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Pulmonary sequelae of treatment for breast cancer: a prospective study
Int. J. Radiation Oncology Biol. Phys., Vol. 50, No. 2, pp. 411– 419, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/01/$–see front matter
PII S0360-3016(01)01438-9
CLINICAL INVESTIGATION
Breast
PULMONARY SEQUELAE OF TREATMENT FOR BREAST CANCER: A PROSPECTIVE STUDY G. C. OOI, F.R.C.R.,* D. L. KWONG, F.R.C.R.,† J. C. HO, M.R.C.P.,‡ D. T. LOCK, M.A.,* F. L. CHAN, F.R.C.R.,* W. K. LAM, M.D.,* H. NGAN, F.R.C.R.,* G. AU, F.R.C.R.,† AND K. W. TSANG, M.D.‡ Departments of *Diagnostic Radiology, †Clinical Oncology, and ‡Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China Purpose: To prospectively study the effects of loco-regional radiotherapy in women with breast cancer. Methods and Materials: Thirty consecutive patients with breast resection underwent clinical, lung function, radiographic, and thoracic high-resolution computed tomography evaluation before and at 1, 3, 6, and 12 months after adjuvant radiotherapy. Chemotherapy was also administered to 15 patients. Results: Nineteen patients reported mild respiratory symptoms at 1 month, which resolved completely at 6 months after radiotherapy. Opacities were present on 80% of chest radiographs and in all patients on highresolution computed tomography by 3 months. These opacities became compact and persisted on high-resolution computed tomography at 12 months. Lung function indices, including FEV1, FVC, TLC, and DLCO, progressively declined after radiotherapy, and was irreversible at 12 months (p < 0.05). Patients who received chemotherapy did not have significantly different lung function indices compared with their counterparts at all time points (p > 0.05). Conclusions: Our results have shown that adjuvant loco-regional radiotherapy, a common practice in breast cancer treatment, is associated with irreversible reduction in lung function parameters. These changes are accompanied by radiological evidence of persistent lung injury. Further studies should be performed to evaluate the incidence and long-term pulmonary sequelae of current treatment for breast cancer. © 2001 Elsevier Science Inc. Breast, Cancer, Loco-regional, Radiotherapy effects.
INTRODUCTION Breast cancer is the commonest female malignancy worldwide. Despite a 6.8% reduction in the breast cancer mortality rate due to recent advances in the management of the disease (1), there were over 40,000 breast cancer deaths in 1998 in the United States alone (2). Controlled trials over the last decades have revealed the benefits of adjuvant local breast irradiation after surgery, which has reduced the 10-year risk of local recurrence from 40% to 10% and the incidence of local recurrence from 18.4% to 2.3% (3, 4). Chemotherapy, on the other hand, reduces the rate of disease progression and is generally offered to patients who have a high risk of metastatic disease (5). These include the presence of large tumor size, highgrade histologic type, extensive lympho-vascular perme-
ation, involvement of axillary lymph nodes, and poor estrogen receptor status (5). Radiation lung injury is a recognized complication of radiotherapy (6 – 8), with two distinct clinical stages, namely radiation pneumonitis and fibrosis. These correspond pathologically to exudation and proliferation and chronic fibrosis in the lung parenchyma, respectively (9). Radiation pneumonitis classically occurs 4 –12 weeks after completion of radiotherapy and is often clinically silent, although patients might experience self-limiting dyspnea, cough, fever, and chest discomfort (9). Whereas some studies have addressed the effects of adjuvant radiotherapy on lung function parameters, the results have been inconsistent (10 –12), possibly due to the nonuniformity in follow-up, treatment protocol, patient population, and disease severity (10 –12). Studies of high-resolution computed tomography
Reprint requests to: Dr. Kenneth W. Tsang, M.D. (Hons), F.R.C.P. F.C.C.P. F.C.P., Associate Professor and Honorary Consultant Physician, University Department of Medicine, The University of Hong Kong, Room 302, New Clinical Building, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China. Tel: (852) 2855-4542; Fax: (852) 2855-1652; E-mail: [email protected] This study was supported by a Committee for Research and
Conference Grant (CRCG), the University of Hong Kong. Acknowledgments—The authors thank the patients for their participation in the study, the CT radiographers at Queen Mary Hospital for their cooperation, and Mr. Stanley Yeung, Department of Medicine, University of Hong Kong, for expert advice on statistical analysis. Accepted for publication 20 December 2000. 411
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(HRCT) features of radiation lung injury after breast irradiation suffer from a lack of concomitant lung function evaluation (13–15). The aims of this longitudinal study are therefore to evaluate the effects of regional lymph node and breast/chest wall irradiation (loco-regional radiotherapy) on lung function and radiologic parameters in breast cancer.
METHODS AND MATERIALS Patient recruitment and characteristics From May 1996 to June 1997, 30 consecutive women (mean age ⫾ SD [52 ⫾ 12 years]; range, 37–78 yr) with histologically confirmed breast cancer undergoing breast surgery within the previous month were recruited from the Department of Clinical Oncology at Queen Mary Hospital with written consent. Inclusion criteria included the presence of histologic evidence of breast cancer, female gender, age between 18 – 80 years, and normal lung function parameters. Exclusion criteria included history of respiratory diseases, previous administration of chemotherapy or radiotherapy, previous or concomitant malignancy, presence of respiratory symptoms for more than two weeks (cough, dyspnea, wheezing, chest pain, sputum production, or hemoptysis) within the previous 12 months, and presence of an abnormal chest radiograph. Twenty-five women underwent mastectomy, while 5 had lumpectomy performed. All patients had axillary dissection, except one woman with intraductal papillary carcinoma. Histologic typings were invasive ductal carcinoma (n ⫽ 22), mixed invasive ductal and lobular carcinoma (n ⫽ 4), intraductal papillary carcinoma (n ⫽ 1), medullary carcinoma (n ⫽ 1), invasive lobular carcinoma (n ⫽ 1), mucinous carcinoma (n ⫽ 1), and undifferentiated infiltrative carcinoma (n ⫽ 1). Breast cancer was staged according to the American Joint Committee on Cancer (16). There was 1 woman with Tis, 5 with T1, 23 with T2, and 1 with T3 disease. Node (N)-staging was N1 (n ⫽ 14) and N0 (n ⫽ 16). None of the patients had known distant metastases, i.e., M0, on routine screening and physical examination. Patients were evaluated before radiotherapy and at 1, 3, 6, and 12 months afterward. At each visit, respiratory symptom inquiry was performed using standardized questionnaire, lung function assessment, chest radiograph, and thoracic HRCT. Respiratory symptoms that were directly inquired about included sputum production, dyspnea (while walking on flat surface, hurrying up gentle slope, or hurrying up steep incline), hemoptysis, cough (dry or productive), and wheeze. The study was performed with the institutional ethics committee approval. None of these patients suffered from other concomitant respiratory illness or required regular medications other than tamoxifen at 20 mg daily (n ⫽ 17). Fifteen patients received chemotherapy. Of these, 12 patients had radiotherapy before or sandwiched between chemotherapy, and 3 patients had radiotherapy after completion of chemotherapy.
