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Annals of Oncology Advance Access published online on May 7, 2008
Annals of Oncology, doi:10.1093/annonc/mdn284
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

A prospective study of pulmonary function in Hodgkin’s lymphoma patients

A. K. Ng1,*, S. Li2, D. Neuberg2, R. Chi1, D. C. Fisher3, B. Silver1 and P. M. Mauch1

1 Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA
2 Department of Biostatistics and Computational Biology
3 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

* Correspondence to: Dr A. K. Ng, Department of Radiation Oncology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02114, USA. Tel: +1-617-732-6310; Fax: +1-617-732-7347; E-mail: ang{at}lroc.harvard.edu


   Abstract
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 Abstract
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 patients and methods
 results
 discussion
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 References
 
Background: To prospectively study changes in lung function in Hodgkin's lymphoma (HL) patients and to explore predictors for these changes over time.

Methods: In all, 52 patients with HL receiving bleomycin-based chemotherapy with (n = 23) or without (n = 29) mediastinal radiotherapy were enrolled. Pretreatment pulmonary function tests were carried out. These were repeated at 1 month, 6 months, and 1 year after therapy.

Results: With chemotherapy alone, the median %DLCO declined significantly at 1 month but returned to baseline by 6 months. The median %DLCO did not further decrease with radiotherapy, but remained persistently reduced at 1 year. In patients who received radiotherapy, having >33% of lung volume receive 20 Gy (V20) and a mean lung dose (MLD) of >13 Gy significantly predicted for persistently reduced %DLCO at 6 months (P = 0.035). Smoking significantly predicted for a persistently reduced %DLCO at 1 year (P = 0.036). On multivariable analysis, significant predictors for decline in %DLCO at 1 year were higher baseline %DLCO (P = 0.01), higher MLD (P = 0.02), and a smoking history (P = 0.02).

Conclusions: Several factors contribute to decline in %DLCO in HL patients who received bleomycin-based computed tomography. The identification of threshold radiation dosimetric parameters for reduced lung function may provide guidance in the radiation planning of these patients.

bleomycin, hodgkin lymphoma, lung toxicity, radiation parameters


   introduction
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patients and methods
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Pulmonary toxicity and lung function impairment as acute and late complications after radiation therapy alone for Hodgkin’s lymphoma (HL) are well documented [1–5]. In the last 10–15 years, combined modality therapy has replaced radiation therapy alone as standard therapy for patients with HL. With the known pulmonary toxicity associated with bleomycin [6], studies have shown that the combination of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with mediastinal irradiation can further potentiate lung toxicity [7–9].

While there are ample data describing the relationship between radiation dosimetric parameters and the risk of pulmonary toxicity in patients receiving radiation therapy for lung cancer [10–14], less information is available on HL patients [15]. In recent years, short-term and long-term treatment-related toxic effects are gaining attention for this highly curable disease [16, 17]. Current trials on the treatment of HL, especially among early-stage patients, have largely focused on treatment reduction to limit complications [18, 19]. Understanding the effects of radiation dose, field size, and volume in the setting of combined modality therapy on the acute and long-term lung function in HL patients can help in identifying a subset of patients at high risk for pulmonary toxicity. Recognizing critical radiation dosimetric parameters that predict for pulmonary toxicity may provide guidance in our efforts to reduce the radiation field size and dose for these patients.

The objectives of this study are to determine changes in pulmonary function in patients with HL treated with bleomycin-based chemotherapy with or without mediastinal radiation therapy over time and to explore predictors for pulmonary toxicity and decline of pulmonary function after treatment, including radiation dosimetric factors for patients who received mediastinal radiation therapy.


   patients and methods
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 Abstract
 introduction
 patients and methods
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 discussion
 funding
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From 2001 to 2005, 52 patients with newly diagnosed, biopsy-proven, classical HL receiving bleomycin-based chemotherapy with or without mediastinal radiotherapy were enrolled at the Dana-Farber Harvard Cancer Center. The patient characteristics are summarized in Table 1. The median age at the time of enrollment was 31 (range 18–69). A majority of the patients received ABVD, and six patients received adriamycin, bleomycin, vinblastine, and gemcitabine as part of a separate prospective clinical trial. All patients who received mediastinal irradiation underwent three-dimensional computed tomography (CT) planning. The treatment field was determined by sites of initial involvement. For example, the axillae were excluded in patients with only mediastinal and neck involvement. The superior and inferior extent of the radiation field was on the basis of the prechemotherapy tumor volume, and the lateral extent was on the basis of the postchemotherapy residual volume. Dose–volume histograms for the bilateral lungs were generated and mean lung dose (MLD), defined as the mean dose of the CT-defined total lung volume, was calculated. Heterogeneity correction for lungs became available midway into the study, after which both heterogeneity-corrected and uncorrected plans were created for each patient. However, it was noted that the radiation dosimetric parameters changed minimally with or without correction. For consistency purposes, the radiation dosimetric data in this report were on the basis of the uncorrected plan.


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  		Table 1. Patient characteristics

 
All patients underwent baseline pulmonary function tests. For patients who were receiving mediastinal irradiation, these were repeated after completion of the chemotherapy and before the start of the radiation therapy. For all patients, the pulmonary function tests were repeated at 1 month, 6 months, and 1 year after therapy. Data on spirometry, lung volume, and diffusion capacity were collected. Clinically significant pulmonary toxic effects, including bleomycin toxicity requiring discontinuation of the bleomycin or symptomatic radiation pneumonitis requiring medication (antibiotics, nonsteroidal anti-inflammatory drugs, steroids), were documented.

Wilcoxon sign rank tests were used to compare the baseline and posttreatment lung function results. Fisher's exact tests were used to identify predictors for clinically significant pulmonary toxicity and the Wilcoxon rank sum test was used to test changes in percentage of predicted carbon monoxide-diffusing capacity with adjustment for hemoglobin concentration (%DLCO) at 6 months and 1 year between groups. General linear models were used to identify independent predictors for decline in %DLCO over time. Factors explored were age (≤30 versus >30), number of cycles of bleomycin (<6 versus ≥6), and smoking history (yes versus no) as categorical variables and MLD (patients treated with chemotherapy alone had a MLD of 0) and baseline %DLCO as continuous variables. %DLCO was used as the primary dependent variable in all analyses because of the well-documented effect of bleomycin-containing regimen on the transfer capacity of the lungs for carbon monoxide [20–23].

This study was approved by the Dana-Farber Harvard Cancer Center Institutional Review Board and all patients gave signed informed consent.


   results
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 Abstract
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For the 29 patients treated with chemotherapy alone, the baseline median %DLCO was 94% (range 53%–121%). At 1 month, 6 months, and 1 year postchemotherapy, the median %DLCO decreased an average of 12% (P < 0.001), 2% (P = 0.09), and 3% (P = 1.0) from baseline, respectively. For the 23 patients treated with combined modality therapy, the baseline median %DLCO was 107% (range 65%–139%). The median %DLCO at postchemotherapy/preradiation therapy and at 1 month, 6 months, and 1 year after radiation therapy decreased an average of 13% (P = 0.0002), 18% (P = 0.005), 10% (P = 0.0005), and 13% (P = 0.003) from baseline, respectively. There was no significant further decline in %DLCO between postchemotherapy/preradiation therapy and subsequent timepoints after radiation therapy. The graphical representations of changes in %DLCO over time for the two groups of patients are shown in Figures 1 and 2.


Figure 1
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  		Figure 1. Changes in median %DLCO over time in patients who received chemotherapy alone. *Comparison between the baseline and posttreatment %DLCO by Wilcoxon sign rank tests.

 

Figure 2
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  		Figure 2. Changes in median %DLCO over time in patients who received combined modality therapy. *Comparison between the baseline and posttreatment %DLCO by Wilcoxon sign rank tests.

 
factors predictive of clinically significant pulmonary toxicity
A total of six patients (12%) experienced symptomatic bleomycin toxicity during chemotherapy requiring discontinuation of the drug. Older age was the only factor that significantly predicted bleomycin toxicity, occurring in three of five (60%) of patients age >60 as opposed to three of 47 (4%) of patients age ≤60 (P = 0.008).

Among the 23 patients treated with combined modality therapy, three patients (13%) developed symptomatic radiation pneumonitis, confirmed radiographically, requiring treatment with antibiotics and/or prednisone at 2–4 weeks after radiation therapy. Their MLD (11.1 Gy, 13.3 Gy, and 13.9 Gy) and V20 (27%, 33%, and 36%) did not differ significantly from the MLD (median 11.2 Gy; range 7.8–14.1 Gy) and V20 (median 29%; range 20%–39%) of patients without radiation pneumonitis (P = 0.15 for MLD, P = 0.32 for V20).

factors predictive of persistently reduced %DLCO over time
Persistently reduced %DLCO (>15% decline from baseline) was observed in 35% of patients at 6 months and 25% of patients at 1 year. Among patients who received radiation therapy, 52% had a persistently reduced %DLCO at 6 months as compared with 20% of patients who received chemotherapy alone (P = 0.03). At 1 year, the addition of radiation therapy no longer significantly predicted for persistently reduced %DLCO (37% versus 14%, P = 0.15). Dosimetric parameters also significantly predicted for persistently reduced %DLCO at 6 months but not at 1 year. Among the 23 patients who received mediastinal irradiation, the median MLD was 11.6 Gy (range 7.8–14.1 Gy), and the median V20 was 30% (range 20%–39%). All patients with a MLD of ≥13 Gy or a V20 of ≥33% had persistently reduced %DLCO at 6 months as compared with 50% of patients with a MLD of <13 Gy or with a V20 of <33% (P = 0.01). At 1 year, 60% of patients with a MLD of ≥13 Gy or a V20 of ≥33% had persistently reduced %DLCO versus 40% patients with a MLD of <13Gy or with a V20 of <33% (P = 0.3). Tobacco use within the 2 years before the HL diagnosis significantly predicted for persistently reduced %DLCO at 1 year in the combined modality therapy cohort. All smokers had persistently reduced %DLCO at 1 year in comparison with only 25% of nonsmokers (P = 0.036). However, tobacco history was not a significant predictor for persistently reduced %DLCO at 1 year for patients who received chemotherapy alone.

For the entire cohort, on linear regression analysis, after adjusting for age and number of cycles of bleomycin, a lower pretreatment %DLCO (P = 0.01), lack of smoking history (P = 0.02), and a lower MLD (P = 0.02) were significantly associated with less of a decline in %DLCO at 1 year. Specifically, for every 1-Gy increase in MLD, the estimated reduction in %DLCO at 1 year was 1% (Table 2).


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  		Table 2. Linear regression analysis of factors predictive of % DLCO change at 1 year (compared with prechemotherapy)

 

   discussion
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 Abstract
 introduction
 patients and methods
 results
 discussion
funding
 References
 
In this prospective study, we found that treatment with bleomycin-based chemotherapy for HL resulted in a significant decline in %DLCO, which returned to baseline within 6 months after therapy. The addition of mediastinal radiation therapy did not further reduce the %DLCO, but did result in persistently decreased %DLCO up to 1 year after therapy. Persistent subclinical pulmonary dysfunction was found in one-quarter of the patients. Among patients who received mediastinal radiation therapy, a MLD of ≥13 Gy or a V20 of ≥33% was associated with persistently reduced %DLCO at 6 months. After adjustment for other factors, the reduction in %DLCO at 1 year was estimated at ~1% per Gy of MLD. Baseline %DLCO and tobacco history were also independent predictors for reduction in %DLCO at 1 year.

Other investigators have prospectively evaluated the pulmonary function of patients with HL receiving combined modality therapy, although detailed radiation dosimetric data were not available in most of those studies. Horning et al. [8] reported on pulmonary function in 119 patients with HL treated on prospective trials at Stanford University. Among 36 patients treated with both bleomycin and radiation therapy and 33 patients treated with bleomycin-based chemotherapy alone, a significant decline in pulmonary function was observed at 15 months for both groups. At 36 months, pulmonary function returned to baseline in patients treated with chemotherapy alone, but remained persistently decreased in patients who also received radiation therapy. On linear regression analysis, higher baseline pulmonary function was the only significant factor predicting a greater decrement in pulmonary function over time.

