Hodgkin's disease

Study objectives: To investigate whether mantle radiotherapy (MRT) for the lung, through its proinflammatory effects, can induce an increase in airway responsiveness.

Design: Follow-up of the changes in lung function and methacholine responsiveness in patients 1, 6, 12, and 24 months after they underwent MRT.

Patients: Thirteen nonasthmatic patients with bulky Hodgkin's lymphoma who were scheduled for MRT.

Measurements and results: Chest radiographs, lung function tests, methacholine thresholds of the bronchi (the provocative dose of methacholine causing a 10% fall in [FEV.sub.1] [[PD.sub.10]]) and central airway (the provocative dose of methacholine causing a 25% fall in the maximal mid-inspiratory flow [[PD.sub.25][MIF.sub.50]]), and the provocative dose of methacholine causing five or more coughs (PDcough) were serially assessed. One month after patients underwent MRT, there were significant decreases in [PD.sub.10] (mean [[+ or -] SEM], 2,583 [+ or -] 414 [micro]g to 1,512 [+ or -] 422 [micro]g, respectively; p [is less than] 0.05), [PD.sub.25][MIF.sub.50] (mean 2,898 [+ or -] 372 [micro]g to 1,340 [+ or -] 356 [micro]g, respectively; p [is less than] 0.05), and PDcough (mean 3,127 [+ or -] 415 [micro]g to 1,751 [+ or -] 447 [micro]g; p [is less than] 0.05), which were independent of the decrease in [FEV.sub.1] and reversed within 6 months in all patients but three. Six months after undergoing MRT, four patients showed radiation-induced lung injury (RI) on chest radiographs, which subsequently evolved into fibrosis. These patients had greater decreases in vital capacity, [FEV.sub.1], [MIF.sub.50], and methacholine thresholds than those without RI, and this persisted up to 2 years after they had undergone MRT. One year after the patients underwent MRT, a close relationship was found overall between the change in [FEV.sub.1] and those in both [PD.sub.10] (r = 0.733; p = 0.004) and [PD.sub.25][MIF.sub.50] (r = 0.712; p = 0.006).

Conclusions: MRT triggers an early transient increase in airway responsiveness, which reverses spontaneously. In patients with RI, the persistence of airway dysfunction long after undergoing MRT may depend on airway remodeling from radiation fibrosis.

(CHEST 2000; 117:1590-1596)

Key words: airway responsiveness; mantle radiotherapy; radiation-induced cough; radiation-induced inflammation; radiation-induced lung injury

Abbreviations: KCO = transfer factor for carbon monoxide; [MIF.sub.50] = maximal mid-inspiratory flow; MRT = mantle radiotherapy; [PD.sub.10] = provocative dose of methacholine causing a 10% fall in [FEV.sub.1]; [PD.sub.25][MIF.sub.50] = provocative dose of methacholine causing a 25% fall in maximal mid-inspiratory flow; PDcough = provocative dose of methacholine causing five or more coughs; RI = radiation-induced lung injury; sACE = serum angiotensin-converting enzyme; sLDH = serum lactate dehydrogenase; TLC = total lung capacity; VC = vital capacity

Lung function changes following mantle radiotherapy (MRT) for Hodgkin's disease are well-documented[1-3] and consist mainly of mild decreases in static lung volumes and lung diffusion capacities. The mechanisms of tissue injury and the sequence of pathophysiologic changes following lung irradiation are summarized in extensive reviews by Gross[4] and by Movsas et al.[5] New evidence suggests that radiation does not simply act by direct damage to cell membranes, proteins, and DNA, but also through the induction of an inflammatory syndrome. Rubin et al[6] demonstrated that a continuous cascade of cytokines begins soon after the start of lung irradiation and persists up to the development of lung fibrosis. Other authors found that intercellular adhesion molecule-1, a ligand involved in T-lymphocyte activation and migration into inflammatory sites,[7] plays an important role in the pathogenesis of radiation-induced inflammation.[8,9] An increased number of lymphocytes have been demonstrated in BAL fluid early after thoracic radiotherapy,[10] particularly in patients who develop radiation pneumonitis.[11] Since inflammatory cells, cytokines, and mediators have been associated with the development of airway hyperresponsiveness either in asthmatic or in nonasthmatic patients,[12] we wondered whether radiation-induced inflammation might trigger an increase in nonspecific airway responsiveness. Airway dysfunction might account for the frequent occurrence of cough and symptoms of airway irritation after lung irradiation, even in the absence of clinically overt radiation pneumonitis syndrome. We reasoned that MRT should have been ideal to evaluate radiation-induced airway dysfunction, since its field involves mainly the upper and central airways and only a small portion of the lung parenchyma.

