years) and 6 years ( 5 months to 20 years) respectively. However, Bagley et al. (4) concluded that when neurologic symptoms appear within one year after RT, the diagnosis is probably RBP. McDermott (13) found that 36% of patients complained of reversible pain or discomfort starting within a few weeks of radiotherapy. A similar discomfort in our patients might, retrospectively, be misregarded as RBP. Most patients in our material had diffuse affection of the brachial plexus. This observation is in accordance with Thomas & Colby ( 5 ) and with Stoll & Andrews (lo), who concluded that the level of the brachial lesion did not allow any distinction between NBP and RBP. Kori et al. (2), however, did observe such a distinction and concluded ‘that painless upper trunk lesion with lymphedema suggests radiation injury, and painful lower trunk lesion with Homer’s syndrome implies tumor infiltration’. Our study is restricted to patients clinically presumed to be without recurrent disease, and we can therefore not make any distinction between RBP and NBP. Homer’s syndrome was not observed in any patient in our material, consistent with Kori et al.’s (2) experience with RBP-patients. Another adverse effect of RT was the development of lymphedema. The frequency of lymphedema in our material (22%, 14-32%) agrees well with those found by others (17). Pezner et al. (18) found that an age of 60 years or more at diagnosis of breast cancer was the most important factor that could be related to lymphedema. In our study, the same preponderance was seen. As RBP seems to occur preferably in the younger patients and lymphedema in the older, the two events seem, at least in part, to occur independently and to display different etiology. A fast reacting sensitivity of nerve tissue, perhaps superimposed by adjuvant CT, was characteristic for our material. Contrary to this, lymphatics display a long-term reactivity. The damaging effect of RT on lymphatics, superimposed on the progressive loss of adequate lympho-venous anastomoses and vascular degeneration, which imperceptibly accompanies aging (18), has a long latency. These topics need further investigations. In conclusion, the damaging effects of RT on plexus brachialis in patients operated for primary breast cancer are documented. The indication for RT in such patients
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N . K. OLSEN ET AL.
must be considered thoroughly. RT and CT should probably be administered sequentially and not concomitantly when indicated.
ACKNOWLEDGEMENT We thank the Danish Breast Cancer Group for placing the operative and histopathological data at our disposal. Request for reprints: Dr Niels Kjaer Olsen, Arne Poulsensvej 7, DK-7100 Vejle, Denmark.
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