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Ann Thorac Surg 2003;76:1674-1678
© 2003 The Society of Thoracic Surgeons
a Respiratory Diseases Center, Kyoto-Katsura Hospital, Kyoto, Japan
Accepted for publication May 29, 2003.
* Address reprint requests to Dr Fujimoto, Respiratory Diseases Center, Kyoto-Katsura Hospital, Yamada-Hirao 17, Nishikyo, Kyoto 615-8256, Japan.
e-mail: fjmtt{at}aol.com
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Abstract |
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METHODS: From January 1992 through December 2001, 64 patients who had simultaneous lung cancer and idiopathic pulmonary fibrosis were treated. Twenty-one (33%) of them underwent surgical resection of lung cancer, and their data were reviewed.
RESULTS: There were 56 men and 8 women with an average age of 69 years (range, 43 to 85 years). In the surgical group, there were no early postoperative deaths, and nonfatal complications occurred in 2 patients (10%). Among the 14 patients with stage I cancer, a second primary lung cancer developed in 5 (36%). The causes of death in the surgical group were cancer related in 7 patients, exacerbation of idiopathic pulmonary fibrosis in 7, and other in 2. Five of the 7 patients who died of a cancer-related cause had development of a second primary lung cancer. The actuarial 2-year survival rate of the surgical group was 52% overall, 58% for patients with N0 or N1 disease and 25% for those with N2 disease (p = 0.05).
CONCLUSIONS: The long-term results in one surgical group were poor partly because of the high incidence of a second primary lung cancer and partly because of the poor natural history of idiopathic pulmonary fibrosis. These patients require intensive surveillance even after curative resection of lung cancer.
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Introduction |
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Thoracic surgeons occasionally encounter patients with IPF as recipients for lung transplants. Although not commonly faced, the resection of concomitant lung cancer is also an important surgical problem. As few studies have addressed the treatment of this patient group, current management is empirical. To further evaluate short-term and long-term mortality, we reviewed our results over a 10-year period. The purposes of this study were to determine the outcome of surgical treatment and to establish the surgical strategy for lung cancer with IPF.
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Material and methods |
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Typically, the diagnosis of IPF was made by surgical biopsy on the basis of pathological evidence of UIP. When a surgical biopsy was not carried out, clinical findings such as fine crackles at the bilateral lower lung and a typical UIP pattern identified by computed tomography were prerequisites for inclusion [9]. In patients who underwent a surgical procedure, the diagnosis of IPF was reconfirmed pathologically using the surgical specimen.
Surgical indications
Twenty-one patients (33%) underwent surgical resection of lung cancer. The eligibility criteria for surgical resection of lung cancer with IPF were the following: adequate lung function (predicted postoperative forced expiratory volume in 1 second > 1.2 L, predicted postoperative carbon monoxide diffusing capacity of the lung > 30%); grade lower than 2 on the modified five-point dyspnea scale developed by Fletcher and associates [10]; clinically stable IPF; T1 or T2 as staged by preoperative computed tomography; N0 or N1 as staged by preoperative mediastinoscopy; possible complete resection; no cardiac disease; and no other extrathoracic malignancy.
Idiopathic pulmonary fibrosis was defined as stable if the patient had not noticed an exacerbation of dyspnea for at least the past 6 months. Chest computed tomography was performed on all patients to evaluate the severity and distribution of both IPF and lung cancer. Ventilation perfusion scintigraphy was done to estimate the postoperative lung function of patients in the surgical group.
The operation was performed through a muscle-sparing anterolateral thoracotomy. Mediastinoscopy was carried out before operation, and systematic mediastinal lymph node dissection was done as part of the surgical procedure in every patient in the surgical group.
Follow-up
After surgical resection, patients were scheduled for follow-up visits every 1 month to 3 months, with medical history, physical examination, and chest radiographs at each visit. New malignancies were evaluated and classified as either recurrence or second primary cancer. A second primary tumor was defined as a second malignancy with a different histology or different anatomic site or a malignancy with the same histology occurring more than 2 years after the first malignancy [11].
All patients stopped smoking before operation and continued to not smoke postoperatively. Exposure to other carcinogens was not identified in any of the patients.