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Radiotherapy protocol All patients received loco-regional radiotherapy comprising opposing tangential chest wall and supraclavicular field irradiation, except one patient with intraductal carcinoma, who received only radiotherapy to the chest wall. Daily fractions of 200 cGy were given to the supraclavicular and tangential chest fields respectively, with a total dose of 5,000 cGy using 6/8 MV photon. The supraclavicular field was comprised of an anterior photon field with its lower border covering the head of ipsilateral clavicle (Fig. 1A). The prescription point was at the 95% isodose level. The chest wall and breast were irradiated with two tangential opposing fields (Fig. 1B). The superior border of the tangential fields was matched with the lower border of the supraclavicular field. The lower field border was at 1 cm below the mammary fold, guided by the opposite breast, if mastectomy had been performed. The medial border was set at midline, with no specific attempt to cover the internal mammary lymph nodes, while the lateral border was set at mid-axillary line. Wedges were used in the tangential field for compensation of the change of contour, and the dose was prescribed at 100% isodose level without correction for lung tissue. A boost dose of 1,000 cGy in 5 fractions was given by electron field (usually 6 MeV) to the original tumor site in patients who had lumpectomy performed. A separate field for internal mammary chain irradiation was not employed. The mean central lung depth, defined as the perpendicular distance from the posterior tangential field edge to the posterior part of the ribs through the isocenter, was 2.4 ⫾ 0.5 cm (range 2.1–3.2 cm). Chemotherapy regime Our center does not administer chemotherapy and radiotherapy concurrently. Patients with less than 4 involved axillary lymph nodes are considered as having moderate risk for development of distant metastases. For this group, radiotherapy was given either before or in a sandwiched fashion, between cycles of chemotherapy. Patients with more than 4 metastatic ipsilateral axillary lymph nodes are considered at high risk of developing distant metastases. They had chemotherapy completed before commencement of radiotherapy (17, 18). Patients with less than 4 malignant axillary lymph nodes were given CMF (oral cyclophosphamide, 150 mg daily for 14 days, methotrexate 40 mg/m2, D1 and D8 and 5-fluorouracil 600 mg mg/m2, D1 and D8, every 4 weeks for 6 cycles). Patients with more than 4 involved lymph nodes had anthracycline-based chemotherapy, either epirubincin for 4 cycles (80 mg/m2 every 3 weeks) followed by 6 cycles of CMF or FAC (5-fluorouracil 500 mg/m2 D1 and D8, adriamycin 50 mg/m2, D1 and cyclophosphamide 500 mg/m2, D1 every 3 weeks for 6 cycles). Tamoxifen, if prescribed postoperatively according to estrogen receptor–positivity of the breast cancer, was continued throughout the treatment period. Eleven patients in this series had adjuvant CMF, and 4 patients had anthracycline-based chemotherapy. One patient also received 3 courses of FEC (epirubincin, 80 mg/m2 replacing adriamy-
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Fig. 1. (A) Planning radiograph of supraclavicular field comprising anterior photon irradiation with lower border covering the ipsilateral clavicle; (B) A CT section at the planning plane of a patient receiving tangential field radiotherapy. Note opposed tangential beams (arrows).
cin in FAC) preoperatively for locally advanced carcinoma of the breast to downstage the disease before surgery (19).
radiographs and HRCT scans were used as baseline reference for each patient.
Lung function evaluation Lung function parameters were assessed using a Sensormedics Computerized Lung Function System 6300 according to the American Thoracic Society recommendation (20). Parameters assessed included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, total lung capacity (TLC), residual volume, and carbon monoxide diffusing capacity (DLCO). Measurements were expressed as percent predicted values after adjustment for age, gender, and height.
Data analysis Repeated-measures ANOVA was used to investigate the effect of radiotherapy and chemotherapy on lung function indices over time. The analysis was performed using Type III sum of squares provided for by SPSS (21). The baseline values were adopted as references. A p value of ⬍0.05 was taken as indicative of statistical significance. The MannWhitney test was used to evaluate differences in lung function changes between patients who had chemotherapy sandwiched between radiotherapy cycles and those who underwent chemotherapy either pre- or postradiotherapy.
HRCT and chest radiograph assessment Thoracic HRCT examination was performed on a single scanner (Hi-Speed Advantage, GE Medical Systems, Milwaukee, WI). The following protocol was used: 1-mm sections at 10-mm intervals with the patient in the supine position and in full inspiration. Images were reconstructed in bone algorithm and imaged at lung window settings (width/level; 1000/-700HU). HRCT images were evaluated together by two experienced radiologists to determine the presence and site of opacities. Chest radiographs were also reviewed for presence of opacities. Preradiotherapy chest
RESULTS Clinical data All patients were asymptomatic for respiratory diseases at baseline. When assessed at 1 month, 19 patients had developed respiratory symptoms that persisted at the 3-month visit. Of these, 8 patients reported dyspnea (2 while hurrying up a gentle slope, and 6 while walking up a steep incline), 7 (5 with dry cough, 2 with productive cough), 7 had chest discomfort, and 3 had sputum production. These symptoms were assessed subjectively by the patients to be
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Table 1. Lung function parameters in 30 patients with breast cancer who had adjuvant loco-regional radiotherapy Follow-up period after radiotherapy Parameters FEV1 FVC FEV1/FVC TLC DLC
Median (mean) [Interquartile range] Median (mean) [Interquartile range] Median (mean) [Interquartile range] Median (mean) [Interquartile range] Median (mean) [Interquartile range]
0 month
1 month
3 month
6 month
12 month
115 (110.7) [97–120] 116 (111) [102–121] 0.81 (0.81) [0.76–0.87] 108.0 (110.9) [95–125] 94 (93.8) [84–103]
102.5 (102.2) [90–114.8] 104.5 (102.8) [92.3–114] 0.80 (0.80) [0.76–0.84] 105 (103.9) [99–110.5] 85.5 (84.6) [78–91]
105 (101.5) [95.8–113.5] 103.5 (101.5) [92.8–114] 0.81 (0.82) [0.79–0.87] 103 (103.1) [95.8–113] 83.5 (83.2) [77.3–90.8]
106 (101.6) [90.3–111.8] 106 (102.3) [93.8–110] 0.79 (0.80) [0.76–0.84] 106.5 (101.7) [93–110.8] 83 (85.7) [76.3–92]
103 (99.6) [91.8–107.8] 101 (98.7) [90–111.3] 0.81 (0.81) [0.78–0.86] 98.5 (98.4) [91–107] 83 (83.3) [76.8–89.3]
Data shown are median (and mean) of percent predicted lung function except for FEV1/FVC ratio.