The purpose of this study was to evaluate the early and late changes in nonspecific airway responsiveness in patients after they underwent MRT in relation to symptoms, lung function changes, and evidence of radiation-induced lung injury (RI).

MATERIALS AND METHODS

Patients

Fifteen patients with Hodgkin's disease were enrolled into the study (9 men and 6 women; mean ([+ or -] SEM) age, 37 [+ or -] 3 years; and 4 were current smokers). All the patients had supradiaphragmatic Hodgkin's disease (stage IIA, according to the Ann Arbor system),[13] with bulky mediastinal/hilar adenopathy (a mediastinal mass greater than one third of the maximum intrathoracic diameter) and no radiographic evidence of extralymphatic involvement. Due to the bulky nature of the disease, all the patients had received a course of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine, and they were scheduled for MRT.[14]

The criteria for inclusion in the study were the following: (1) normal results of lung function tests; (2) no respiratory infections in the preceding 2 months; (3) no history of cardiac or broncho-pulmonary disease prior to the diagnosis of Hodgkin's lymphoma; and (4) no pulmonary complications following treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine.

Study Protocol

The protocol of the study was approved by the institutional ethics committee, and appropriate informed consent was obtained from the subjects. The patients were examined before the start of MRT and 1, 6, 12, and 24 months after the end of MRT. At each visit, the patients underwent the following procedures: clinical examination; lung function tests; tests of lung diffusing capacity; arterial blood gas analysis; methacholine inhalation challenge; venipuncture for CBC counts and measurement of some serum markers of lung injury; and chest radiograph. A CT scan was performed before the patients underwent MRT and 6, 12, and 24 months after MRT.

RI was diagnosed in patients if a chest radiograph that was performed in the first 6 months after they had undergone MRT showed diffuse haziness or fuzziness within or outside the radiation fields that was not attributable to other pathologic processes and subsequently evolved into linear or patchy densities that were consistent with fibrosis,[15] and/or if a lung CT scan showed areas of attenuation that evolved into soft-tissue density changes that were consistent with fibrosis.[16] Radiation pneumonitis was diagnosed if radiographic and CT scan abnormalities were associated with symptoms (fever, dyspnea, and cough).[17]

Lung Function Tests: The measurements were performed following the European Respiratory Society criteria,[18] using a computerized water-sealed spirometer connected to helium and carbon monoxide analyzers (BAIRES, with revo and dimo modules; Biomedin; Padua, Italy). The following parameters were measured: (1) static lung volumes (vital capacity [VC], residual volume [by the helium dilution technique in closed circuit], and total lung capacity [TLC]); (2) [FEV.sub.1], as an index of total airway patency, forced inspiratory volume in 1 s, and maximal mid-inspiratory flow ([MIF.sub.50]) as indexes of the central airway (larynx and extrathoracic or intrathoracic trachea) patency; and (3) transfer factor for carbon monoxide (KCO), by the single-breath method.[19] Reference values were obtained from Quanjer.[18]

Arterial Blood Gas Analysis: [PO.sub.2] and [PCO.sub.2] were measured by a blood gas analyzer (ABL 330; Radiometer; Copenhagen, Denmark).