Statistical analysis
The medical records of both the surgical group and the nonsurgical group were reviewed for information related to age, sex, degree of dyspnea, pulmonary function test results: arterial blood gas studies, use of corticosteroids, tumor histology, TNM classification, operations performed, other treatments including chemotherapy and radiotherapy, complications, and survival. Clinical data are reported as the mean ± the standard deviation. Cumulative survival was estimated with a Kaplan-Meier model. The actuarial survival of the surgical group was calculated from the day of operation and the actuarial survival of the nonsurgical group was calculated from the time the cancer was discovered. The comparison of survival between groups was made with the log-rank test, performed using StatView Version 5.0 statistical software (SAS Institute Inc, Cary, NC).
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Results |
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Surgical group
The preoperative characteristics of the surgical group (n = 21) including pulmonary function test results and arterial blood gas analyses are summarized in Table 1.
Most of these patients had mild IPF.
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Seventeen patients (81%) underwent a lobectomy (4, upper; 3, middle; 10, lower), and 2 patients (10%) each underwent a segmental resection and a wedge resection. A right thoracotomy was done in 11 patients, and a left thoracotomy, in 10 patients.
Histological findings included squamous cell carcinoma in 12 patients (57%), adenocarcinoma in 7 (33%), adenosquamous cell carcinoma in 1 patient (5%); and large cell carcinoma in 1 (5%). Clinical and pathological staging are shown in Table 2.
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Among the 14 patients with stage I cancer, a second primary lung cancer developed in 5 patients (36%). The intervals between the first operation and the discovery of the second lung cancer were 16, 17, 31, 37, and 44 months. The second primary lung cancers were squamous cell carcinoma in 3 patients who initially had squamous cell carcinoma and small cell carcinoma in 1 patient who initially had adenocarcinoma and 1 patient with adenosquamous cell carcinoma initially. Three of these patients underwent systemic chemotherapy for the second primary lung cancer, 1 patient underwent a partial resection, and 1 received only pain-control therapy.
Nonsurgical group
Forty-three patients were excluded from surgical intervention. The reasons for exclusion were advanced stage of lung cancer in 24 patients (56%), poor respiratory status in 14 patients (33%), and other in 5 patients (12%) (patient refusal in 3, cardiac disease in 1, extrathoracic malignancy in 1). Forty-one (95%) of the patients were smokers. Eight patients (19%) were on a regimen of oral corticosteroids, the dose ranging from 5 to 30 mg. During the course of the disease progression, long-term oxygen supplementation was administered nasally for > 3 months in 11 patients (26%). The diagnosis of IPF was obtained by open lung biopsy in 7 patients (16%). In the others, the diagnosis of IPF was made clinically according to the criteria already described. Thirty-six patients (84%) underwent flexible bronchoscopy, but transbronchial lung biopsy did not reveal findings suggestive of UIP or other diseases.
Lung cancer was detected simultaneously with IPF in 27 patients (63%). In the other 16 patients (37%), lung cancer was found during routine follow-up for IPF, with a median interval of 4 years (range, 1 to 10 years), between the detection of IPF and the detection of lung cancer. The histological findings included squamous cell carcinoma in 17 patients (40%), adenocarcinoma in 17 (40%), small cell carcinoma in 5 (12%), large cell carcinoma in 3 (7%), and unclassified non–small cell carcinoma in 1 patient (2%). Clinical staging of the patients was as follows: stage IA, 4; stage IB, 3; stage IIA, 1; stage IIB, 3; stage IIIA, 10; stage IIIB, 8; and stage IV, 14.
Platinum-based chemotherapy was administered to 15 patients (35%). Cisplatin-etoposide was used for small cell carcinoma, and cisplatin-vinblastine sulfate-mitomycin or cisplatin-docetaxel was used for non–small cell carcinoma. The staging and the results of treatment of these patients are summarized in Table 3. No severe complications were observed in these patients (all 43 in the group). Seven patients (16%) received curative radiation therapy with a median total dose of 63 Gy (range, 59.4 to 66 Gy). Partial remission was achieved in 2 (29%) of them; the other 5 (71%) showed no change or no measurable change. A fatal acute lung injury occurred in 2 patients (29%), and 3 patients (43%) experienced exacerbation of dyspnea caused by radiation pneumonitis 2 to 5 months after radiation therapy and required increased supplemental oxygen.
