Chest Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Myers, J. N.
Right arrow Articles by Johnson, B. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Myers, J. N.
Right arrow Articles by Johnson, B. E.
(Chest. 2005;128:3261-3268.)
© 2005 American College of Chest Physicians

The Pulmonary Status of Patients With Limited-Stage Small Cell Lung Cancer 15 Years After Treatment With Chemotherapy and Chest Irradiation*

Janet N. Myers, MD, FCCP; Kevin M. O’Neil, MD, FCCP; Thomas E. Walsh, MD, FCCP; Karen J. Hoffmeister, MD; David J. Venzon, PhD and Bruce E. Johnson, MD

* From the Department of Medicine, Uniformed Services University of the Health Sciences (Dr. Myers), Pulmonary and Critical Care Division, Hematology/Oncology Division, National Naval Medical Center (Dr. Hoffmeister), Pulmonary and Critical Care Division, National Naval Medical Center (Dr. O’Neil), Bethesda, MD; Montgomery County Department of Health (Dr. Walsh), Bethesda, MD; Medicine Branch at the Navy (Dr. Venzon), Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD; and the Department of Adult Oncology (Dr. Johnson), Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA.

Correspondence to: Janet N. Myers, LCDR, MC, USNR, Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814-4712; e-mail: JMyers{at}usuhs.mil


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To describe pulmonary symptoms, signs, pulmonary function, and lung imaging studies in patients with limited-stage small cell lung cancer (SCLC) 2 to 15 years after receiving treatment with chemotherapy and chest radiotherapy.

Design: Retrospective review of clinical records and radiographic studies of patients treated in three different prospective combined-modality studies.

Setting: Federal hospital.

Patients: One hundred fifty-six patients with SCLC who were enrolled between 1974 and 1994.

Interventions: Patients with limited-stage SCLC treated on prospective therapeutic studies of combined chemotherapy and radiation therapy were identified. Pulmonary symptoms, physical findings, pulmonary function tests, arterial blood gas measurements, and chest imaging studies were assessed at baseline, and at 1 to 2 years, at 3 to 5 years, and at > 5 years following the initiation of treatment.

Measurements and results: Initial symptoms included cough in 84 (55%), dyspnea in 59 (39%), and sputum production in 26 (17%). Twenty-three patients lived beyond 5 years (15%) without evidence of recurrence. Seven of these 5-year survivors were without pulmonary symptoms. Pulmonary function test results showed no significant changes in percent predicted values for FVC, FEV1, and FEV1/FVC ratio over the time periods reviewed. The percent predicted values for the diffusing capacity of the lung for carbon monoxide decreased from 71% before the start of treatment to 56% (p < 0.032) at 1 to 2 years. Values improved in most patients beyond 5 years after starting treatment. Radiologist interpretations of chest imaging studies were available for 17 of 23 patients surviving > 5 years. Most patients had minimal to no changes in imaging study findings beyond 5 years.

Conclusions: Long-term survivors with limited-stage SCLC who were treated with combined chemotherapy and chest radiotherapy have minimal changes in pulmonary symptoms or function from 5 to 15 years after the start of treatment. A concern for late toxicity from combined-modality therapy should not dissuade clinicians from offering therapy with potentially curative result with minimal to no pulmonary dysfunction.

Key Words: lung cancer • oncology • pulmonary function test • radiology • toxicity


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Nearly all of the long-term survivors of small cell lung cancer (SCLC) are patients with limited-stage disease who have been treated with combined-modality therapy and achieve a complete response.12 The survival advantage of combined chemotherapy and chest irradiation for patients with limited-stage SCLC is well-established and has now been adapted as part of the standard treatment.3 Chest radiotherapy for patients with limited-stage SCLC increases the survival rate at 3 years by 5%.4 Reports of both short-term and long-term toxicity initially impeded the widespread adaptation of chest and cranial irradiation as part of the standard management of patients with SCLC. Both modalities have a potential for further damaging pulmonary function in patients with lung cancer in this population of cigarette smokers with underlying pulmonary disease.

In a review by Marks et al,5 thoracic radiation was found to be associated with lung injury in 5 to 20% of patients with lung cancer; a lower incidence of 5 to 15% was found in patients with mediastinal lymphoma and breast cancer. Long-term functional impairment in 116 survivors of Hodgkin disease who were followed up for 5 to 13 years after treatment has shown that nearly 30% of patients developed dyspnea on exertion, but that no evidence or slight radiographic evidence of fibrosis was seen in 32% and 54% of those patients, respectively.6 Pulmonary toxicity is manifested by the following two well-recognized syndromes: acute radiation pneumonitis; and late radiation fibrosis. Acute radiation pneumonitis, usually ranging from 1 to 6 months following the completion of a course of radiotherapy has been well-described in lung cancer patients.5 Symptoms may occur prior to radiographic changes, with the most common complaints being dyspnea in 93% of patients and cough in 58% of patients in a study by Perry et al.7 The severity of symptoms can be variable, ranging from minimal to no symptoms in patients with a small area of lung involvement to severe respiratory insufficiency and respiratory failure occurring over a few days. The rate of symptomatic pneumonitis ranges from 1 to 34%, and the rate of radiographic changes ranges from 13 to 100%. Many factors affect the risk of developing pulmonary damage, including timing, dose and extent of radiation, history of radiation therapy, use of chemotherapy, steroid therapy, and preexisting lung disease. Radiation fibrosis causes permanent changes that may take 6 to 24 months to evolve but is generally thought to remain stable after about 2 years.8 The incidence and severity of radiation fibrosis in lung cancer patients are variable, and depend on timing, dose intensity, technique of irradiation, volume of the lung irradiated, and chemotherapy. Physiologic changes in pulmonary function as a result of thoracic radiation and chemotherapy are closely related to the degree of preexisting pulmonary reserve, the region of treatment volume, and the presence of a significant (ie, > 10%) shift in ventilation or perfusion to the opposite lung by a centrally located primary tumor or lymph nodes causing the obstruction of the major bronchi and/or pulmonary vessels.9

The standard of treatment for patients with stage III non-SCLC (NSCLC) has also become chemotherapy plus chest radiotherapy.10 There are approximately three times as many patients with stage III NSCLC as patients with limited-stage SCLC. The number of patients surviving their lung cancer will increase with the routine application of chest radiotherapy and chemotherapy to both of these populations of patients with lung cancer. Given the high prevalence of lung cancer and the survival advantage gained with combined-modality therapy, the data from our patients treated for limited-stage SCLC may help to clarify the long-term impact of concurrent therapies on pulmonary function.

Studies have reported on the pulmonary toxicities that take place within 1 to 2 years after the start of treatment, but the potential long-term pulmonary impairment 2 to 15 years after the start of treatment has not been reported. SCLC is the lung cancer that is most closely associated with cigarette smoking, and pulmonary symptoms and signs are common in patients before they initiate treatment.11 Although most patients with SCLC who survive beyond 2 years have quit smoking cigarettes, their pulmonary function beyond 2 years from the start of treatment remains undefined.

The National Cancer Institute of the United States has conducted prospective, therapeutic, combined-modality studies for patients with limited-stage SCLC starting in 1973, and the long-term functional status and clinical outcomes of these patients have been reported on for > 15 years. As part of the following report, the clinical outcome of these long-term survivors, pulmonary symptoms, signs, and function have been assessed. The goals of this study were to describe the long-term pulmonary effects, including pulmonary symptoms, pulmonary function testing results, and radiographic findings, in patients who have been treated with combined-modality therapy. The documentation of the stable or improving pulmonary status of patients with SCLC > 5 years after undergoing treatment with chemotherapy and chest radiotherapy will give further confidence for the routine application of combined-modality treatment for these patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The clinical records of patients with newly diagnosed SCLC treated in the United States National Cancer Institute intramural therapeutic trials from 1974 to 1994 were reviewed. The patients had participated in clinical trials that were approved by the institutional review board and all patients signed a written informed consent form. Prior to the initiation of treatment, all patients underwent an evaluation that included a medical history and physical examination, serum chemistry examination, CBC count with differential count, and urine analysis. Imaging studies included posterior-anterior and lateral chest radiographs, CT scans or tomograms of the chest, CT scans or MRI of the head or radionuclide bone scan, and CT scan of the liver. Patients also underwent bilateral bone marrow aspiration and biopsy, pulmonary function studies with arterial blood gas measurements, and fiberoptic bronchoscopy. Patients were classified as having limited-stage disease when the tumor was confined to one hemithorax and to hilar, mediastinal, and supraclavicular nodes, and was encompassed within a tolerable radiotherapy portal after completion of the staging evaluation.12 The eligibility criteria for patient entry included no active second malignancy and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients also needed adequate hematologic function, which was defined as a WBC count of > 4,000 cells/µL and a platelet count > 100,000 cells/µL, adequate renal function with a serum creatinine level of < 2.0 mg/dL, and adequate cardiac function, which was defined as no symptomatic heart disease, no less than fully compensated congestive heart failure, and no significant arrhythmia or myocardial infarction within the past 3 months. Patients needed adequate pulmonary function, which was defined as an arterial PO2 of > 50 mm Hg and a PCO2 of < 50 mm Hg while breathing room air. Patients with visible pleural effusions on posterior-anterior chest radiographs, chest wall involvement, pericardial tumor, or pericardial effusion were classified as having extensive-stage disease and were excluded from the study. Determination of the ability to administer chest irradiation safely was made jointly by the radiation oncologists and medical oncologists after a review of the medical evaluation and staging studies.

Combined-Modality Regimen
The treatment regimens have been previously reported.121314 Between 1973 and 1986, patients were treated with a regimen of three to four drugs, including a minimum cyclophosphamide dose of 1 g/m2 body surface area plus thoracic radiation therapy consisting of 40 Gy given in 15 fractions over 3 weeks within 3 days of the start of chemotherapy. Patients with limited-stage SCLC were treated with a combination of etoposide, 80 mg/m2 on days 1, 2, and 3, and cisplastin, 80 mg/m2 on day 1, followed by chest irradiation administered in twice-daily fractions to a total dose of 45 Gy over 3 weeks. The change in chemotherapy in 1986 reflects the widespread transition from cyclophosphamide-based chemotherapy to etoposide/cisplatin. The details of these regimens have been reported elsewhere.1215

Response Assessment
The response of surviving patients was assessed 6 months to 2 years after starting treatment, as previously described.14 The patients with a complete response to combined-modality treatment were evaluated. The patients with residual SCLC were not included in the analyses because of the potential adverse impact of progressive or recurrent disease on their pulmonary function. Patients surviving for > 2 years from the start of treatment have returned regularly to the National Cancer Institute for long-term follow-up studies.14 These studies have included an assessment of their pulmonary status. Their survival was measured from the initial day of treatment until the last date of follow-up evaluation or death.

Symptoms, Signs, and Radiographic Findings
The clinical records of surviving patients were evaluated for pulmonary symptoms, including cough, sputum production, dyspnea, and chest pain. Signs of decreased breath sounds, wheezes, crackles, rales, and rhonchi on physical examination were also recorded. Reports of plain film chest radiography and CT scans of the chest were also reviewed for changes in the appearance of tumors, infiltrates, or pleural effusions. Reports of regional "linear stranding or streaking," "patchy densities," "fibrosis," and "scarring" were thought to be consistent with radiation therapy when noted > 6 to 9 months after the completion radiotherapy.5816

Pulmonary Function
Baseline pulmonary function testing was evaluated. FEV1, FVC, and FEV1/FVC ratios were calculated from the best of three to six flow-volume curves. Total lung capacity (TLC), residual volume, and functional residual capacity were measured using a helium dilution technique and body plethysmography. The diffusing capacity of the lung for carbon monoxide (DLCO) was determined using a single-breath technique. Arterial blood samples for PO2, PCO2, and pH were obtained while the patient breathed room air. The percentages of predicted normal values were obtained from standard tables to allow for variations in age, sex, height, and race.