Methacholine Airway Responsiveness: The assessment of methacholine airway responsiveness followed a slightly modified standard method.[20] A freshly prepared solution of 1% methacholine chloride (Lofarma; Milan, Italy) was delivered by a compressed air nebulizer that was controlled by a breath-actuated dosimeter (MEFAR MB3; Markos; Monza, Italy). The dosimeter was set to nebulize for 1 s (output, 0.01 mL/breath); the mass median diameter of particles was 1.69 [micro]m (geometric SD, 3.3). Methacholine was inhaled from a mouthpiece connected to the nebulizer in doubling doses that were obtained by increasing the number of VC breaths from 100 to 3,200 [micro]g. Two minutes after each dose step, three flow-volume loops were recorded 1 min apart to avoid the effect of deep inhalation. The interval between doses was about 5 min. [FEV.sub.1] was used as an index of bronchial narrowing. [MIF.sub.50] was arbitrarily used as an index of central airway (larynx and/or extrathoracic and intrathoracic trachea) narrowing, since previously we had found that this test nicely reflects the changes in upper airway patency during bronchial challenge.[21] Coughs were counted at each dose step to calculate the cough threshold.[22] The challenge was stopped when a 20% fall in [FEV.sub.1] from baseline was obtained or when the highest methacholine dose had been reached. Bronchial and central airway thresholds were computed by plotting the methacholine dose against the relative percentage drops in [FEV.sub.1] and [MIF.sub.50]. The bronchial threshold was calculated as the provocative dose of methacholine causing a 10% fall in [FEV.sub.1] ([PD.sub.10]) from baseline. The choice of using [PD.sub.10] to calculate the bronchial threshold instead of the provocative dose of methacholine causing a 20% fall in [FEV.sub.1] ([PD.sub.20]) was made to limit the need for extrapolation from the data points, since subjects were not expected to be hyperresponsive before undergoing MRT. However, the diagnosis of bronchial hyperresponsiveness was based on the classic criterion of a [PD.sub.20] [is less than or equal to] 800 [micro]g.[20] The central airway threshold was expressed arbitrarily as the provocative dose of methacholine causing a 25% fall in [MIF.sub.50] ([PD.sub.25][MIF.sub.50]),[21] and the cough threshold was expressed as the provocative dose causing five or more coughs (PDcough).[22] Central airway and cough hyperresponsiveness were diagnosed if [PD.sub.25][MIF.sub.50] and PDcough were 800 [micro]g.

Serum Markers of Tissue Injury: Serum lactate dehydrogenase (sLDH), C-reactive protein, and serum angiotensin-converting enzyme activity (sACE) were used as markers of lung injury.[23-25] A decrease in sACE was considered to be indicative of endothelial injury,[25] and a rise was considered to be indicative of macrophage activation.[26]

MRT Technique: MRT was performed following the technique proposed by Carmel and Kaplan.[27] The standard mantle field included cervical, supraclavicular, infraclavicular, axillary, mediastinal, and hilar lymph node-bearing regions. Customized Cerrobend blocks (Multimedica; Genoa, Italy) were used to shield the healthy lung parenchyma, heart, cervical spinal cord, humoral heads, and larynx. The dose of radiation to the mantle field was 36 to 40 Gy administered in 1.8-Gy fractions. Doses given to the mantle fields were weighted 1:1, anterior to posterior, and both anterior and posterior fields were treated daily. With standard mantle blocks, the underlying lung parenchyma received a maximum of 5 to 10% of the specified dose at the central axis due to transmission and scatter.

Statistical Analysis

The changes in the results of lung function tests, KCO, blood gas analyses, methacholine thresholds, and levels of serum markers of lung injury that were observed before patients underwent MRT and 1, 6, 12, and 24 months following MRT were analyzed using analysis of variance for repeated measures and the Tukey-Kramer multiple comparisons test. The relationships among the changes of lung function tests and those of the methacholine thresholds were evaluated by linear regression analysis. A p value [is less than] 0.05 was considered statistically significant.

RESULTS

One woman was excluded from the study because of the occurrence of pneumococcal pneumonia 5 months after undergoing MRT, and one man was unavailable for follow-up.

The mean ([+ or -] SEM) values for the results of lung function tests, blood gas analyses, methacholine responsiveness tests, WBC counts, and measurements of serum markers of lung injury before patients undergoing MRT and 1, 6, 12, and 24 months following MRT of the 13 patients who completed the study are reported in Table 1.

Before MRT

The results of lung function tests, arterial [PO.sub.2] and [PCO.sub.2] measurements, blood cell counts, and serum marker measurements were within the normal range in all the patients. Five patients had decreased lung diffusing capacity (KCO [is less than] 80% predicted value). Methacholine thresholds were in the normal range in most of the patients; only one patient had mild bronchial hyperresponsiveness ([PD.sub.20][FEV.sub.1], 780 [micro]g), and three patients had cough hyperresponsiveness. Chest radiographs and CT scans showed a regression of mediastinal bulk in all the patients.

After MRT

Lung Function Tests: Overall, there was a small but significant decrease in TLC 1 month after patients underwent MRT, which persisted until the end of the study. VC levels significantly decreased only 1 month after MRT. [FEV.sub.1] levels, airflow rates, and arterial blood gas levels showed no significant change throughout the study. There was a small progressive decrease in the KCO up to 6 months after MRT, and then it improved.