mild and did not require specific treatment. All respiratory symptoms resolved spontaneously by 6 months. The remaining 11 patients remained completely asymptomatic throughout the follow-up period. Lung function parameters Table 1 summarizes lung function parameters in the 30 patients. There was a significant reduction in all lung volume indices (FEV1, FVC, TLC) and DLCO after radiotherapy (Fig. 2). FEV1 showed a decreasing trend over 12 months (p ⬍ 0.001), with significant decreases at 1, 3, 6, and 12 months after radiotherapy compared with baseline values (p ⬍ 0.001, ⬍0.001, ⬍0.001, and 0.01, respectively). FVC also displayed a similar trend of decreasing lung function over the study period (p ⬍ 0.001), with significant decreases at all time points of assessment compared with baseline values (p ⫽ 0.003, 0.002, 0.001, and 0.001, respectively). Although TLC displayed an overall reducing trend (p ⫽ 0.04) over the study period, the reductions compared to baseline values were only significantly reduced at 6 and 12 months (p ⫽ 0.03 and 0.04, respectively) after treatment. DLCO showed a significant reducing trend within the study period (p ⫽ 0.009) and was significantly reduced from baseline levels at 1, 3, and 12 months after radiotherapy (p ⫽ 0.005, 0.003, and 0.004, respectively). No significant difference was found at 6 months (p ⫽ 0.17). Patients who received chemotherapy did not have significant differences in lung volume parameters (including DLCO) when compared with their counterparts over the assessment time points (p ⬎ 0.05, data not shown). There were also no statistically significant differences in lung function changes between patients who received chemotherapy sandwiched with radiotherapy and those who received chemotherapy either before radiotherapy (Table 2). Appendix 1 summarizes the lung function changes between these different groups of patients. HRCT and chest radiograph assessment The chest radiograph and HRCT findings are summarized in Table 3. Opacities were detected on chest radiographs in
9 (30%) patients at 1 month, 24 (80%) patients at 3 months, and 26 (87%) patients at 6 and 12 months after radiotherapy. The chest radiographs of 2 patients remained normal throughout the study period. Supraclavicular field changes were evident in the apex of the ipsilateral upper lobe (Fig. 3A), while tangential field changes were found in the ipsilateral right middle lobe or lingula. Early changes (at 1 month) were more readily observed on HRCT scans than on chest radiographs. HRCT scans were also more sensitive in recording tangential field changes compared with chest radiographs (Table 1). HRCT detected air-space opacities (Fig. 3B) in 27 patients at 1 month postradiotherapy and in all 30 patients by 3 months. These opacities became more compact with time and persisted in all 30 patients at 12 months (Fig. 3C). The appearance and compaction of these opacities on sequential HRCT examinations were concordant with the rapid decline in lung volume in the early postradiotherapy period. Their persistence at 12 months was also in accordance with the lack of recovery of lung volume by the end of the study period. DISCUSSION The results of this longitudinal study show significant gradual reduction in lung volume indices (FEV1, FVC and TLC) and DLCO over a 12-month period in patients who underwent loco-regional radiotherapy for breast cancer. Administration of chemotherapy appeared to have no deleterious effect on lung function parameters. In addition, radiologic evidence of sequential radiation lung changes were documented one month after radiotherapy and persisted in all patients one year later. Radiation fibrosis classically follows radiation pneumonitis, although the former has been reported without previous pneumonitis (8, 14, 22). Our documentation on HRCT of sequential parenchymal opacities developing from the acute through to the chronic phase of radiation lung injury has refuted the existence of a delayed and independent second phase. This under-recognition of lung changes might have been due to under-utilization of HRCT in the past. There are recognized risk factors for developing radiation
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Fig. 2. Graphs depicting sequential changes (% predicted) from baseline values of (A) FEV1, (B) FVC, (C) TLC, and (D) DLCO after radiotherapy over the course of 12 months. There was marked decline of FEV1, FVC, and TLC within the first 3 months after radiotherapy; thereafter the decline became more gradual. For DLCO, the trough value was reached earlier, at 1 month postradiotherapy, after which the decline became a plateau.
lung injury. These include volume of lung irradiated, total radiation dose, radiation dose rate (fractionated regimes are better tolerated than single large doses), and administration of chemotherapy (22–24). Bilateral lung irradiation, particularly the mid and lower zones, and the use of lateral or oblique multidirectional ports are associated with severe radiation pneumonitis (23). The current practice of using tangential ports to minimize radiation lung damage has reduced the incidence of radiation pneumonitis from 60% to 7% (25). There is no consensus in the current literature on the effects of radiotherapy on lung function parameters, and available studies do not evaluate clinical, physiologic, and radiologic parameters concomitantly (10 –12, 26 – 28). Some of these studies lack longitudinal data, and most did not include radiologic assessment. There is, however, some evidence to suggest that there may be subtle differences in the effects of radiotherapy between patients who have been given only local radiotherapy to the breast and those who have received local and regional
lymph node (loco-regional) irradiation (11, 28). Reversible reduction, ranging from 3–22%, in FEV1, FVC, FEV1/FVC, and DLCO have been reported 3 to 4 months after adjuvant local radiotherapy (12, 26). In contrast, irreversible lung function impairment after adjuvant loco-regional radiotherapy has also been reported in breast cancer (10, 11, 27, 28). In one study of 144 women with Stage II breast cancer who had either loco-regional or local radiotherapy, significant statistical but not clinical reduction (3–5%) in DLCO, FEV1, and VC were observed only in women who underwent loco-regional radiotherapy, but not local radiotherapy (10). Similar findings were also found in another comparative study in which there was a twofold increase in incidence of pulmonary symptoms in the loco-regional group compared to no functional impairment in the local radiotherapy cohort (28). Our data confirm that loco-regional radiotherapy is associated with increased incidence of radiation lung injury and irreversible lung function impairment (10 –12,
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Table 2. Differences in lung function changes over time between patients with chemotherapy sandwiched with radiotherapy (Group 1, n ⫽ 12) and those with chemotherapy after radiotherapy (Group 2, n ⫽ 3). Median, interquartile ranges and p values are shown. Follow-up period after radiotherapy 0 month Parameters FEV1 median (Interquartile p value FVC median (Interquartile p value TLC median (Interquartile p value DLCO median (Interquartile p value
Group 1
1 month
Group 2
106.5 range) 88–120.8
Group 1
119 84.5–124 0.77 106.5 120 range) 97.5–116.8 97–125 0.42 95 110 range) 90.5–109.3 98–124 0.30 89.5 86 range) 82.8–104.8 82.5–100.5 0.77
3 month
Group 2
Group 1
101 86–116.5
106 81–122 0.78 107 114 89.5–116.5 86–120 0.71 103 97 86.5–112 82–114 0.78 85 85 72.5–91 81–96 0.71
Group 2
100 80–112
116 87–121 0.13 103 116.5 77–105 86.8–121.5 0.19 92.5 113 80.3–103.5 83.3–124.8 0.44 81 81.5 69.5–84.8 67.5–85.8 0.93
6 month Group 1
Group 2
91 109 78.5–108.5 102.5–111.8 0.17 93 109 77.5–112 108.3–109.8 0.17 93 112.5 81–108 96–117 0.09 84 79 70.5–95.5 76.3–81.8 0.76
12 month Group 1
Group 2
97 78.5–107
102.5 83.3–109.8 0.49 98 101 76–114 81.5–109.3 0.35 91 102.5 83.5–103.5 80–123.5 0.35 81 86 75.5–90 77.8–89.8 0.64
Group 1: 12 patients with radiotherapy instituted in a sandwiched fashion between cycles of chemotherapy. Group 2: 3 patients with chemotherapy instituted after radiotherapy.
Although there have been studies documenting synergistic or potentiating toxicity effects of chemotherapy in the lung after radiotherapy in thoracic malignancies, including breast cancer (10, 27, 30 –33), chemotherapy in our study did not adversely affect lung function. Blomquist et al. reported a sixfold increase in symptomatic radiation pneumonitis in patients with breast cancer who had both chemotherapy and radiotherapy, compared to those who were given radiotherapy alone (33). Concurrent chemotherapy and radiotherapy for breast cancer have also been reported to be associated with increased incidence of radiation pneumonitis compared with sequential chemotherapy and radiotherapy (27). Our patients had chemotherapy delivered sequentially with radiotherapy. There were no women who received concurrent chemotherapy and radiotherapy. However, the discrepancy between our results and those of other studies may also be related to the type of cytotoxic used. Our chemotherapy protocol largely utilized combinations of cyclophosphamide and 5-fluorouracil together with methotrexate, which are less likely to induce pulmonary toxicity. We did not use high-dose chemotherapy or cytotoxics such as carmustine and ftorafur, which are
26 –28). What distinguishes our study from others is the concomitant radiologic and lung function assessment, which showed serial lung changes occurring in tandem with reductions in lung function indices. Lung volume parameters appear to be the most vulnerable, and the resultant restrictive defect is probably due to reduced elasticity in both the irradiated lung parenchyma and chest wall (26, 29). Irreversible reduction in DLCO capacity, reported after both local and loco-regional radiotherapy, is probably due to persistent interstitial damage after the initial pneumonitis phase. It is interesting to note that although the incidence of respiratory symptoms reported in our cases in the early postradiotherapy period was high (63%), these were mild and self-limiting, with resolution occurring at 12 months post-treatment. Direct inquiry into patients’ respiratory status at baseline and subsequent visits may have led to increased sensitivity to and over-reporting of acute phase symptoms, whether real or otherwise. The resolution of these symptoms, despite persistent reduction in lung volume parameters 12 months later, would reflect the compensatory effect of residual areas of normal lung reserve in these otherwise fit women.
Table 3. Chest radiograph and high-resolution computed tomography assessment of 30 patients with breast cancer who received adjuvant loco-regional radiotherapy Number of patients with abnormalities 1 month
3 months
6 months
12 months
Abnormality
CXR
HRCT
CXR
HRCT
CXR
HRCT
CXR
HRCT
Opacities Supraclavicular field changes Tangential field changes
9 9 4
27 26 15
24 20 11
30 29 27
26 23 11
30 29 28
26 23 3
30 27 28
Abbreviations: CXR ⫽ chest radiograph; HRCT ⫽ high-resolution computed tomography.
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Fig. 3. A 58-year-old woman with invasive ductal carcinoma of the left breast treated with simple mastectomy and adjuvant loco-regional radiotherapy. (A) Chest radiograph at 1 month after radiotherapy shows consolidation in the left lung apex corresponding to the supraclavicular field. (B) High resolution computed tomography (HRCT) scan at 1 month shows acute radiation pneumonitis in the tangential field (ipsilateral anterior segment of the left upper lobe), which was not obvious on the chest radiograph. (C) Fibrosis (arrows) is noted on the HRCT scan performed 1 year later.
associated with increased lung toxicity and in some cases have caused premature termination of radiotherapy (32– 34). In conclusion, our data suggest that adjuvant locoregional radiotherapy in breast cancer led to a significant reduction in lung function parameters, with no additional adverse effects arising from adjuvant chemotherapy. This paper has also presented concomitant radiologic evidence of a high incidence of radiation lung injury as a consequence of loco-regional radiotherapy. Although patients with normal lungs before treatment would have adequate
lung reserve to compensate for the radiation injury, treatment may cause problems for patients with pre-existing lung disease who have compromised lung function. Radioprotectors such as amifostine may be useful (35), and we are currently planning a trial to test the efficacy of amifostine in reducing pulmonary radiation toxicity. For women with pre-existing lung disease who are being considered for adjuvant loco-regional radiotherapy for breast cancer, the potential risk should be discussed; serial lung function tests and thoracic HRCT after treatment would be useful for monitoring.
