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© 1999 American Society for Clinical Oncology Effect of Radiotherapy and Chemotherapy on Pulmonary Function After Treatment for Breast Cancer and Lymphoma: A Follow-Up StudyFrom the Departments of Radiotherapy, Nuclear Medicine, and Chest Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Amsterdam, the Netherlands. Address reprint requests to J.V. Lebesque, MD, PhD, Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; email jlebes{at}nki.nl
PURPOSE: To determine the changes in pulmonary function tests (PFTs) 0 to 48 months after treatment for breast cancer and lymphoma. PATIENTS AND METHODS: The alveolar volume (VA), vital capacity, forced expiratory volume in 1 second, and corrected transfer factor of carbon monoxide (TL,COc) were measured in 69 breast cancer and 41 lymphoma patients before treatment and 3, 18, and 48 months after treatment with radiotherapy alone or radiotherapy in combination with chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine; cyclophosphamide, epidoxorubicin, fluorouracil; cyclophosphamide, thiotepa, carboplatin; cyclophosphamide, methotrexate, fluorouracil). The three-dimensional dose distribution in the lung of each patient was converted to the mean lung dose. Statistical analysis was used to evaluate the changes in PFT values over time in relation to age, sex, smoking, chemotherapy, and the mean lung dose. RESULTS: After an initial reduction in PFT values at 3 months, significant recovery was seen at 18 months for all patients. Thereafter, no further improvement could be demonstrated. Reductions in spirometry values and VA were related to the mean lung dose only (0.9% per Gy at 3 months and 0.4% per Gy mean dose at 18 months). TL,COc decreased 1.1% per Gy mean dose and additionally decreased 6% when chemotherapy was given after radiotherapy. Chemotherapy administered before radiotherapy reduced baseline TL,COc values by 8% to 21%. All patients showed an improvement of 5% at 18 months. CONCLUSION: On the basis of the mean lung dose and the chemotherapy regimen, the changes in PFT values can be estimated before treatment within 10% of the values actually observed in 72% to 85% of our patients with healthy lungs.
THE LUNG IS ONE of the major dose-limiting organs for radiotherapy within the thorax. Therefore, the total dose that can safely be delivered to patients with malignant tumors in the thoracic cavity has to be limited because of the risk of radiation pneumonitis (developing 1 to 6 months after treatment) and radiation fibrosis (developing from 6 months onward). The probability and severity of early and late pulmonary damage primarily depends on the radiation dose and the irradiated volume,1 although some other biologic factors (eg, additional chemotherapy,2-5 smoking,4,6,7 and pretreatment pulmonary function8) may play a role as well. Knowledge of the relation between the dose-volume parameters and normal tissue damage, as well as the influence of biologic factors, is necessary when choosing the optimal treatment plan. Several authors have described empiric9 and biologic10-12 models for estimating the probability of developing radiation pneumonitis, based on the irradiated volume and radiation dose of an individual radiotherapy plan. Other investigators have tried to correlate the reduction in pulmonary function after radiotherapy for lung cancer patients with the "perfused volume" of lung irradiated with a dose greater than 40 Gy.13-15 Until now, no consensus has been reached about which method and parameter values should be used to adequately predict the risk and severity of side effects after radiotherapy. The literature contains numerous reports of changes in pulmonary function after radiotherapy for breast cancer,16,17 malignant lymphoma,18-20 and lung cancer.15,21 Generally, a decrease in all pulmonary function parameters within the first 3 to 9 months after irradiation of the thorax has been described. Thereafter, the lung function may recover partially or completely, unless fibrosis develops.22 Some studies tried to assess the relation between pulmonary function changes and treatment- and patient-related factors. However, most of these studies were small, and the complete treatment plan was not taken into account. In a previous study,5 we analyzed the influence of patient- and treatment-related factors on the pulmonary function early (3 to 4 months) after irradiation for 81 patients treated for breast cancer and malignant lymphoma. A relationship between the (relative) reduction in pulmonary function and the mean radiation dose in the lung was observed. This relationship was influenced by biologic factors such as chemotherapy and, probably, smoking. In this article, we present the longer follow-up data (for up to 4 years after radiotherapy) for an extended data set of 110 patients with different treatment regimens. The aim of this report was to study whether the course in pulmonary function changes over time (alveolar volume [VA], vital capacity [VC], forced expiratory volume in 1 second [FEV1], and corrected transfer factor of carbon monoxide [TL,COc]) varied between the different treatment regimens and whether recovery of early pulmonary damage occurred. The second aim was to investigate whether the reduction in pulmonary function test (PFT) results 3 and 18 months after treatment could be estimated for an individual patient on the basis of the treatment parameters.