In a study from Memorial Sloan-Kettering Cancer Center, 60 patients with HL enrolled in randomized trials underwent prospective pulmonary function testing [9]. All patients received six cycles of ABVD with or without mantle/mediastinal irradiation. A significant decline in pulmonary function was observed after treatment. Within 6 months after treatment, patients who received consolidative radiation therapy were significantly more likely to have pulmonary symptoms compared with patients who received chemotherapy alone, although at a median follow-up of 30 months, the difference between the two groups was no longer significant. As in the Stanford study, higher pretreatment pulmonary function was significantly predictive of subsequent abnormal pulmonary function. Our results showed a similar relationship between baseline lung function and a decline in lung function after treatment. This likely reflects improvement in pulmonary function in response to treatment in patients with low baseline %DLCO as a result of their mediastinal disease. This response to treatment in turn offsets subsequent treatment-related lung function impairment.

Investigators from St Jude's Hospital conducted serial pulmonary function tests in 37 children with HL receiving cyclophosphamide, vincristine, and prednisone, alternating with ABVD, followed by low-dose mantle radiation therapy to 18–20 Gy[24]. The %DLCO was found to be persistently reduced up to 2 years after diagnosis. However, all but one patient were without clinical pulmonary symptoms. The cumulative bleomycin dose, additional whole-lung radiation therapy, and smoking status did not significantly affect the %DLCO change, although the analysis may be restricted by the limited power.

In the era of three-dimensional radiation therapy, much has been published on the contribution of radiation dosimetric parameters to pulmonary toxicity in patients receiving chest radiation therapy, although the studies are largely limited to lung cancer patients [10–14]. The most commonly reported parameters were V20 and MLD, which have been shown to significantly correlate with the risk of radiation pneumonitis after radiation therapy for lung cancer. Similarly, V20 has been found to be the most significant dosimetric parameter significantly predicting for symptomatic radiation pneumonitis and radiographically detected radiation pneumonitis among women receiving radiation therapy for breast cancer [25].

Limited data are available on the relationship between radiation dosimetric parameters in the treatment of HL and pulmonary toxicity. Patients with HL tend to be younger, are less likely to be smokers, and are less likely to have underlying lung disease. In addition, lung resections are typically not part of lymphoma therapy. The types of chemotherapy received by HL patients are different, and are given sequentially, rather concurrently, with the radiation therapy. The radiation field size may be comparable in some cases, but the total radiation dose used in lymphoma therapy is lower. In a retrospective series reported by Koh et al. [15], the radiation dosimetric parameters of 64 patients with HL who received mediastinal irradiation (91% also received ABVD) were reviewed. Two patients developed clinically significant pneumonitis. The V20 values of these two patients were 47% and 40.7%, respectively, and their MLD values were 17.6 Gy and 16.4 Gy, respectively. On the basis of their data, a V20 of 36% and a MLD of 14 Gy were identified as cut-off values, above which the risk of radiation pneumonitis would be considered clinically significant. These threshold radiation parameter values are slightly higher than those identified in the current study. The small difference may reflect our less stringent end point of persistently reduced %DLCO. In our study, we were not able to detect any significant relationship between radiation dosimetric parameters and risk of radiation pneumonitis. This is likely due to the overall lower radiation treatment dose and volume in our cohort. None of our patients had a MLD >14.1 Gy or a V20 of >39%.

One noteworthy finding from this study is the significantly higher likelihood of persistently reduced pulmonary function among smokers who received mediastinal irradiation compared with nonsmokers. There are several important reasons for patients with HL to refrain from smoking, including its multiplicative effect on subsequent lung cancer risk and its contribution to the risk of cardiovascular disease among long-term survivors [17, 26]. Its persistent negative effect on lung function over time provides additional incentive for smoking cessation in patients receiving HL therapy.

Our study is the first to quantify the decrement in pulmonary function in relationship to radiation dose to the lungs. After adjustment for other factors, the reduction in %DLCO at 1 year was 1% per Gy of MLD. While this is statistically significant, the long-term clinical implications still remain to be elucidated. A majority of patients were clinically asymptomatic despite the reduced %DLCO, highlighting the relatively low toxicity profile of combining bleomycin-based chemotherapy with modern involved-field radiation therapy to the mediastinum. Nevertheless, the findings provide further support for current efforts to explore the use of lower radiation doses and smaller fields in the treatment of HL [18, 19].


   funding
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 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
References
 
American Society of Hematology Junior Faculty Clinical Research Award.

Received for publication April 3, 2008. Accepted for publication April 8, 2008.


   References
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 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 References
 
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