Methacholine Airway Responsiveness: All the methacholine thresholds showed a significant decrease 1 month after MRT, particularly in the [PD.sub.25][MIF.sub.50], which in eight patients (62%) was consistent with central airway hyperresponsiveness. Six patients (46%) had bronchial hyperresponsiveness, and seven patients (54%) had cough hyperresponsiveness. As shown in Figure 1, the changes in [PD.sub.10] and [PD.sub.25][MIF.sub.50] levels were not related to the changes in [FEV.sub.1] levels. The decrease in methacholine thresholds rapidly recovered, so that, 6 months after MRT, the mean values of [PD.sub.10], [PD.sub.25][MIF.sub.50], and PDcough were only slightly, and not significantly, lower than those before treatment. However, three patients showed persistent airway and cough hyperresponsiveness up to the end of the study. As shown in Figure 1, 1 year after the patients underwent MRT, the changes in [PD.sub.10] and [PD.sub.25][MIF.sub.50] levels were closely and directly related to the changes in [FEV.sub.1] levels.

[Figure 1 ILLUSTRATION OMITTED]

Symptoms: The only symptom recorded during the study was a mild dry cough, which occurred without fever, dyspnea, leukocytosis, or clinical/radiographic evidence of radiation pneumonitis, in five patients during or immediately after they underwent MRT. Cough was invariably associated with airway hyperresponsiveness. The cough resolved spontaneously within 6 months in two patients, and persisted, in attenuated form, in the other three patients.

Markers of Radiation Injury: As shown in Table 1, the only significant changes were a transient decrease in WBC count and sACE activity 1 month after MRT. Four patients showed a brisk increase in sACE levels 1 year after undergoing MRT. sLDH and C-reactive protein levels remained in the normal range during the entire study.

Lung Imaging: No further relapse of Hodgkin's disease was observed during 2 years of follow-up. Six months after undergoing MRT, four patients (31%) presented parenchymal infiltrates that were consistent with RI. The lesions were limited to the radiation fields in two patients, were at the apex of the right lower lobe in one patient, and were in the left lower lobe in one patient, a condition that subsequently evolved into patchy densities that were consistent with fibrosis.

Three of the patients with RI had persistent cough and airway dysfunction, but none displayed the classic radiation pneumonitis syndrome. No significant differences were found between patients with and without RI before they underwent MRT, including smoking history (only one of the four RI patients was a smoker). By contrast, after MRT, patients with RI had persistent and significantly greater decreases in VC, [FEV.sub.1], [MIF.sub.50], and methacholine threshold levels (Fig 2). The decrease in [PD.sub.10], [PD.sub.25][MIF.sub.50], and PDcough levels showed the following dual trend: an early decrease 1 month after MRT, and a second decrease after 1 year, which was associated with a brisk increase in sACE and fibrotic evolution of radiographic lesions.

[Figure 2 ILLUSTRATION OMITTED]

DISCUSSION

The results of this study indicate that MRT causes an early transient increase in nonspecific airway responsiveness, particularly in the central airway, and in cough responsiveness. In fact, 1 month after patients underwent MRT, the mean values for the [PD.sub.10], [PD.sub.25][MIF.sub.50], and PDcough were significantly lower than those before treatment, and in more than half of the patients, these values were consistent with airway and cough hyperresponsiveness. MRT had only mild negligible effects on lung function tests, arterial blood gas levels, levels of serum markers of lung injury, and the findings of chest radiographs throughout the follow-up, which is in agreement with the data in the literature.[1-5]

The increase in airway responsiveness observed 1 month after MRT could hardly be attributed to lung inflammatory changes caused by Hodgkin's lymphoma. In fact, before MRT, airway responsiveness was in the normal range in all the patients but one, and its increase after treatment was never associated with lymphoma relapse.

None of the patients showed clinical evidence of radiation pneumonitis shortly after undergoing MRT. In fact, although five patients complained of cough, none had fever, dyspnea, leukocytosis, radiographic abnormalities, or increases in levels of serum markers of lung injury. There were, rather, significant decreases in WBC counts, due to the combined effect of chemotherapy and radiotherapy, and in sACE levels, which probably are the expression of endothelial injury.[25] In 9 of the 13 patients, the possibility that airway dysfunction was the consequence of radiation pneumonitis seems very unlikely. In fact, in these patients no radiographic abnormalities appeared throughout the follow-up, and the [PD.sub.10], [PD.sub.25][MIF.sub.50], and PDcough levels recovered to pretreatment values within 6 months, just at the time when radiation pneumonitis would have become clinically apparent.[28,29] In these patients, we may suppose that airway and cough hyperresponsiveness were sustained by transient radiation-induced airway inflammation,[6-11] which caused epithelial cell damage with an increased mucosal permeability of irritants and an increased sensitivity of the submucosal receptors. The reduction of cough and airway hyperresponsiveness that was observed 6 months after the patients underwent MRT might, thus, depend on the resolution of the inflammatory process with its consequent repair of the epithelium, since bronchial epithelial cells have an estimated doubling time of 1 to 3 weeks.[30]