Patients Eighty-six patients with breast cancer and malignant lymphoma, who were described in previous publications,4,5 and 29 additional breast cancer patients were entered onto this study. Five patients were excluded from analysis as described previously4,5: three patients suffered from chronic obstructive pulmonary disease, one patient had lung infiltrates before radiotherapy started, and one patient refused to undergo the PFTs. The patient population included 25 male and 85 female patients, with a mean age of 44 years (range, 17 to 74 years). Thirty-one of 110 patients were cigarette smokers before radiotherapy and were defined as smokers. Of these smokers, five patients had stopped smoking between 0 and 18 months after the start of the study. Six different treatment groups could be distinguished. The characteristics of these groups are summarized in Table 1. The breast cancer patients were treated with radiotherapy alone (n = 16) or with combined-modality therapy (n = 53). Adjuvant chemotherapy consisted of six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) after radiotherapy, four to five cycles of cyclophosphamide, epidoxorubicin, and fluorouracil (FEC) before radiotherapy or four cycles of FEC and one cycle of high-dose cyclophosphamide, thiotepa, and carboplatin (CTC) followed by peripheral-blood stem-cell reinfusion before radiotherapy. The lymphoma patients were treated with radiotherapy alone (n = 18) or had chemotherapy (primarily six cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine [MOPP/ABV]) before irradiation (n = 23).
Breast cancer patients were irradiated with internal mammary node (IMN) fields only, tangential breast fields only, or IMN fields combined with tangential breast fields or locoregional fields (irradiation of the chest wall, sub- and supraclavicular regions, and the axilla) to a total dose of 40 to 50 Gy in fractions of 2.0 to 2.67 Gy (Table 1). The malignant lymphoma patients were primarily irradiated with mantle fields in case radiotherapy alone was given and with involved fields (ie, irradiation of the involved regions) in case chemotherapy was administered before radiotherapy (Table 1). The average prescribed dose (defined in the mediastinum) was 39 Gy (range, 30 to 42 Gy) for the patients treated with radiotherapy alone and 37 Gy (range, 25 to 42 Gy) for the patients treated with a combined modality. Twenty-four patients were irradiated on the para-aortic lymph nodes and spleen as well to an average prescribed total dose of 36 Gy (range, 24 to 40 Gy). The fraction size varied between 1.0 and 2.0 Gy. All treatment fields were treated with photons, except the chest wall (electrons) and the IMN fields (half photons, half electrons). PFTs were performed before, 3 to 4 months after, 18 months after, and 48 months after irradiation. In addition, for nine patients treated with CTC chemotherapy before radiotherapy, PFTs were performed after FEC and before CTC was administered. The first follow-up examinations at 3 to 4 months were performed in all 110 patients (Table 1). At 18 months, 31 patients were not available for follow-up: 12 patients received additional treatment for recurrent disease, eight patients refused further participation, and for 11 breast cancer patients treated with FEC or CTC chemotherapy, the follow-up time was too short at the time of analysis. Only lymphoma patients were observed for 48 months. Eighteen lymphoma patients were not available for 4 years of follow-up because recurrent disease was present (n = 12), further participation was refused (n = 4), or the follow-up time was too short (n = 2). The study was approved by the hospital's ethics committee, and all patients gave informed consent.
Pulmonary Function Tests
Dose Calculation
Statistical Analysis A repeated measurement analysis of covariance (RM-ANCOVA) was used to analyze whether the changes in PFT values over time (0 to 18 months) differed among patients treated with different treatment regimens. In the full RM-ANCOVA model, time-specific changes in pulmonary function (between 3 and 18 months after radiotherapy) were studied in relation to all of the patient- and treatment-related factors described above and pre-RT pulmonary function. Variables with P > .05 were eliminated backward from the RM-ANCOVA model. The chemotherapy factors (FEC, CTC, MOPP/ABV, and CMF) were regarded in a specific hierarchy to determine whether the impact of all of the different chemotherapy regimens were the same and could be described with one simple model. If this strategy failed, no structure between the chemotherapy regimens was assumed. Inclusion of the baseline value as a covariate, rather than evaluating the ratios from the values at 3 and 18 months, resulted in slope estimates from RM-ANCOVA of relative changes in PFT values versus mean lung dose that were approximately 0.2% steeper than those determined by linear regression analysis. One explanation for the steeper slope is that RM-ANCOVA adjusts for measurement error in the baseline value. To enable comparison with previous analyses,5 the slopes resulting from the regression analysis are quoted. A t test for paired observations was used to study the changes in PFT values between 18 and 48 months for the lymphoma patients. RM-ANCOVA calculations were based on the restricted maximum likelihood technique as implemented in the MIXED procedure of the statistical package SAS 6.12 for Windows 95 (SAS Institute, Cary, NC). For testing fixed effects, this program uses approximate type III F tests with approximate denominator degrees of freedom. No structure was assumed for the within-patients covariance matrix. On the basis of residual analyses, it was also allowed to differ between different groups of patients in some analyses. Paired analysis and regression analysis were performed using SPSS (Superior Performing Software Systems) version 6.1 for Windows 95 (SPSS Inc, Chicago, IL). P values were not adjusted for multiple comparisons, unless otherwise stated. When they were adjusted, the Bonferroni criterion was used.26
The mean values from two PFTs are shown in Fig 1 as a function of time for the six different treatment groups. We have presented the results for FEV1 and TL,COc only, because the amount of pulmonary damage and the course in pulmonary function changes were basically the same for VA, VC, and FEV1 and quite different for TL,COc. Baseline (pre-RT) values were, on average, between 95% and 110% of predicted for VA, VC, and FEV1 and, for TL,COc, between 70% and 100% of predicted. When the changes in VA, VC, and FEV1 over time were studied, two trends could be distinguished (Fig 1A and 1B, illustration for FEV1). The breast cancer patients showed almost no changes in PFT values over time (Fig 1A), whereas the lymphoma patients showed an initial reduction in PFT values 3 months after radiotherapy to approximately 80% of predicted and a partial recovery of pulmonary function at 18 months to 90% of predicted (Fig 1B). The changes in TL,COc over time were more complicated and seemed to be different for all six treatment regimens (Fig 1C and 1D). Significant changes in pulmonary function were only found at 3 and 18 months. Between 18 and 48 months, no significant changes in any PFT values were observed.
Mean Lung Dose
The relative reduction in TL,COc was equal to 1.1% per Gy mean lung dose at 3 months and was equal to 0.9% per Gy at 18 months (Table 3). This change in slope was not significant (RM-ANCOVA), in contrast to the lung-volume parameters.
Chemotherapy
For TL,COc, CTC and MOPP/ABV chemotherapy were clearly associated with low pre-RT TL,COc values (P < .001), but for FEC chemotherapy, the association was less evident (P = .03, adjusted P level using Bonferroni = .12). The pre-RT TL,COc values for patients treated with FEC, CTC, and MOPP/ABV chemotherapy were 8%, 21%, and 11% lower, respectively, in comparison to those for nonsmoking patients not treated with chemotherapy before irradiation (pre-RT TL,COc = 98% of predicted normal values; Table 4 and Fig 1C and 1D). For a subgroup (n = 9) of CTC patients, PFTs were also performed 2 months before radiotherapy, ie, after four cycles of FEC and before administration of high-dose CTC chemotherapy (Fig 1). After FEC chemotherapy, the baseline TL,COc value was lowered to 80% (SE, 4%) and a further decrease to 74% (SE, 3%; P = .02, paired analysis) was seen after administration of CTC chemotherapy (Fig 1C). No significant changes were seen for VA, VC, and FEV1 (Fig 1A, illustration for FEV1). This confirms that both FEC and CTC regimens were responsible for a decrease in TL,COc. In general, when chemotherapy and radiotherapy are combined, two different effects may occur: an interaction between both modalities, resulting in an enhancement of radiation-induced damage (ie, a change in slope) or an additional effect (ie, a change in offset). For the lung-volume parameters in our data set, neither an enhancement of radiation-induced injury due to chemotherapy (P range, .2 to .99) nor an additional effect of chemotherapy was seen (P range, .2 to .7) 3 and 18 months after treatment. This means that for all patients, irrespective of whether they were treated with additional chemotherapy, the changes in VA, VC and FEV1 were related to the mean radiation dose only. For TL,COc also, no evidence was found for an interaction between radiotherapy and chemotherapy, either 3 or 18 months after radiotherapy. However, at both time points, an additional effect of chemotherapy (pre-RT and post-RT chemotherapy), independent of the mean lung dose, was observed (Table 3). For patients treated with pre-RT chemotherapy (FEC, CTC, and MOPP/ABV), the relative decrease in TL,COc was smaller, compared with that for patients treated with radiotherapy alone (Fig 3). Because the magnitude of this chemotherapy effect was not found to differ between the pre-RT chemotherapy regimens (RM-ANCOVA), the average change in offset was presented (on average, 6.9% at 3 months and 12.2% at 18 months; Table 3). Post-RT chemotherapy (CMF) affected the TL,COc in the opposite direction: 3 months after radiotherapy, CMF patients had a 6.2% larger reduction in TL,COc than did patients treated with radiotherapy alone. At 18 months, an additional effect of CMF was no longer seen (Fig 3 and Table 3). RM-ANCOVA analysis, which was used to test the significance of the changes that occurred between 3 and 18 months, showed a significant improvement in TL,COc for all patients, irrespective of treatment regimen (5%; P < .0001).
Smoking, Age, and Sex
The results of this 4-year follow-up study show that the changes in VA, VC, and FEV1 over time are related to the mean lung dose only, whereas the changes in TL,COc are affected by chemotherapy as well. Furthermore, a partial recovery of pulmonary damage was seen from 3 to 18 months after treatment for all pulmonary function parameters that was larger for VA, VC, and FEV1 than for TL,COc. Thereafter, no further recovery was measured. In nonrandomized studies like this, no causal relationship can be proven definitely. Still it seems unlikely that treatment choice has been influenced by pulmonary function–related variables other than those used in this study (age, sex, and smoking). Therefore, statistical associations are interpreted as causal relationships. For all patients (irrespective of their treatment regimen), the mean lung dose (a combination of radiation dose and irradiated volume) is the most important predictor for changes in PFT values over time (P < .0001). Previously,5 we found that 3 months after radiotherapy, the relative decrease in lung function parameters was 1% to 1.1% per Gy mean lung dose for all patients. Inclusion of 29 additional breast cancer patients with different chemotherapy regimens in this study only slightly modified this relationship to 0.8% to 1.1% per Gy. At 18 months, a clear recovery of radiation-induced pulmonary damage was seen for VA, VC, and FEV1 (from approximately 0.9% at 3 months to approximately 0.4% per Gy mean lung dose), whereas the improvement in TL,COc was only small (5%). Because the mean lung dose for breast cancer patients was very low (approximately 6 Gy), only very small changes in lung-volume parameters over time were seen (Fig 1A), comparable to those in other studies.27,28 When the irradiated volume increased, the reduction in PFT values also increased.16,29 The pattern of PFT changes for the lymphoma patients were in accordance with other studies,18-20,30-32 which reported a transient decline in lung-volume parameters (VA, VC, and FEV1) of between 5% and 20%, 1 to 8 months after irradiation, with a partial improvement after 1 or 2 years.18,19,30-34 Late follow-up studies (5 to 18 years after radiotherapy)19,35-38 reported values between 85% and 95% of baseline function, which are in agreement with our 4-year results (90%). This suggests that a small but significant impairment in lung-volume parameters remains at long-term follow-up. The decrease in TL,COc is, in general,30,36,38 proportional to the decrease in lung-volume parameters in the first 3 months after mantle field irradiation, with no or only minimal recovery thereafter. Some series19,30 reported that the improvement in PFT values over time was primarily confined to the subset of lymphoma patients with regression of mediastinal tumors. In our patient group, tumor regression between 0 and 18 months after radiotherapy (scored on CT-thorax) was present in 11 of the 41 lymphoma patients. The course of pulmonary function was similar for the patients with and without tumor regression, indicating that regression of mediastinal tumor did not influence our results. In line with the findings of other authors,39-41 chemotherapy (regardless of the type of drug) primarily affected the diffusion capacity, whereas the lung-volume parameters were primarily unaffected. For all patients treated with chemotherapy before radiotherapy, low baseline TL,COc values were observed. However, the baseline values of breast cancer patients treated with FEC and high-dose CTC chemotherapy were much lower than those for patients treated with FEC chemotherapy alone (77% and 90%, respectively; Fig 1C). This may be attributed to the higher cyclophosphamide dose in the CTC regimen, compared with the FEC regimen (8 g/m2 v 2.5 g/m2). A dose-dependent increase in breathing rate due to cyclophosphamide has also been reported in animal studies.42,43
For lymphoma patients, lower baseline values might be due to MOPP/ABV treatment or to mediastinal tumors. However, after exclusion of the patients with mediastinal tumors (22 of 41) in our study, an effect of MOPP/ABV still seems to be present for all PFTs (lung-volume parameters, P When chemotherapy is combined with radiotherapy, time interval and sequence between both treatment modalities seems to play an important role. In animal studies, Von der Maase et al43 reported a strong radiation-modifying effect when the time interval between various drugs and radiotherapy was shorter than 28 days, whereas no interaction was observed when this interval was longer. In our study, no enhancement of radiation-induced pulmonary damage was seen for the lung-volume parameters or for TL,COc, which may be explained by the fact that time between chemotherapy and radiotherapy was rather long (usually between 1 and 2 months). Consequently, interaction effects were not to be expected. An additional effect of chemotherapy (independent of the radiation dose) was only seen for the TL,COc parameter. The extra reduction in TL,COc for CMF patients 3 months after irradiation (6%, post-RT chemotherapy) could be explained by a pure additive effect of chemotherapy and radiotherapy. Patients treated with pre-RT chemotherapy showed less reduction in TL,COc (-7%), probably because they may recover from the lowered pre-RT TL,COc values, which we ascribed to chemotherapy damage. Between 3 and 18 months, it was not possible to show differences in recovery between the different patient groups, so we cannot decide whether the improvement in TL,COc of 5% is due to a recovery of the chemotherapy effect, the radiotherapy effect, or both. Although MOPP/ABV chemotherapy influenced all baseline lung function parameters, no recovery was seen at 3 months for the lung-volume parameters. Other lymphoma studies did not report an additional effect of chemotherapy on VA, VC, and FEV1 at any time point after radiotherapy.19,20,34,36,38,44 As expected,45,46 the baseline TL,COc values were lower for smokers, compared with nonsmokers. The decrease in PFT values 3 months after treatment was not different between smokers and nonsmokers, although a borderline effect was found for VA both in this analysis and in the previous analysis.5 There are some indications that smokers experience less pulmonary damage early after irradiation,4,7 which might be attributed to a disorder in their immune response.6 We did not find differences between smokers and nonsmokers with respect to the amount of late pulmonary damage (18 months after radiotherapy) and the recovery from radiation-induced pulmonary injury. For all patients, the reduction in VA, VC, FEV1, and TL,COc can be estimated up to 18 months after irradiation on the basis of the mean lung dose, the chemotherapy regimen, and the pre-RT value (Tables 2 and 3). Using the parameters in Tables 2 and 3, the changes in PFTs over time can be predicted within 10% of the values actually observed in 72% to 85% of the patients. The accuracy of these predictions is acceptable, because the reproducibility of the PFTs are generally considered to be between 5% and 10%.23 An advantage of using the mean lung dose as a predictor for pulmonary changes is that this parameter can be calculated relatively easily. Moreover, more advanced methods, such as the parallel functional subunit model by Niemierko et al11 did not reveal better predictions5 so far. One comment should be made. When using the mean lung dose, one implicitly assumes that each part of the lung contributes equally effectively to the overall lung function. Although this assumption seems to be valid for breast cancer and lymphoma patients with healthy lungs, this may not be the case for patients with preexisting pulmonary disease and intrapulmonary tumors, because local pulmonary function (ventilation and perfusion) in these patients is not uniformly distributed throughout the lungs. The application of the mean lung dose in these patients might therefore not be adequate for the prediction of pulmonary function loss, although we showed47 that the mean lung dose could be used to predict the incidence of radiation pneumonitis. Marks et al8 demonstrated that for patients with low baseline values (< 60% of predicted), due to chronic obstructive pulmonary disease or tumor, for example, the relationship between pulmonary damage and irradiation dose and volume was not as good as that for patients with "good" baseline values (> 60% of predicted). In addition, other chemotherapy regimens and other factors, such as transforming growth factor-beta level,48 for example, might affect the changes in pulmonary function after radiotherapy as well. In conclusion, a partial recovery in pulmonary function was seen between 3 and 18 months after treatment for all patients. For VA, VC, and FEV1, this improvement was large and could be attributed to a recovery from radiotherapy damage. For TL,COc, only a small improvement was seen, which did not depend on the treatment regimen. From 18 months onward, no further changes were seen for the lymphoma patients. Early and late reduction in VA, VC, and FEV1 could be estimated before radiotherapy for all patients on the basis of the mean radiation dose only (0.9% per Gy and 0.4% per Gy, respectively), whereas the reduction in TL,COc is influenced by chemotherapy as well. The impact of chemotherapy depends on the sequence in which chemotherapy and radiotherapy are given. Chemotherapy given before radiotherapy reduces the baseline TL,COc values, whereas chemotherapy after radiotherapy is responsible for an extra reduction in TL,COc 3 months after treatment.
Supported by the grant no. NKI 94-819 from the Dutch Cancer Society. The authors thank Dr H. Bartelink and Dr B. Mijnheer for their critical reading of the manuscript; A. Wagenaar, who assisted in processing the data; M. Meyer, who performed the pulmonary function tests; and E. Damen, for continuous support and useful discussions.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
), CMF after radiotherapy (•), FEC (
) or CTC before radiotherapy (
) and lymphoma patients (— —, B and D) treated with radiotherapy alone (
) or MOPP/ABV before radiotherapy (
).
PFTs) 3 and 18 Months After Radiotherapy
) and 18 months (
.05; TL,COc, P = .03). 