Statistical Analysis
The changes in symptoms and signs were compared from baseline to 1 to 2 years, 3 to 5 years, and > 5 years after treatment. Changes in percent predicted values for pulmonary function data were also compared using the Wilcoxon signed rank test on the baseline values and the mean values for each patient over each of the three follow-up intervals. Due to the difficulty in comparing absolute changes in pulmonary function studies over time for different patients, the percent predicted change in each of the parameters was used for comparison. Because of the strongly correlated outcomes and the number of missing values, corrections for multiple comparisons were not made.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
One hundred fifty-six patients with limited-stage SCLC have been enrolled in combined-modality trials from 1974 through 1994. One hundred three patients were treated with cyclophosphamide-based regimens, while 53 patients were treated with etoposide/cisplatin regimens previously plus twice-daily chest radiotherapy. The baseline characteristics of the patients are shown in Table 1 . All but one of the patients had a history of smoking at the time of their initial treatment, including 17 patients who had quit on average 6.7 years prior to receiving a diagnosis (range, 1 to 20 years). These patients had smoked for an average of 58.3 pack-years (range, 20 to 138 pack-years). Of the three patients who were asymptomatic at the last follow-up, one patient was a prior smoker with 60 pack-years of smoking, and another patient was a lifetime nonsmoker. The third patient continued to smoke 50 pack-years at the time of treatment.


View this table:
[in this window]
[in a new window]

  		Table 1.. Baseline Characteristics*

 
Baseline pulmonary symptoms were available for 152 patients. The results for pulmonary symptoms are shown in Table 2 . Records were not available for three patients, and baseline symptom data were missing for one patient. Additional presenting complaints included chest pain in 35 patients (22%), fatigue in 9 patients (6%), neck masses in 5 patients (3%), and voice changes in 4 patients (3%). Twenty of the patients with sputum production also had hemoptysis. One hundred twenty-two patients were assessed and had a complete response to combined-modality treatment. Forty-eight of the original 156 patients died within the first year of treatment. Of the remaining patients, 81 patients had information available about their pulmonary symptoms for 1 to 2 years after the start of treatment. Thirty-nine patients survived 3 to 5 years. Twenty-three patients (15%) survived beyond 5 years. Seven of these 23 patients (30%) reported no pulmonary symptoms beyond 5 years. One patient reported no respiratory complaints until developing a new cardiomyopathy 7 years after therapy. Cough and/or dyspnea was reported in nine patients (39%) and eight patients (35%), respectively, with most patients reporting only mild symptoms. One patient reported the resolution of cough and dyspnea after 10 years. None of these patients complained of chronically increased sputum production. Three patients remained asymptomatic at the last follow-up, including two patients who are alive 10 and 15 years after the start of treatment. One patient remained asymptomatic until developing atypical mycobacteria after 8 years. Nine patients were asymptomatic or mildly symptomatic until they developed second cancers after 6 to 14 years. One of these patients was successfully treated for squamous cell carcinoma of the lip at 11 years and was alive without evidence of cancer after 15 years. The remaining eight patients developed respiratory symptoms arising from NSCLC. Details of second cancers in patients surviving treatment for SCLC, including a subset of patients who were included in this study, have been reported previously.17


View this table:
[in this window]
[in a new window]

  		Table 2.. Pulmonary Symptoms*

 
Baseline pulmonary signs were recorded for 136 patients. In addition to rhonchi, rales, wheezes, crackles, dullness to percussion, or decreased breath sounds, patients were also noted to have fever (14 patients; 10%), supraclavicular or neck masses (4 patients) including one patient with facial swelling and superior vena cava syndrome, and vocal cord paralysis (2 patients). At 1 to 2 years, additional signs included weight loss and tachypnea, without evidence of recurrence for two patients. The results for each time period are noted in Table 3 . Of the 23 patients living beyond 5 years, only 4 of them were without pulmonary signs or symptoms at presentation. One subject presented during an evaluation for abdominal pain, two subjects were referred for incidentally noted abnormal chest radiograph findings, and one subject presented with supraclavicular lymphadenopathy. All four of these patients had chest radiograph findings that were consistent with SCLC.