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Comment |
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The most striking finding in our report was the high rate of occurrence of a second primary lung cancer in this population (36% of stage I patients). In the general population, the likelihood of a new primary lung cancer developing after curative-intent therapy for a non–small cell carcinoma is 1% to 2% per patient per year [12, 13]. The reason for the high rate of occurrence of new malignancies in patients with IPF is unknown. However, we speculate that inflammatory cells produce various kinds of cytokines that can stimulate the proliferation of epithelial cells, a process resulting in carcinoma formation along with oncogene activation [14]. The poor long-term results after surgical resection of lung cancer in patients with IPF can be attributed in part to this high rate of occurrence of a new malignancy. Several subgroups of patients who are at high risk for metachronous lung cancer have been identified (ie, patients whose primary lung cancer was radiographically occult or centrally located and patients surviving for more than 2 years after treatment for small cell lung cancer) [12]. We propose that patients with IPF be included in these high-risk subgroups who need a more intensive surveillance program.
Hubbard and associates [5] reported an increased incidence of lung cancer in patients with IPF compared with an age- and sex-matched control group in a population-based cohort study, but other studies [15, 16] did not show an increased risk of lung cancer. Because cigarette smoking is an independent risk factor for both diseases, an association between the two diseases may be difficult to establish. Another possible mechanism for the development of lung cancer is carcinogenesis caused by pulmonary fibrosis through the promotion of atypical epithelial proliferation [17]. The clinical characteristics of lung cancer with IPF were demonstrated by Mizushima and Kobayashi [14], who reported a preponderance of male patients and heavy smokers with cancer in the lower lobe and peripheral locations. Our results support those of their study. Patients with IPF should be urged to stop smoking and should also received vigilant screenings [18].
In the recent report by Martinod and colleagues [19], the long-term survival of patients with lung cancer was not affected by the association with interstitial lung disease. This contradiction with our results is explained by the lower proportion of patients with IPF (10%) in their study. In addition, the interstitial lung disease was discovered after the surgical resection of lung cancer in some of their patients. Our study was limited to patients with a preoperative diagnosis of UIP or IPF, which has a substantially worse prognosis than the other interstitial lung diseases. We stress the importance of a definite diagnosis of IPF before surgical resection of lung cancer.
In our study, the 7 patients who were in clinical stage N2 or N3 had no metastases in the upper mediastinum at mediastinoscopy. The discrepancy between the clinical and the pathological staging may have been due to swelling of the lymph nodes, which is related to persistent inflammation in the lung parenchyma caused by IPF. Definite preoperative staging by mediastinoscopy is recommended because N2 patients had an extremely poor prognosis even after curative resection.
Radiation therapy worsens the respiratory symptoms in patients with IPF. Although we could find no report addressing the association between IPF and radiation pneumonitis, Monson and coauthors [20] suggested that a low Karnofsky performance status, comorbid lung disease, a history of smoking, low pulmonary function test results, and no surgical resection were associated with the development of clinical radiation pneumonitis. In the early period of our study, curative radiation therapy was performed without definite selection criteria. Consequently, 43% of the patients experienced radiation pneumonitis after radiation therapy, and fatal acute lung injury occurred in 29%. We now consider this treatment to be contraindicated for this patient group and no longer recommend its use.
Our strategy for resection of lung cancer with IPF is based on two key principles: making a definite preoperative diagnosis of IPF and avoiding procedures that interfere with the quality of life of the patient. If IPF and lung cancer are discovered simultaneously, the diagnosis of IPF should be made first. Video-assisted or open thoracotomy is recommended if the clinical diagnosis is difficult [21]. This diagnostic procedure can be combined with mediastinoscopy for staging lung cancer. Considering the high recurrence rate in and the poor prognosis for this patient population, a limited resection is acceptable if the resection can be achieved with an adequate margin. Patients with lung cancer invading the chest wall were excluded from operation in our study because chest wall resection is associated with major morbidity [22]. Pneumonectomy should be avoided for the same reason.
In conclusion, surgical intervention for lung cancer in patients with IPF can be safely performed with acceptable morbidity. However, the long-term results tend to be poor because of the high incidence of a second primary lung cancer and because of the poor natural history of IPF itself. Patients with concomitant lung cancer and IPF need intensive surveillance even after curative resection of lung cancer.
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References |
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  T. Okuma, T. Matsuoka, S. Hamamoto, K. Nakamura, and Y. Inoue Percutaneous computed tomography-guided radiofrequency ablation of lung tumors complicated with idiopathic interstitial pneumonia. Ann. Thorac. Surg., March 1, 2009; 87(3): 948 - 950. [Abstract] [Full Text] [PDF]
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