Idiopathic pulmonary fibrosis (IPF), also referred to as

Operation for Lung Cancer in Patients With Idiopathic Pulmonary Fibrosis: Surgical Contraindication? Toshio Fujimoto, MD, Tsuyoshi Okazaki, MD, Tadashi Matsukura, MD, Takeshi Hanawa, MD, Naoki Yamashita, MD, Koichi Nishimura, MD, Masayoshi Kuwabara, MD, and Yoshito Matsubara, MD Respiratory Diseases Center, Kyoto-Katsura Hospital, Kyoto, Japan Background. Patients with idiopathic pulmonary fibrosis have an increased incidence of lung cancer. The purpose of this study was to determine the outcome of surgical treatment of lung cancer with idiopathic pulmonary fibrosis. 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. (Ann Thorac Surg 2003;76:1674 9) 2003 by The Society of Thoracic Surgeons Idiopathic pulmonary fibrosis (IPF), also referred to as cryptogenic fibrosing alveolitis, is a specific form of chronic fibrosing interstitial pneumonia confined to the lungs and is associated with the histological appearance of usual interstitial pneumonia (UIP). Idiopathic pulmonary fibrosis is relatively frequent among diffuse infiltrative lung disorders and has a progressive course. Although empirically corticosteroids can be used for the management of the disease, their use has not generated strongly positive results. There is no doubt that patients with IPF have a poor prognosis with a mortality rate ranging from 59% to 70% and a mean survival of 5 to 6 years [1 4]. Exacerbation of IPF, concomitant acute lung injury, and an increased incidence (9.8% to 38%) of lung cancer account for the major causes of death in patients with IPF [5 8]. 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, 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@aol.com. 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. Material and Methods From January 1992 through December 2001, 64 patients with simultaneous lung cancer and IPF were seen at the Respiratory Diseases Center, Kyoto-Katsura Hospital, and their records were analyzed in the present study. The three entry criteria were as follows: lung cancer was discovered during follow-up for a past case of IPF or was discovered simultaneously with IPF; the diagnosis of lung cancer was confirmed either histologically or cytologically; and the diagnosis of IPF was confirmed as will be described. Patients in whom IPF was an incidental finding after surgical resection of lung cancer were not included in this study. Patients with diffuse interstitial lung disease with a known cause such as collagen vascular disease and environmental lung disease were also excluded. 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 2003 by The Society of Thoracic Surgeons 0003-4975/03/$30.00 Published by Elsevier Inc doi:10.1016/s0003-4975(03)00966-4

Ann Thorac Surg FUJIMOTO ET AL 2003;76:1674 9 OPERATION FOR LUNG CANCER WITH IPF 1675 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 musclesparing 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 Table 1. Characteristics of 21 Patients in Surgical Group a Variable 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). Results Value b Age (y) 68 7 Sex Male 20 Female 1 Smoker 20 (95) Dyspnea score 1.3 0.5 Pulmonary function test results FVC (ml) 2,926 480 FVC (% predicted) 99 17 Dco (ml min 1 mm Hg 1 ) 10 4 Dco (%) 68 23 Arterial blood gas analysis (at rest) Po 2 (mm Hg) 85 9 Pco 2 (mm Hg) 40 5 Clinical stage I, II 14 III, IV 7 Tumor location Upper 7 Middle 3 Lower 11 (52) a Where applicable, data are shown as the mean the standard deviation. b Numbers in parentheses are percentages. Dco diffusion capacity of lung for carbon monoxide; FVC forced vital capacity; Pco 2 carbon dioxide tension; Po 2 oxygen tension. The group of 64 patients comprised 56 men and 8 women with an average age of 68.8 years (range, 43 to 85 years). 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. Lung cancer was detected simultaneously with IPF in 8 patients (38%). In these patients, the diagnosis of IPF was made either clinically or pathologically before the cancer operation. In the other 13 patients (62%), lung cancer was found during routine follow-up for IPF, with a median interval of 4.5 years (range, 3 months to 10 years) between the detection of IPF and the detection of lung cancer. Twenty patients (95%) had a smoking history longer than 20 pack-years. None of the patients in this group had used oral or inhaled corticosteroids before operation. After operation, 5 patients (24%) received supplemental oxygen nasally for 3 months.

1676 FUJIMOTO ET AL Ann Thorac Surg OPERATION FOR LUNG CANCER WITH IPF 2003;76:1674 9 Table 2. TNM Classification of Surgical Group TNM No. of Patients Clinical T1 N0 5 T2 N0 2 T2 N1 7 T1 N2 2 T2 N2 4 T2 N3 1 Total 21 Pathological T1 N0 5 T2 N0 9 T1 N1 1 T2 N1 2 T1 N2 1 T2 N2 2 T4 N2 1 Total 21 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. There were no postoperative deaths within 90 days after operation. Complete resection was achieved in all of the patients. Nonfatal complications occurred in 2 patients (10%). One of them had a persistent air leak for 2 weeks, and the other had sputum retention, which required bronchoscopic aspiration. 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 sulfatemitomycin 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 Table 3. Tumor Response and Survival of Patients Undergoing Chemotherapy Histology No. of Patients Staging No. of Patients Tumor response CR PR NC PD Median Survival (m) NSCLC 12 III A 5 0 5 5 2 6.6 III B 1 IV 6 SCLC 3 II B 1 1 2 0 0 11.6 III B 2 CR complete remission; NC no change; NSCLC non small cell lung carcinoma; PD progressive disease; PR partial remission; SCLC small cell lung carcinoma.

Ann Thorac Surg FUJIMOTO ET AL 2003;76:1674 9 OPERATION FOR LUNG CANCER WITH IPF 1677 Fig 1. Survival curves for entire surgical group and subgroups classified by lymph node status. The overall 2-year survival rate was 52%. Patients in stage N0 or N1 (N0-1) showed a significantly higher survival rate (58%) compared with those in stage N2 (25%) at 2 years (p 0.05) (Black circles patients alive at the end of the survey.) 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. Survival Follow-up was complete for all patients in the surgical group, and the mean follow-up was 22 17 months. In this group, 16 patients (76%) had died by the end of the survey. The causes of death were cancer-related in 7 (44%), respiratory failure related to IPF in 7 (44%), pneumonia in 1 (6%), and acute myocardial infarction in 1 (6%). Of the seven patients with a cancer-related death, 5 had a second primary lung cancer. The overall actuarial 2-year survival rate calculated from the day of operation was 52%; it was 58% for patients with N0 or N1 disease and 25% for those with N2 disease. The difference in 2-year survival rates between the N0-N1 and N2 subgroups was significant (p 0.05) (Fig 1). In the non-surgical group, the survival rate at 2 years was 17% calculated from the time of discovery of cancer. Four patients (9%) were lost during follow-up, and 35 patients (81%) had died by the end of the survey. The causes of death were lung cancer related in 17 patients (49%), respiratory failure related to IPF in 14 (40%), bacterial pneumonia in 2 (6%), cardiac disease in 1 patient (3%), and extrathoracic malignancy in 1 (3%). Comment This is one of the first reports compiling the surgical results for patients with concomitant UIP or IPF and lung cancer. Our study showed a poor prognosis for these patients even after complete resection of the lung cancer, with 2- and 5-year survival rates of 52% and 0%, respectively. The question of whether to operate is under debate, as patients with IPF are known to have a poor prognosis, and those with unresected lung cancer have a terrible course. We should consider not only whether to operate, but also whether surgical resection will improve the long-term prognosis for and the quality of life of these patients. Our study demonstrated that surgical risk can be mitigated by careful examination of the indications for operation. However, more importantly, we should consider the patient s prognosis. 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 longterm 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

1678 FUJIMOTO ET AL Ann Thorac Surg OPERATION FOR LUNG CANCER WITH IPF 2003;76:1674 9 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. 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