View this table:
[in this window]
[in a new window]

  		Table 3.. Pulmonary Signs*

 
Pulmonary function testing was available for 107 patients. Baseline pulmonary function tests were available for 96 patients. Spirometry results beyond 5 years were recorded for 11 patients. The results of pulmonary function testing are shown in Table 4 . Compared with the baseline values, the only significant change at 1 to 2 years was a decrease in mean (± SE) DLCO to 56 ± 5% (p = 0.032). None of the other values differed significantly from baseline at 3 to 5 years or > 5 years. Pulmonary function was shown to improve in four of the patients. The baseline data were unavailable for 3 of the 23 patients surviving for > 5 years. The percent predicted changes noted for FEV1, FVC, FEV1/FVC ratio, and DLCO for the 23 patients living beyond 5 years are shown in Figure 1 .


View this table:
[in this window]
[in a new window]

  		Table 4.. Percent Predicted Spirometry Values*

 


View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Mean percent predicted values for FEV1, FVC, FEV1/FVC ratio, and DLCO over follow-up intervals for the 23 patients living beyond 5 years. Vertical bars represent the mean ± SE.

 
The results of arterial blood gas analyses were available at baseline for 76 patients. Changes in arterial blood gas measurements are shown in Table 5 . The mean values for pH remained 7.43 to 7.44 from baseline through year 5, at which time only eight patients had arterial blood gas measurements made. Baseline PCO2 levels showed a mean level of 36.8 mm Hg at baseline (n = 76), which dropped to 33.4 mm Hg at 6 months (n = 21) and returned to 39.3 mm Hg at 1 to 2 years (n = 15). For the patients with data at baseline and at 6 months, the decline in PCO2 was significant (p = 0.0044).


View this table:
[in this window]
[in a new window]

  		Table 5.. Arterial Blood Gas Measurements

 
The results from baseline chest radiographs and either chest tomograms or CT scans of the chest were available for 140 patients. All available radiographs demonstrated a baseline mass and/or adenopathy that was consistent with a SCLC. Reports of radiographs were available for 40 patients surviving 1 to 2 years, for 22 patients surviving 3 to 5 years, and for 17 patients surviving beyond 5 years. These results are shown in Table 6 . In two patients (12%), an improvement in infiltrates was noted as long as 9 years after therapy. Of note, lung masses or adenopathy in all of the 17 patients surviving for > 5 years showed decreases in size within the first 6 to 12 months following treatment, which is consistent with a response to therapy.


View this table:
[in this window]
[in a new window]

  		Table 6.. Radiograph Findings

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study presents functional as well as anatomic information on the pulmonary status of patients surviving limited-stage SCLC for > 5 years. To our knowledge, this study includes the most extensive long-term pulmonary follow-up of patients with limited-stage SCLC who have been treated with chest radiation and chemotherapy. Patients with lung cancer treated with chemotherapy and chest radiotherapy typically have a decrement in pulmonary function within the first year after the start of treatment. Pulmonary symptoms, signs, and function in the survivors beyond 5 years were impaired but did not continue to decline in patients surviving beyond 5 years. Some of the survivors with pulmonary function study results beyond 5 years since therapy showed marked improvement initially that persisted over time.