By contrast, RI might well have occurred in the four patients who developed typical abnormalities on chest radiographs and CT scans that were performed 6 months after they underwent MRT. According to Morgan et al,[31] these abnormalities could be defined in two patients as classic pneumonitis, which is confined to the radiation field, and in the other two patients as sporadic pneumonitis, which is outside the radiation field. Airway dysfunction in these four patients might have been an early sign of ongoing RI. As shown in Figure 2, these four patients, compared with those without RI, had significantly greater decreases in VC, [FEV.sub.1] levels, [MIF.sub.50] levels, and methacholine thresholds throughout the follow-up, and three patients had persistent cough and airway hyperresponsiveness. Interestingly, the methacholine thresholds of the patients with RI showed a dual trend, with an early decrease at 1 month, a transient improvement at 6 months, and a second worsening at 1 year. The latter was associated with radiographic signs of fibrosis and with a brisk increase in sACE levels. We may suppose that the increase in sACE levels was the expression of macrophage activation,[26] which contributed to the fibrotic process.[32,33] The close relationship between the decreases in both [PD.sub.10] and [PD.sub.25][MIF.sub.50] levels and the decreases in [FEV.sub.1] that was found in all patients 1 year after they had undergone MRT, but that was not found 1 month after they had undergone MRT, suggests that persistent increases in airway responsiveness long after MRT may be sustained by airway remodeling that is the consequence of radiation fibrosis.

The relatively high incidence of RI found in our series (31%) was probably the consequence of combined chemotherapy and radiotherapy.[34] Despite the high incidence of RI, its physiologic consequences were rather mild, and no patient had the classic radiation pneumonitis syndrome. In three of the four patients with RI, the only symptom that ensued after they had undergone MRT was persistent cough, which did not require any treatment. Actually, MRT is not likely to produce significant symptoms or damage, since its radiation field involves only a small volume of the upper lung zones, where both ventilation and perfusion are lowest.[29] No predictor of the development of radiation pneumonitis could be found from the comparison between patients with and without RI. However, due to the selection criteria, all the patients had a negative history for bronchopulmonary disease, had normal results of baseline lung function tests, had the same lymphoma stage and extension, and had received the same chemotherapeutic regimen and the same total and fractional radiation dose.

CONCLUSIONS

The results of this study indicate that MRT causes an early marked increase in airway and cough responsiveness, which is independent of changes in airway patency and reverses spontaneously within 6 months. Such airway dysfunction may be attributed to radiation-induced inflammation, affecting airway responsiveness much more than resting airway caliber. Susceptible patients, presenting with radiographically detectable RI, may have persistent cough and airway dysfunction. In these patients, airway dysfunction may show a late worsening, which may be sustained by airway remodeling due to radiation fibrosis.

These findings suggest that the assessment of airway responsiveness is much more sensitive than lung function tests, chest radiographs, and serum markers of lung injury in the early detection of radiation-induced airway inflammation. An increase in airway responsiveness, early after treatment, may account for the occurrence of symptoms of airway irritation, such as cough, in patients without overt radiation pneumonitis. While medications such as steroids are known to be useful in treating airway hyperresponsiveness in patients with asthma, further investigation is needed to assess whether topical corticosteroids may improve airway dysfunction and prevent late radiation-induced airway remodeling.

ACKNOWLEDGMENT: The authors thank Gian Luca Sannazzari, MD, chief of the Radiotherapy Division, for a thoughtful review of the manuscript.

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Giovanni Rolla, MD, FCCP; Umberto Ricardi, MD; Paola Colagrande, MD; Daniela Nassisi, MD; Luca Dutto, MD; Giovanni Chiavassa, MD; and Caterina Bucca, MD

(*) From the Department of Biomedical Sciences and Human Oncology (Drs. Rolla, Colagrande, Dutto, Chiavassa, and Bucca), the Radiotherapy Division (Drs. Ricardi and Nassisi), University of Torino, Torino, Italy.

Supported by a grant from the Italian Ministry of University and Scientific Research.

Manuscript received July 29, 1999; revision accepted January 25, 2000.

Correspondence to: Caterina Bucca, MD, Associate Professor in Clinical Pathophysiology, Department of Biomedical Sciences and Human Oncology, University of Torino, Via Genova 3, 10126 Torino, Italy

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