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cyclophosphamide, methothrexate and fluorouracil in nodepositive breast cancer. N Engl J Med 1995;332:901–906. American Thoracic Society. Standardization of spirometry— 1987 update. Am Rev Respir Dis 1987;136:1285–1298. SPSS Advanced Modes 10.0. Chicago: SPSS Inc.; 1999. Cherniack RM, Abrams J, Kalica AR. NHLBI Workshop summary. Pulmonary disease associated with breast cancer therapy. Am J Respir Crit Care Med 1994;150:1169 –1173. Rubin P. Respiratory system. In: Rubin P, Casarett GW, editors. Clinical radiation pathology. Philadelphia: Saunders; 1968. p. 423– 470. Libshitz HI, Southard ME. Complications of radiation therapy: The thorax. Semin Roentgenol 1974;9:41– 49. Chu FCH, Phillips R, Nickson JJ, et al. Pneumonitis following radiation therapy of cancer of the breast by tangential technic. Radiology 1955;64:642– 654. Lund MB, Myhre KI, Melsom H, et al. The effect on pulmonary function of tangential field technique in radiotherapy for carcinoma of the breast. Br J Radiol 1991;64:520 –523. Lingos TI, Recht A, Vicini F, et al. Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1991;21:355– 360. Hardman PDJ, Tweeddale PM, Kerr GR, et al. The effect of pulmonary function of local and loco-regional irradiation for breast cancer. Radiother Oncol 1994;30:33– 42. Host H, Vale J. Lung function after mantle field irradiation in Hodgkin’s disease. Cancer 1973;32:328 –332. Sostman HD, Putnam CE, Gamsug G. Diagnosis of chemotherapy lung. Am J Roentgenol 1981;136:33– 40. Castellino RA, Glatstein E, Turbow MM, et al. Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann Intern Med 1974;80:593–599. Marks LB, Halperin EC, Prosnitz LR, et al. Post-mastectomy radiotherapy following adjuvant chemotherapy and autologous bone marrow transplantation for breast cancer patients with ⱖ 10 positive axillary lymph nodes. Int J Radiat Oncol Biol Phys 1992;23:1021–1026. Blomqvist C, Tiusanen K, Elomaa I, et al. The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamidedoxorubicin-ftorafur) and tamoxen in stage II breast cancer. Long-term follow-up results of a randomised trial. Br J Cancer 1992;66:1171–1176. Rosiello RA, Merrill WW. Radiation induced lung injury. Clin Chest Med 1990;11:65–71. Mehta MP. Amifostine and combined-modality therapeutic approaches. Semin Oncol 1999; 26(2 Suppl. 7):95–101.
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PII S0360-3016(01)01438-9
CLINICAL INVESTIGATION
Breast
PULMONARY SEQUELAE OF TREATMENT FOR BREAST CANCER: A PROSPECTIVE STUDY G. C. OOI, F.R.C.R.,* D. L. KWONG, F.R.C.R.,† J. C. HO, M.R.C.P.,‡ D. T. LOCK, M.A.,* F. L. CHAN, F.R.C.R.,* W. K. LAM, M.D.,* H. NGAN, F.R.C.R.,* G. AU, F.R.C.R.,† AND K. W. TSANG, M.D.‡ Departments of *Diagnostic Radiology, †Clinical Oncology, and ‡Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China Purpose: To prospectively study the effects of loco-regional radiotherapy in women with breast cancer. Methods and Materials: Thirty consecutive patients with breast resection underwent clinical, lung function, radiographic, and thoracic high-resolution computed tomography evaluation before and at 1, 3, 6, and 12 months after adjuvant radiotherapy. Chemotherapy was also administered to 15 patients. Results: Nineteen patients reported mild respiratory symptoms at 1 month, which resolved completely at 6 months after radiotherapy. Opacities were present on 80% of chest radiographs and in all patients on highresolution computed tomography by 3 months. These opacities became compact and persisted on high-resolution computed tomography at 12 months. Lung function indices, including FEV1, FVC, TLC, and DLCO, progressively declined after radiotherapy, and was irreversible at 12 months (p < 0.05). Patients who received chemotherapy did not have significantly different lung function indices compared with their counterparts at all time points (p > 0.05). Conclusions: Our results have shown that adjuvant loco-regional radiotherapy, a common practice in breast cancer treatment, is associated with irreversible reduction in lung function parameters. These changes are accompanied by radiological evidence of persistent lung injury. Further studies should be performed to evaluate the incidence and long-term pulmonary sequelae of current treatment for breast cancer. © 2001 Elsevier Science Inc. Breast, Cancer, Loco-regional, Radiotherapy effects.
INTRODUCTION Breast cancer is the commonest female malignancy worldwide. Despite a 6.8% reduction in the breast cancer mortality rate due to recent advances in the management of the disease (1), there were over 40,000 breast cancer deaths in 1998 in the United States alone (2). Controlled trials over the last decades have revealed the benefits of adjuvant local breast irradiation after surgery, which has reduced the 10-year risk of local recurrence from 40% to 10% and the incidence of local recurrence from 18.4% to 2.3% (3, 4). Chemotherapy, on the other hand, reduces the rate of disease progression and is generally offered to patients who have a high risk of metastatic disease (5). These include the presence of large tumor size, highgrade histologic type, extensive lympho-vascular perme-
ation, involvement of axillary lymph nodes, and poor estrogen receptor status (5). Radiation lung injury is a recognized complication of radiotherapy (6 – 8), with two distinct clinical stages, namely radiation pneumonitis and fibrosis. These correspond pathologically to exudation and proliferation and chronic fibrosis in the lung parenchyma, respectively (9). Radiation pneumonitis classically occurs 4 –12 weeks after completion of radiotherapy and is often clinically silent, although patients might experience self-limiting dyspnea, cough, fever, and chest discomfort (9). Whereas some studies have addressed the effects of adjuvant radiotherapy on lung function parameters, the results have been inconsistent (10 –12), possibly due to the nonuniformity in follow-up, treatment protocol, patient population, and disease severity (10 –12). Studies of high-resolution computed tomography
Reprint requests to: Dr. Kenneth W. Tsang, M.D. (Hons), F.R.C.P. F.C.C.P. F.C.P., Associate Professor and Honorary Consultant Physician, University Department of Medicine, The University of Hong Kong, Room 302, New Clinical Building, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China. Tel: (852) 2855-4542; Fax: (852) 2855-1652; E-mail: [email protected] This study was supported by a Committee for Research and
Conference Grant (CRCG), the University of Hong Kong. Acknowledgments—The authors thank the patients for their participation in the study, the CT radiographers at Queen Mary Hospital for their cooperation, and Mr. Stanley Yeung, Department of Medicine, University of Hong Kong, for expert advice on statistical analysis. Accepted for publication 20 December 2000. 411
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(HRCT) features of radiation lung injury after breast irradiation suffer from a lack of concomitant lung function evaluation (13–15). The aims of this longitudinal study are therefore to evaluate the effects of regional lymph node and breast/chest wall irradiation (loco-regional radiotherapy) on lung function and radiologic parameters in breast cancer.
METHODS AND MATERIALS Patient recruitment and characteristics From May 1996 to June 1997, 30 consecutive women (mean age ⫾ SD [52 ⫾ 12 years]; range, 37–78 yr) with histologically confirmed breast cancer undergoing breast surgery within the previous month were recruited from the Department of Clinical Oncology at Queen Mary Hospital with written consent. Inclusion criteria included the presence of histologic evidence of breast cancer, female gender, age between 18 – 80 years, and normal lung function parameters. Exclusion criteria included history of respiratory diseases, previous administration of chemotherapy or radiotherapy, previous or concomitant malignancy, presence of respiratory symptoms for more than two weeks (cough, dyspnea, wheezing, chest pain, sputum production, or hemoptysis) within the previous 12 months, and presence of an abnormal chest radiograph. Twenty-five women underwent mastectomy, while 5 had lumpectomy performed. All patients had axillary dissection, except one woman with intraductal papillary carcinoma. Histologic typings were invasive ductal carcinoma (n ⫽ 22), mixed invasive ductal and lobular carcinoma (n ⫽ 4), intraductal papillary carcinoma (n ⫽ 1), medullary carcinoma (n ⫽ 1), invasive lobular carcinoma (n ⫽ 1), mucinous carcinoma (n ⫽ 1), and undifferentiated infiltrative carcinoma (n ⫽ 1). Breast cancer was staged according to the American Joint Committee on Cancer (16). There was 1 woman with Tis, 5 with T1, 23 with T2, and 1 with T3 disease. Node (N)-staging was N1 (n ⫽ 14) and N0 (n ⫽ 16). None of the patients had known distant metastases, i.e., M0, on routine screening and physical examination. Patients were evaluated before radiotherapy and at 1, 3, 6, and 12 months afterward. At each visit, respiratory symptom inquiry was performed using standardized questionnaire, lung function assessment, chest radiograph, and thoracic HRCT. Respiratory symptoms that were directly inquired about included sputum production, dyspnea (while walking on flat surface, hurrying up gentle slope, or hurrying up steep incline), hemoptysis, cough (dry or productive), and wheeze. The study was performed with the institutional ethics committee approval. None of these patients suffered from other concomitant respiratory illness or required regular medications other than tamoxifen at 20 mg daily (n ⫽ 17). Fifteen patients received chemotherapy. Of these, 12 patients had radiotherapy before or sandwiched between chemotherapy, and 3 patients had radiotherapy after completion of chemotherapy.
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Radiotherapy protocol All patients received loco-regional radiotherapy comprising opposing tangential chest wall and supraclavicular field irradiation, except one patient with intraductal carcinoma, who received only radiotherapy to the chest wall. Daily fractions of 200 cGy were given to the supraclavicular and tangential chest fields respectively, with a total dose of 5,000 cGy using 6/8 MV photon. The supraclavicular field was comprised of an anterior photon field with its lower border covering the head of ipsilateral clavicle (Fig. 1A). The prescription point was at the 95% isodose level. The chest wall and breast were irradiated with two tangential opposing fields (Fig. 1B). The superior border of the tangential fields was matched with the lower border of the supraclavicular field. The lower field border was at 1 cm below the mammary fold, guided by the opposite breast, if mastectomy had been performed. The medial border was set at midline, with no specific attempt to cover the internal mammary lymph nodes, while the lateral border was set at mid-axillary line. Wedges were used in the tangential field for compensation of the change of contour, and the dose was prescribed at 100% isodose level without correction for lung tissue. A boost dose of 1,000 cGy in 5 fractions was given by electron field (usually 6 MeV) to the original tumor site in patients who had lumpectomy performed. A separate field for internal mammary chain irradiation was not employed. The mean central lung depth, defined as the perpendicular distance from the posterior tangential field edge to the posterior part of the ribs through the isocenter, was 2.4 ⫾ 0.5 cm (range 2.1–3.2 cm). Chemotherapy regime Our center does not administer chemotherapy and radiotherapy concurrently. Patients with less than 4 involved axillary lymph nodes are considered as having moderate risk for development of distant metastases. For this group, radiotherapy was given either before or in a sandwiched fashion, between cycles of chemotherapy. Patients with more than 4 metastatic ipsilateral axillary lymph nodes are considered at high risk of developing distant metastases. They had chemotherapy completed before commencement of radiotherapy (17, 18). Patients with less than 4 malignant axillary lymph nodes were given CMF (oral cyclophosphamide, 150 mg daily for 14 days, methotrexate 40 mg/m2, D1 and D8 and 5-fluorouracil 600 mg mg/m2, D1 and D8, every 4 weeks for 6 cycles). Patients with more than 4 involved lymph nodes had anthracycline-based chemotherapy, either epirubincin for 4 cycles (80 mg/m2 every 3 weeks) followed by 6 cycles of CMF or FAC (5-fluorouracil 500 mg/m2 D1 and D8, adriamycin 50 mg/m2, D1 and cyclophosphamide 500 mg/m2, D1 every 3 weeks for 6 cycles). Tamoxifen, if prescribed postoperatively according to estrogen receptor–positivity of the breast cancer, was continued throughout the treatment period. Eleven patients in this series had adjuvant CMF, and 4 patients had anthracycline-based chemotherapy. One patient also received 3 courses of FEC (epirubincin, 80 mg/m2 replacing adriamy-
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Fig. 1. (A) Planning radiograph of supraclavicular field comprising anterior photon irradiation with lower border covering the ipsilateral clavicle; (B) A CT section at the planning plane of a patient receiving tangential field radiotherapy. Note opposed tangential beams (arrows).
cin in FAC) preoperatively for locally advanced carcinoma of the breast to downstage the disease before surgery (19).
radiographs and HRCT scans were used as baseline reference for each patient.
Lung function evaluation Lung function parameters were assessed using a Sensormedics Computerized Lung Function System 6300 according to the American Thoracic Society recommendation (20). Parameters assessed included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, total lung capacity (TLC), residual volume, and carbon monoxide diffusing capacity (DLCO). Measurements were expressed as percent predicted values after adjustment for age, gender, and height.
Data analysis Repeated-measures ANOVA was used to investigate the effect of radiotherapy and chemotherapy on lung function indices over time. The analysis was performed using Type III sum of squares provided for by SPSS (21). The baseline values were adopted as references. A p value of ⬍0.05 was taken as indicative of statistical significance. The MannWhitney test was used to evaluate differences in lung function changes between patients who had chemotherapy sandwiched between radiotherapy cycles and those who underwent chemotherapy either pre- or postradiotherapy.
HRCT and chest radiograph assessment Thoracic HRCT examination was performed on a single scanner (Hi-Speed Advantage, GE Medical Systems, Milwaukee, WI). The following protocol was used: 1-mm sections at 10-mm intervals with the patient in the supine position and in full inspiration. Images were reconstructed in bone algorithm and imaged at lung window settings (width/level; 1000/-700HU). HRCT images were evaluated together by two experienced radiologists to determine the presence and site of opacities. Chest radiographs were also reviewed for presence of opacities. Preradiotherapy chest
RESULTS Clinical data All patients were asymptomatic for respiratory diseases at baseline. When assessed at 1 month, 19 patients had developed respiratory symptoms that persisted at the 3-month visit. Of these, 8 patients reported dyspnea (2 while hurrying up a gentle slope, and 6 while walking up a steep incline), 7 (5 with dry cough, 2 with productive cough), 7 had chest discomfort, and 3 had sputum production. These symptoms were assessed subjectively by the patients to be
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Table 1. Lung function parameters in 30 patients with breast cancer who had adjuvant loco-regional radiotherapy Follow-up period after radiotherapy Parameters FEV1 FVC FEV1/FVC TLC DLC
Median (mean) [Interquartile range] Median (mean) [Interquartile range] Median (mean) [Interquartile range] Median (mean) [Interquartile range] Median (mean) [Interquartile range]
0 month
1 month
3 month
6 month
12 month
115 (110.7) [97–120] 116 (111) [102–121] 0.81 (0.81) [0.76–0.87] 108.0 (110.9) [95–125] 94 (93.8) [84–103]
102.5 (102.2) [90–114.8] 104.5 (102.8) [92.3–114] 0.80 (0.80) [0.76–0.84] 105 (103.9) [99–110.5] 85.5 (84.6) [78–91]
105 (101.5) [95.8–113.5] 103.5 (101.5) [92.8–114] 0.81 (0.82) [0.79–0.87] 103 (103.1) [95.8–113] 83.5 (83.2) [77.3–90.8]
106 (101.6) [90.3–111.8] 106 (102.3) [93.8–110] 0.79 (0.80) [0.76–0.84] 106.5 (101.7) [93–110.8] 83 (85.7) [76.3–92]
103 (99.6) [91.8–107.8] 101 (98.7) [90–111.3] 0.81 (0.81) [0.78–0.86] 98.5 (98.4) [91–107] 83 (83.3) [76.8–89.3]
Data shown are median (and mean) of percent predicted lung function except for FEV1/FVC ratio.
mild and did not require specific treatment. All respiratory symptoms resolved spontaneously by 6 months. The remaining 11 patients remained completely asymptomatic throughout the follow-up period. Lung function parameters Table 1 summarizes lung function parameters in the 30 patients. There was a significant reduction in all lung volume indices (FEV1, FVC, TLC) and DLCO after radiotherapy (Fig. 2). FEV1 showed a decreasing trend over 12 months (p ⬍ 0.001), with significant decreases at 1, 3, 6, and 12 months after radiotherapy compared with baseline values (p ⬍ 0.001, ⬍0.001, ⬍0.001, and 0.01, respectively). FVC also displayed a similar trend of decreasing lung function over the study period (p ⬍ 0.001), with significant decreases at all time points of assessment compared with baseline values (p ⫽ 0.003, 0.002, 0.001, and 0.001, respectively). Although TLC displayed an overall reducing trend (p ⫽ 0.04) over the study period, the reductions compared to baseline values were only significantly reduced at 6 and 12 months (p ⫽ 0.03 and 0.04, respectively) after treatment. DLCO showed a significant reducing trend within the study period (p ⫽ 0.009) and was significantly reduced from baseline levels at 1, 3, and 12 months after radiotherapy (p ⫽ 0.005, 0.003, and 0.004, respectively). No significant difference was found at 6 months (p ⫽ 0.17). Patients who received chemotherapy did not have significant differences in lung volume parameters (including DLCO) when compared with their counterparts over the assessment time points (p ⬎ 0.05, data not shown). There were also no statistically significant differences in lung function changes between patients who received chemotherapy sandwiched with radiotherapy and those who received chemotherapy either before radiotherapy (Table 2). Appendix 1 summarizes the lung function changes between these different groups of patients. HRCT and chest radiograph assessment The chest radiograph and HRCT findings are summarized in Table 3. Opacities were detected on chest radiographs in
9 (30%) patients at 1 month, 24 (80%) patients at 3 months, and 26 (87%) patients at 6 and 12 months after radiotherapy. The chest radiographs of 2 patients remained normal throughout the study period. Supraclavicular field changes were evident in the apex of the ipsilateral upper lobe (Fig. 3A), while tangential field changes were found in the ipsilateral right middle lobe or lingula. Early changes (at 1 month) were more readily observed on HRCT scans than on chest radiographs. HRCT scans were also more sensitive in recording tangential field changes compared with chest radiographs (Table 1). HRCT detected air-space opacities (Fig. 3B) in 27 patients at 1 month postradiotherapy and in all 30 patients by 3 months. These opacities became more compact with time and persisted in all 30 patients at 12 months (Fig. 3C). The appearance and compaction of these opacities on sequential HRCT examinations were concordant with the rapid decline in lung volume in the early postradiotherapy period. Their persistence at 12 months was also in accordance with the lack of recovery of lung volume by the end of the study period. DISCUSSION The results of this longitudinal study show significant gradual reduction in lung volume indices (FEV1, FVC and TLC) and DLCO over a 12-month period in patients who underwent loco-regional radiotherapy for breast cancer. Administration of chemotherapy appeared to have no deleterious effect on lung function parameters. In addition, radiologic evidence of sequential radiation lung changes were documented one month after radiotherapy and persisted in all patients one year later. Radiation fibrosis classically follows radiation pneumonitis, although the former has been reported without previous pneumonitis (8, 14, 22). Our documentation on HRCT of sequential parenchymal opacities developing from the acute through to the chronic phase of radiation lung injury has refuted the existence of a delayed and independent second phase. This under-recognition of lung changes might have been due to under-utilization of HRCT in the past. There are recognized risk factors for developing radiation
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Fig. 2. Graphs depicting sequential changes (% predicted) from baseline values of (A) FEV1, (B) FVC, (C) TLC, and (D) DLCO after radiotherapy over the course of 12 months. There was marked decline of FEV1, FVC, and TLC within the first 3 months after radiotherapy; thereafter the decline became more gradual. For DLCO, the trough value was reached earlier, at 1 month postradiotherapy, after which the decline became a plateau.
lung injury. These include volume of lung irradiated, total radiation dose, radiation dose rate (fractionated regimes are better tolerated than single large doses), and administration of chemotherapy (22–24). Bilateral lung irradiation, particularly the mid and lower zones, and the use of lateral or oblique multidirectional ports are associated with severe radiation pneumonitis (23). The current practice of using tangential ports to minimize radiation lung damage has reduced the incidence of radiation pneumonitis from 60% to 7% (25). There is no consensus in the current literature on the effects of radiotherapy on lung function parameters, and available studies do not evaluate clinical, physiologic, and radiologic parameters concomitantly (10 –12, 26 – 28). Some of these studies lack longitudinal data, and most did not include radiologic assessment. There is, however, some evidence to suggest that there may be subtle differences in the effects of radiotherapy between patients who have been given only local radiotherapy to the breast and those who have received local and regional
lymph node (loco-regional) irradiation (11, 28). Reversible reduction, ranging from 3–22%, in FEV1, FVC, FEV1/FVC, and DLCO have been reported 3 to 4 months after adjuvant local radiotherapy (12, 26). In contrast, irreversible lung function impairment after adjuvant loco-regional radiotherapy has also been reported in breast cancer (10, 11, 27, 28). In one study of 144 women with Stage II breast cancer who had either loco-regional or local radiotherapy, significant statistical but not clinical reduction (3–5%) in DLCO, FEV1, and VC were observed only in women who underwent loco-regional radiotherapy, but not local radiotherapy (10). Similar findings were also found in another comparative study in which there was a twofold increase in incidence of pulmonary symptoms in the loco-regional group compared to no functional impairment in the local radiotherapy cohort (28). Our data confirm that loco-regional radiotherapy is associated with increased incidence of radiation lung injury and irreversible lung function impairment (10 –12,
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Table 2. Differences in lung function changes over time between patients with chemotherapy sandwiched with radiotherapy (Group 1, n ⫽ 12) and those with chemotherapy after radiotherapy (Group 2, n ⫽ 3). Median, interquartile ranges and p values are shown. Follow-up period after radiotherapy 0 month Parameters FEV1 median (Interquartile p value FVC median (Interquartile p value TLC median (Interquartile p value DLCO median (Interquartile p value
Group 1
1 month
Group 2
106.5 range) 88–120.8
Group 1
119 84.5–124 0.77 106.5 120 range) 97.5–116.8 97–125 0.42 95 110 range) 90.5–109.3 98–124 0.30 89.5 86 range) 82.8–104.8 82.5–100.5 0.77
3 month
Group 2
Group 1
101 86–116.5
106 81–122 0.78 107 114 89.5–116.5 86–120 0.71 103 97 86.5–112 82–114 0.78 85 85 72.5–91 81–96 0.71
Group 2
100 80–112
116 87–121 0.13 103 116.5 77–105 86.8–121.5 0.19 92.5 113 80.3–103.5 83.3–124.8 0.44 81 81.5 69.5–84.8 67.5–85.8 0.93
6 month Group 1
Group 2
91 109 78.5–108.5 102.5–111.8 0.17 93 109 77.5–112 108.3–109.8 0.17 93 112.5 81–108 96–117 0.09 84 79 70.5–95.5 76.3–81.8 0.76
12 month Group 1
Group 2
97 78.5–107
102.5 83.3–109.8 0.49 98 101 76–114 81.5–109.3 0.35 91 102.5 83.5–103.5 80–123.5 0.35 81 86 75.5–90 77.8–89.8 0.64
Group 1: 12 patients with radiotherapy instituted in a sandwiched fashion between cycles of chemotherapy. Group 2: 3 patients with chemotherapy instituted after radiotherapy.
Although there have been studies documenting synergistic or potentiating toxicity effects of chemotherapy in the lung after radiotherapy in thoracic malignancies, including breast cancer (10, 27, 30 –33), chemotherapy in our study did not adversely affect lung function. Blomquist et al. reported a sixfold increase in symptomatic radiation pneumonitis in patients with breast cancer who had both chemotherapy and radiotherapy, compared to those who were given radiotherapy alone (33). Concurrent chemotherapy and radiotherapy for breast cancer have also been reported to be associated with increased incidence of radiation pneumonitis compared with sequential chemotherapy and radiotherapy (27). Our patients had chemotherapy delivered sequentially with radiotherapy. There were no women who received concurrent chemotherapy and radiotherapy. However, the discrepancy between our results and those of other studies may also be related to the type of cytotoxic used. Our chemotherapy protocol largely utilized combinations of cyclophosphamide and 5-fluorouracil together with methotrexate, which are less likely to induce pulmonary toxicity. We did not use high-dose chemotherapy or cytotoxics such as carmustine and ftorafur, which are
26 –28). What distinguishes our study from others is the concomitant radiologic and lung function assessment, which showed serial lung changes occurring in tandem with reductions in lung function indices. Lung volume parameters appear to be the most vulnerable, and the resultant restrictive defect is probably due to reduced elasticity in both the irradiated lung parenchyma and chest wall (26, 29). Irreversible reduction in DLCO capacity, reported after both local and loco-regional radiotherapy, is probably due to persistent interstitial damage after the initial pneumonitis phase. It is interesting to note that although the incidence of respiratory symptoms reported in our cases in the early postradiotherapy period was high (63%), these were mild and self-limiting, with resolution occurring at 12 months post-treatment. Direct inquiry into patients’ respiratory status at baseline and subsequent visits may have led to increased sensitivity to and over-reporting of acute phase symptoms, whether real or otherwise. The resolution of these symptoms, despite persistent reduction in lung volume parameters 12 months later, would reflect the compensatory effect of residual areas of normal lung reserve in these otherwise fit women.
Table 3. Chest radiograph and high-resolution computed tomography assessment of 30 patients with breast cancer who received adjuvant loco-regional radiotherapy Number of patients with abnormalities 1 month
3 months
6 months
12 months
Abnormality
CXR
HRCT
CXR
HRCT
CXR
HRCT
CXR
HRCT
Opacities Supraclavicular field changes Tangential field changes
9 9 4
27 26 15
24 20 11
30 29 27
26 23 11
30 29 28
26 23 3
30 27 28
Abbreviations: CXR ⫽ chest radiograph; HRCT ⫽ high-resolution computed tomography.
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Fig. 3. A 58-year-old woman with invasive ductal carcinoma of the left breast treated with simple mastectomy and adjuvant loco-regional radiotherapy. (A) Chest radiograph at 1 month after radiotherapy shows consolidation in the left lung apex corresponding to the supraclavicular field. (B) High resolution computed tomography (HRCT) scan at 1 month shows acute radiation pneumonitis in the tangential field (ipsilateral anterior segment of the left upper lobe), which was not obvious on the chest radiograph. (C) Fibrosis (arrows) is noted on the HRCT scan performed 1 year later.
associated with increased lung toxicity and in some cases have caused premature termination of radiotherapy (32– 34). In conclusion, our data suggest that adjuvant locoregional radiotherapy in breast cancer led to a significant reduction in lung function parameters, with no additional adverse effects arising from adjuvant chemotherapy. This paper has also presented concomitant radiologic evidence of a high incidence of radiation lung injury as a consequence of loco-regional radiotherapy. Although patients with normal lungs before treatment would have adequate
lung reserve to compensate for the radiation injury, treatment may cause problems for patients with pre-existing lung disease who have compromised lung function. Radioprotectors such as amifostine may be useful (35), and we are currently planning a trial to test the efficacy of amifostine in reducing pulmonary radiation toxicity. For women with pre-existing lung disease who are being considered for adjuvant loco-regional radiotherapy for breast cancer, the potential risk should be discussed; serial lung function tests and thoracic HRCT after treatment would be useful for monitoring.
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