Other investigators have reported on the long-term pulmonary toxicity of radiation in combination with chemotherapy. Miller et al18 evaluated long-term changes in pulmonary function tests in 128 patients surviving 3 to 8 years after definitive radiotherapy for unresectable lung cancer, and found a decline in percent predicted values for FEV1 and FVC at 6 months, an increase to baseline values at 12 months, then a subsequent decline at 7% and 9.5% per year, respectively. While the median values continued to decline overall beyond 2 years, the individual values appeared to plateau beyond 2 years, though long-term changes beyond 10 years were not described.18 Initial improvements in FEV1 and FEV1/FVC ratio have been reported in 45 patients who were treated with radiation therapy alone, with subsequent deterioration in DLCO 6 to 12 months after starting chemotherapy reflecting the recurrence of the cancer.9 A similar improvement was seen in our patients, and was likely due to the shrinkage of bulky central tumors leading to improvement in obstructive atelectasis and pulmonary function, as has been noted in other studies.1920 Abratt21 hypothesized that additional processes may be present causing the initial improvement in spirometry, including an increased bronchial patency from traction as a result of pulmonary fibrosis within the first year, as well as increased stiffening of the lungs and chest wall from progressive fibrosis, which may contribute to late decreases in lung volume study results. Acute pulmonary toxicity has been previously described by Brooks et al22 in a subset of our patients who were treated with combined radiation and chemotherapy compared with patients treated with chemotherapy alone. In the combined-modality group, life-threatening pulmonary toxicity was found to occur in 28% of patients at a at a median time of 63 days (range, 21 to 150 days) following the initiation of therapy, compared with only 5% of patients receiving chemotherapy alone. Despite the increased pulmonary toxicity in the combined-modality group, overall survival at 12 months favored patients in the combined-modality treatment arm.22 Most studies of lung cancer patients undergoing radiation and chemotherapy are limited by a short duration of follow-up.

The late effects of combined-modality therapy have been evaluated in other cancers, specifically Hodgkin disease and breast cancer. Villani et al23 followed a group of 32 patients with Hodgkin disease who had been treated with radiotherapy (median dose, 36 Gy) and doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. The median age of their patients was 28 years at follow-up, which is far younger than the patients in our present study, with an overall survival rate of 95%. These patients had a significant initial impairment of pulmonary function, and most returned to normal values within 18 months after the start of treatment, although 9 of their patients (28%) showed a persistent decline in DLCO. Clinical symptoms were minimally impaired with 12 of their patients having pulmonary complaints of cough or mild dyspnea on exertion at follow-up.23 The preservation of lung function has been demonstrated in 116 long-term survivors of Hodgkin disease who had been treated with radiation and/or chemotherapy 5 to 13 years following treatment, with treatment with bleomycin-anthracyclines (median cumulative bleomycin dose, 120 mg) as the only significant predictor for lung function impairment.6 Similar findings were obtained by Hassink et al,24 who evaluated pulmonary morbidity in 78 patients 10 to 18 years after they had undergone irradiation for Hodgkin disease. In their study, 21 patients also received chemotherapy combined with a lower radiation dose. In these patients, a slight but significant decline in TLC was found. Significant differences in cough (39.7% vs 21.1%, respectively) and dyspnea on exertion (44.7% vs 32.7%, respectively) were found in patients vs control subjects (ie, hospital visitors). Most of these patients with Hodgkin disease were without pulmonary function impairment prior to undergoing therapy, with mean percent predicted values reported for FEV1, TLC, FEV1/VC ratio, and DLCO within the normal range,24 vs lung cancer patients who have demonstrated lower average FEV1 percent predicted values for both SCLCs and NSCLCs.920

Combined therapy in lung cancer patients has more detrimental effects on lung parenchyma that have already been injured by smoking. In a review of 1,244 patients treated in Japanese Clinical Oncology Group trials25 from 1992 to 1997, patients with lung cancer who were treated with thoracic radiotherapy or radiotherapy with chemotherapy experienced a 1 to 2% mortality rate overall. The 84 patients with lung cancer with a history of COPD and patients who were treated with mitomycin C or adriamycin coupled with a large daily chest radiation dose of > 40 Gy were more likely to develop radiation pneumonitis.26 Patients with Hodgkin disease treated with dactinomycin, cyclophosphamide, vincristine, bleomycin, and doxorubicin with chest radiation therapy are at increased risk for radiation pneumonitis.1627 Of the pulmonary function test results reported, DLCO appears to be the most affected compared with the other parameters.5 Our patient group appeared to have relatively stable pulmonary function test results over time, with an initial decrement in DLCO that appeared to plateau over time. The use of etoposide and cisplatin vs regimens containing cyclophosphamide or doxorubicin, as well as the moderate doses and twice-daily dosing of radiotherapy are thought to minimize the morbidity associated with thoracic radiation. Similar to SCLC, NSCLC has been shown to have improved local control and improved survival with the addition of chemotherapy prior to radiation therapy.28 Our data for limited-stage SCLC patients may be applicable to this population of unresectable NSCLC patients who could potentially have a long-term cure with radiation therapy in situations in which surgery is not an option. Despite the relative stability in pulmonary function test results and in radiographic findings in our patients, pulmonary symptoms ultimately remain the most important determinant of the success of treatment for the patient.

In our cohort, the majority of patients at presentation complained of dyspnea, cough, chest pain, or sputum production. Among the survivors, pulmonary symptoms were not prominent, as all patients had either no pulmonary complaints or reported mild dyspnea or cough. This is not unexpected in a group of former and current smokers. Although nine of the patients who survived for > 5 years developed second cancers, it should be noted that all patients would continue to be at increased risk of developing cancer due to a history of smoking. The risk of a second primary malignancy in patients treated for SCLC is approximately 5% per patient per year and increases with time to 14% after 10 years, vs 1 to 2% per year for patients undergoing resection for NSCLC.17 Physicians should remain aware of the increased risk of developing a second NSCLC or aerodigestive cancer in these patients. Patients who continue to smoke are at even greater risk and should be encouraged to stop.1

In conclusion, limited-stage SCLC is an aggressive tumor that can be cured in a minority of patients. Despite the known toxicities of radiation and chemotherapy, our review suggests that survivors of limited-stage SCLC who have been treated with combined therapy can be reassured that major negative changes in pulmonary function or symptoms should not be expected over time. The potential toxicity of combined-modality therapy should not dissuade clinicians from offering their patients therapy with known survival benefit and potential cure with generally minimal to no pulmonary dysfunction.


   Footnotes
 
Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer; TLC = total lung capacity

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or the Department of Defense.

Received for publication March 3, 2005. Accepted for publication May 17, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Tucker, MA, Murray, N, Shaw, EG, et al (1997) Second primary cancers related to smoking and treatment of small-cell lung cancer: Lung Cancer Working Cadre. J Natl Cancer Inst 89,1782-1788[Abstract/Free Full Text]
  2. Lewinski, T, Zulawski, M Small cell lung cancer survival: 3 years as a minimum for predicting a favorable outcome. Lung Cancer 2003;40,203-213[CrossRef][ISI][Medline]
  3. Spira, A, Ettinger, DS Multidisciplinary management of lung cancer. N Engl J Med 2004;350,379-392[Free Full Text]
  4. Pignon, JP, Arriagada, R Role of thoracic radiotherapy in limited-stage small-cell lung cancer: quantitative review based on the literature versus meta-analysis based on individual data. J Clin Oncol 1992;10,1819-1820[Free Full Text]
  5. Marks, LB, Yu, X, Vujaskovic, Z, et al Radiation-induced lung injury. Semin Radiat Oncol 2003;13,333-345[CrossRef][ISI][Medline]
  6. Lund, MB, Kongerud, J, Nome, O, et al Lung function impairment in long-term survivors of Hodgkin’s disease. Ann Oncol 1995;6,495-501[Abstract/Free Full Text]
  7. Perry, MC, Eaton, WL, Propert, KJ, et al Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 1987;316,912-918[Abstract]
  8. Movsas, B, Raffin, TA, Epstein, AH, et al Pulmonary radiation injury. Chest 1997;111,1061-1076[Free Full Text]
  9. Choi, NC, Kanarek, DJ Toxicity of thoracic radiotherapy on pulmonary function in lung cancer. Lung Cancer 1994;10(suppl),S219-S230
  10. Dillman, RO, Herndon, J, Seagren, SL, et al Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88,1210-1215[Abstract/Free Full Text]
  11. Adjei, AA, Marks, RS, Bonner, JA Current guidelines for the management of small cell lung cancer. Mayo Clin Proc 1999;74,809-816[ISI][Medline]
  12. Johnson, BE, Ihde, DC, Bunn, PA, et al Patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation: data on potential cures, chronic toxicities, and late relapses after a five- to eleven-year follow-up. Ann Intern Med 1985;103,430-438[ISI][Medline]
  13. Bunn, PA, Jr, Lichter, AS, Makuch, RW, et al Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer: a prospective, randomized trial. Ann Intern Med 1987;106,655-662[ISI][Medline]
  14. Johnson, BE, Bridges, JD, Sobczeck, M, et al Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 1996;14,806-813[Abstract/Free Full Text]
  15. Catane, R, Lichter, A, Lee, YJ, et al Small cell lung cancer: analysis of treatment factors contributing to prolonged survival. Cancer 1981;48,1936-1943[CrossRef][ISI][Medline]
  16. McDonald, S, Rubin, P, Phillips, TL, et al Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys 1995;31,1187-1203[CrossRef][ISI][Medline]
  17. Johnson, BE, Linnoila, RI, Williams, JP, et al Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years. J Clin Oncol 1995;13,101-111[Abstract/Free Full Text]
  18. Miller, KL, Zhou, SM, Barrier, RC, Jr, et al Long-term changes in pulmonary function tests after definitive radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 2003;56,611-615[CrossRef][ISI][Medline]
  19. Vaaler, AK, Forrester, JM, Lesar, M, et al Obstructive atelectasis in patients with small cell lung cancer: incidence and response to treatment. Chest 1997;111,115-120[Abstract/Free Full Text]
  20. Maas, KW, van der Lee, I, Bolt, K, et al Lung function changes and pulmonary complications in patients with stage III non-small cell lung cancer treated with gemcitabine/cisplatin as part of combined modality treatment. Lung Cancer 2003;41,345-351[CrossRef][ISI][Medline]
  21. Abratt, RP Long-term changes in pulmonary function tests after definitive irradiation for lung cancer. Int J Radiat Oncol Biol Phys 2004;58,1008[ISI][Medline]
  22. Brooks, BJ, Jr, Seifter, EJ, Walsh, TE, et al Pulmonary toxicity with combined modality therapy for limited stage small-cell lung cancer. J Clin Oncol 1986;4,200-209[Abstract]
  23. Villani, F, De Maria, P, Bonfante, V, et al Late pulmonary toxicity after treatment for Hodgkin’s disease. Anticancer Res 1997;17,4739-4742[ISI][Medline]
  24. Hassink, EA, Souren, TS, Boersma, LJ, et al Pulmonary morbidity 10–18 years after irradiation for Hodgkin’s disease. Eur J Cancer 1993;29,343-347[CrossRef]
  25. Ohe, Y Treatment-related death from chemotherapy and thoracic radiotherapy for advanced cancer. Panminerva Med 2002;44,205-212[ISI][Medline]
  26. Rancati, T, Ceresoli, GL, Gagliardi, G, et al Factors predicting radiation pneumonitis in lung cancer patients: a retrospective study. Radiother Oncol 2003;67,275-283[CrossRef][ISI][Medline]
  27. Segawa, Y, Takigawa, N, Kataoka, M, et al Risk factors for development of radiation pneumonitis following radiation therapy with or without chemotherapy for lung cancer. Int J Radiat Oncol Biol Phys 1997;39,91-98[CrossRef][ISI][Medline]
  28. Solomon, B, Ball, DL, Richardson, G, et al Phase I/II study of concurrent twice-weekly paclitaxel and weekly cisplatin with radiation therapy for stage III non-small cell lung cancer. Lung Cancer 2003;41,353-361[CrossRef][ISI][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Myers, J. N.
Right arrow Articles by Johnson, B. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Myers, J. N.
Right arrow Articles by Johnson, B. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS