Abstract
Background: The frequency and grade of pulmonary complications after radiotherapy for breast cancer are still debated. This study evaluated changes in pulmonary function tests (PFTs) after radiotherapy in women with breast cancer. Patients and Methods: Thirty-five consecutive eligible women with breast cancer underwent pulmonary function testing before and 3 months after adjuvant radiotherapy. Twenty-one of them also received chemotherapy. Results: A significant decrease of forced vital capacity, forced expiratory volume in one second and carbon monoxide diffusing capacity was observed in the women treated with locoregional adjuvant radiotherapy and chemotherapy, whereas no decrease of the above parameters was evidenced in women treated exclusively with local adjuvant radiotherapy. Conclusion: Local adjuvant radiotherapy is not associated with any reduction in lung function parameters, however, locoregional adjuvant radiotherapy combined with chemotherapy shows a significant reduction in PFTs 3 months after radiotherapy completion.
Abbreviations: PFTs: pulmonary function tests; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 second; MMEF25-75: maximum midexpiratory flow; VO2max: maximal oxygen consumption; DLCO: carbon monoxide diffusing capacity; ROS: reactive oxygen species.
Breast cancer is the most common malignancy affecting women and its incidence is increasing by 1% per year. Nowadays it is often detected at an early stage and it is often managed with surgery, radiotherapy and systemic chemotherapy. Radiotherapy has an important role in treating breast cancer by optimizing locoregional control and survival (1-7). Chemotherapy, on the other hand, reduces the rate of disease progression and is generally offered to women who have a high risk of metastatic disease, including those with large tumor size, high-grade histological type, involvement of axillary lymph nodes, extensive lymphovascular permeation and negative estrogen receptor status.
During radiotherapy with tangential fields, a small portion of the underlying lung is typically included within the radiation field and this may result in lung tissue injury. Pulmonary complications are related to factors such as lung volume irradiated within the tangential field (8-10), involvement or not of supraclavicular field (11-13), radiotherapy techniques (14, 15), smoking habits (16, 17), age (15), preradiotherapy lung functional level (15), prior chemotherapy (9, 18, 19) and the use of concurrent tamoxifen (20). The frequency and grade of pulmonary complications following radiotherapy for breast cancer are, however, still debated.
It is well known that radiation lung injury typically presents with two distinct clinical stages, namely radiation pneumonitis and fibrosis (7, 21, 22). Radiation pneumonitis is early damage of the cells in the alveolar space progressing to an acute exudative inflammation process, which occurs within 4-12 weeks after radiotherapy completion. Pulmonary fibrosis is a late injury that can take months to years to evolve and is characterized by progressive fibrosis of the alveolar septa and pleura as well. Radiation pneumonitis can be clinically silent, although some patients may experience cough, dyspnea, fever, and chest discomfort (23). These alterations can regress to complete restitution or evolve into fibrosis when present in a more severe grade.
Pulmonary complications of treatment of breast cancer are related to several factors such as total radiation dose, radiation dose rate and the administration of chemotherapy (24-26). In this study, possible acute changes in pulmonary function tests (PFTs) after radiotherapy in women with breast cancer that would represent possible radiation lung injury were analyzed.
Patients and Methods
Patients. Thirty-five consecutive eligible women presenting with breast cancer were treated with postoperative radiotherapy after breast-conserving surgery or mastectomy depending on the stage. Of these 35 women, 21 had undergone chemotherapy. Laterality was the left breast for 16 women and the right breast for 19 women. Twenty-three were given 56 Gy to the thoracic wall after mastectomy and 12 were given 58 Gy after breast-conserving surgery. Fourteen were given 50 Gy to the supraclavicular fossa due to infiltrated axillary lymph nodes.
The eligibility criteria included histologically proved breast cancer, female gender, age 32-82 years, stage IIIA or less. The exclusion criteria included concomitant malignancies, a history of chronic respiratory disease or the presence of respiratory symptoms one month before PFT evaluation. All the women were clinically assessed as having no registered respiratory symptoms of cough, dyspnea or fever, nor respiratory symptoms judged by the clinician to be caused by radiotherapy.
The study was approved by the Ethics Committee of the University Hospital of Patras. A written informed consent was obtained from the patients before inclusion in the study.
Radiotherapy. All the 35 women were simulated with a Philips conventional simulator with the patients lying supine with their ipsilateral arms raised above the head. All the women were treated with a Linear Accelerator (ELEKTA ex-Philips SL 75-5) using 6 MeV photon beam. Opposed tangential 6 MeV photon fields 58 Gy in total, in 2 Gy daily fractions 5 days per week were applied to the entire breast in the patients with breast conserving surgery. Fifty-six Gy in 2 Gy daily fractions 5 days per week were applied in the women with mastectomy. The women with infiltrated axillary lymph nodes had also been given 50 Gy to the axillary and supraclavicular fossa. The upper margin of the field was placed at the 2nd or 3rd intercostal space and the inferior margin was drawn 1 cm below the breast fold. The median margin included the internal mammary field and the lateral margin was placed at the midaxillary line. Both the lungs and the heart were delineated as organs at risk.
Chemotherapy. Twenty-one women had undergone adjuvant chemotherapy that was completed 4-6 weeks before radiotherapy. Of these, 6 had been given chemotherapy with anthracycline-containing regimens (farmorubicin, adriamycin), 13 had been given chemotherapy with anthracycline- and taxane-containing regimens (farmorubicin, adriamycin, taxol, taxotere) and 2 had been given non-anthracycline-, non-taxane-containing regimens (cyclo-phosphamide, methotrexate, 5-fluorouracil). All of the above women received at least 6 cycles of these regimens.
PFTs. All the women underwent PFTs consisting of forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum midexpiratory flow (MMEF25-75), maximal oxygen consumption (VO2max), and carbon monoxide diffusing capacity (DLCO). The measurements were performed before radiation therapy and three months after completion, by the same pneumonologist, using the same device (PFTs: ZAN-GPI 300, nSpire Health Inc, Longmont, CO, USA; VO2max: Power Cube, Ganshorn Medizin Electronic GmbH, Niederlauer, Germany).
FVC is a measure of lung volume, FEV1 reflects the mechanical properties of large and medium-size airways, MMEF25-75 is the average expiratory flow over the middle half of the FVC and is regarded as a more sensitive measure of small airway (bronchioles) narrowing than FEV1, VO2max is the maximum capacity of the body to transport and utilize oxygen during incremental exercise (which reflects the physical fitness of the person) and DLCO represents the diffusing capacity through the alveolar-capillary barrier. All the above parameters are reduced in cases of pulmonary fibrosis.
Statistical analysis. The data were analyzed using SPSS 15.0 for Windows (SPSS, Chicago, IL, USA) and the comparison of variables between groups was performed with paired t-tests after checking data for normality. The significance level was set at p=0.05.
Results
Specific demographic characteristics, histological types and staging of the breast cancer, as well as the chemotherapy regimens in the study population are presented in Table I.
Comparison of the baseline PFT measurements and those obtained after treatment are presented in Table II. A significant decrease of post-treatment FVC, FEV1 and DLCO was observed (Table II).
In Table III, the PFT measurements before and after treatment in the local radiotherapy and the locoregional radiotherapy and chemotherapy subgroups are presented. A significant decrease of FVC, FEV1 and DLCO was observed in the patients treated with radiotherapy and chemotherapy, whereas in the patients treated exclusively with local radiotherapy, post-treatment PFTs were not significantly affected (Table III, Figure 1).
Discussion
To our knowledge this was the first study investigating pulmonary function changes in breast cancer patients in relation to local radiotherapy or local radiotherapy and adjuvant chemotherapy with or without locoregional radiotherapy, and the first time that MMEF25-75 and VO2max measurements have been included.
In the entire study population, a reduction of the FVC, FEV1, DLCO was observed at three months after treatment (Table II). However, no deterioration of FVC, FVE1 nor DLCO was observed in the subgroup of women who had undergone only local adjuvant radiotherapy (to the breast or to the thoracic wall), while a statistically significant decrease was detected in the subgroup of women who received adjuvant chemotherapy with or without additional radiotherapy to the supraclavicular fossa (Table III). None of them, however, had respiratory symptoms, i.e. cough, dyspnea, fever or chest pain.
Other studies have also shown differences in the effects of radiotherapy between patients receiving only local radiotherapy and those who received local and regional lymph node irradiation (27-29). The combination of chemotherapy and radiotherapy can increase the extent of pulmonary injury and the time interval between these treatment modalities (6, 18, 29-31), although the exact mechanism(s) are not fully understood (32-36).
In the present study the decrease of DLCO may reflect interstitial damage due to inflammatory infiltrates, with impairment in diffusion capacity of the alveolar membrane leading to restrictive lung injury in the women who had undergone chemotherapy. DLCO is, in fact, one of the most sensitive variables of pulmonary function changes due to drug-induced toxicity (37) Furthermore, the decrease of FVC and FEV1, but the unchanged relationship between them may also indicate restrictive lung injury explained by the fact that changes in FVC and FEV1 may reflect an acute exudative process in the alveolar space. Moreover, MMEF25-75 deterioration might represent damage to bronchioles evolving to obstructive lung disease, but since MMEF25-75 was not significantly affected, the probability of restrictive lung injury was strengthened. VO2max is an indicator of the physical fitness of a person and the fact that it remained unchanged indicated that although FVC, FEV1 and DLCO decreased, this result did not reflect any clinical symptoms most probably because the healthy lung compensated for the radiation lung injury. A very important factor for the reduction of PFTs following radiotherapy was the inclusion of supraclavicular fossa irradiation explained by the fact that a larger lung volume was irradiated.
Although this study was based on a relatively small number of patients with a short follow-up period, its possible implication is that any studies evaluating the effects of radiotherapy regimens (particularly hypofractionation-accelerated or partial breast irradiation) on lung function should include a detailed study of PFTs. Another possible implication is that since asymptomatic patients can have abnormal PFTs, the follow-up of women who have undergone radiotherapy and chemotherapy should include PFTs for the early detection of late pulmonary injury.
Prolonged follow-up of these patients and an increase in the sample size is intended, so that some general conclusions about the potential clinical value of PFTs in women diagnosed with breast cancer and particularly the possible association of FVC, FEV1, MMEF25-75, DLCO, VO2max and late lung injury, may be drawn.
- Received March 9, 2009.
- Revision received June 22, 2009.
- Accepted July 8, 2009.
- Copyright © 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved