Smoking Cessation after Successful Treatment of Small-Cell Lung Cancer Is Associated with Fewer Smoking-related Second Primary Cancers

Combination chemotherapy for small-cell lung cancer results in objective responses in 80% to 90% of patients and in 3% to 13% of 2-year cancer-free survivors [1-7]. Relapses 2 years after initiation of therapy occur in approximately one third of 2-year survivors [1, 6, 7]. In addition, deaths from second malignancies, particularly of the lung, and from nonmalignant smoking-related medical problems have been reported in patients with small-cell lung cancer who survive free of cancer for more than 2 years [3, 5, 7-10]. Consequently, the overall 5-year survival rate for all patients with small-cell lung cancer is low, reported as 2.4% to 6% [1, 5, 7-9, 11, 12]. To estimate the risk for second primary cancers in survivors of small-cell lung cancer, we evaluated all patients with this malignancy who remained disease free for 2 years after the initiation of therapy at the National Cancer Institute. The potential change in the risk for a second cancer during follow-up was studied to determine whether the risk increases or decreases with time. In addition, the influence of smoking cessation on the development of subsequent primary smoking-related cancers is undefined [13-20]. Smoking history in our patient population was therefore carefully assessed, and the effect of smoking cessation was evaluated. Methods Patients From April 1973 to December 1989, 540 consecutive patients with histologically confirmed, previously untreated small-cell lung cancer were treated in National Cancer Institute intramural therapeutic trials. All had primary small-cell carcinoma of the lung with evaluable tumor lesions; none were treated in an adjuvant setting after surgical resection. The majority of patients were assigned a performance status, metastatic sites identified, and they were classified as having either limited- or extensive-stage disease as previously defined [21, 22]. The patients began treatment with combination chemotherapy with or without radiotherapy using various regimens that have been reported previously [11, 21-29]. The current status of all patients was determined. The locations of the initial small-cell lung cancers were identified by reviewing reports of chest roentgenograms, thoracic computed tomography, fiberoptic bronchoscopies, mediastinoscopies, and thoracotomies in all patients who were free of cancer for 2 or more years after the initiation of chemotherapy. The sites of subsequent intrathoracic cancer were localized by reviewing reports of chest roentgenograms, thoracic computed tomography, fiberoptic bronchoscopies, thoracotomies, and autopsies. Chest roentgenograms and computed tomographic scans from patients with second primary non-small-cell lung cancers were compared with pretreatment radiotherapy chest roentgenograms showing treatment ports. All initial and subsequent pathologic material was reviewed by one of two pathologists from our institution. The diagnosis of small-cell lung cancer was made and confirmed using the previously defined histologic criteria [30, 31]. Smoking history in all 55 2-year cancer-free survivors was repeatedly determined by a combination of patient follow-up visits, chart and protocol database review, and contact of either patients alive at the time of manuscript preparation or relatives of deceased patients. Smoking cessation was defined as completely stopping smoking by the end of treatment, which was usually of 6 months duration. Definitions The upper aerodigestive tract includes the epithelial regions of the head and neck, lung, and esophagus [13, 32-34]. Smoking-related cancers include cancers of the lung, head and neck, esophagus, bladder, pancreas, kidney, and possibly the stomach [35]. A second primary non-small-cell lung cancer after an initial small-cell lung cancer occurs when 1) tumor histologic findings show non-small-cell lung cancer without small-cell elements; 2) no evidence suggests local or distant recurrence of small-cell lung cancer; and 3) the second cancer is identified more than 2 years after diagnosis of the original small-cell lung cancer [3, 36, 37]. Statistical Analysis For estimation of the expected values of second cancer development, the period of risk began 2 years after diagnosis of the small-cell lung cancer and ended with the date of death, date of last follow-up, or date of diagnosis of a second cancer, whichever occurred first. Person-years of observation were accumulated using the computer program of Monson [38]. Age, sex, and time-specific rates for mortality obtained from the National Mortality Statistics and for cancer incidence obtained from the Surveillance, Epidemiology, and End Results (SEER) program were applied to the appropriate person-years of observation, had this population experienced the same rates prevailing in the national or SEER populations, respectively. Statistical methods for risk estimation were based on the assumption that the observed number of second cancers followed a Poisson distribution [39]. Test of significance and confidence intervals (CIs) for the relative risk (observed and expected) were calculated by using exact Poisson probabilities. To determine the absolute risk, or excess cases of cancer per 1000 persons per year, the number of expected cases was subtracted from the number observed; the difference was divided by the number of person-years of observation and multiplied by 104. Trends and homogeneity were tested as described by Breslow and colleagues [39]. Results Patient characteristics at time of initiation of treatment for both the entire patient population and for the 2-year cancer-free survivors are summarized in Table 1. Of the 540 patients, 55 (10%) were alive and free of cancer 2 or more years after the initiation of treatment protocols Figure 1, corresponding to 22% of 204 patients with limited-stage and 3% of 336 patients with extensive-stage disease. Eighty-six of the patients did not have a performance status assigned or metastatic sites identified prospectively. Compared with the entire patient population, the 2-year cancer-free survivors had a higher percentage of women, of patients with limited-stage disease, and of fully ambulatory patients (Eastern Cooperative Oncology Group performance status, 0-1). These favorable prognostic factors are thoroughly described in the literature [40-43]. The other 485 patients died or had relapsed with small-cell lung cancer within 2 years. The median follow-up from initiation of therapy was 6.1 years (range, 2.1 to 15.1 years) for the 55 patients. Ten patients have remained free of cancer since initial treatment. Five other patients remain alive; three developed second primary cancers that were successfully treated; and two relapsed with small-cell lung cancer, one achieving a prolonged second complete response (>3 years) after recurrence and the other currently receiving salvage chemotherapy. Of the 55 patients, 40 have died: 16 from recurrent small-cell lung cancer, 13 from second primary cancers, 1 from a suspected second primary lung cancer (lung mass without histologic confirmation), and 10 from other causes. Table 1. Patient Characteristics Figure 1. Flow diagram of the outcome of 540 patients with small-cell lung cancer treated at the National Cancer Institute from 1973 to 1989. Eighteen of the 55 patients developed recurrent small-cell lung cancer 2.1 to 12.2 years (median, 3.2 years) after beginning chemotherapy (see Figure 1). The histopathologic features of 4 of the 18 (22%) recurrent small-cell lung cancer tumors included subpopulations of cells with prominent nucleoli but were still in the histologic spectrum of small-cell lung cancer [30]. Eighteen of the 55 2-year cancer-free survivors developed one or more second primary cancers 3.5 to 13.3 years (median, 7.5 years) after beginning therapy for small-cell lung cancer. One of the 18 patients with a second primary cancer had invasive squamous cell carcinoma of the lip, which metastasized to the regional lymph nodes. Another patient died of a central nervous system disorder but had an incidental esophageal cancer discovered at postmortem examination. These cancers were not included in the calculations of the relative risk because incidence data are not available from SEER on nonmelanoma skin cancer and on incidental cancers discovered at postmortem examination (Table 2). The sarcoma was included with other lung cancers because the SEER incidence rates are based on the classification of cancers by site of origin, not by histologic findings. Table 2. Incidence of Second Primary Cancers after at Least 2 Years of Survival with Small-Cell Lung Cancer* The risk for development of a second cancer more than 2 years after the diagnosis of small-cell lung cancer increased by approximately four times, mostly due to the 16-fold increase in second non-small-cell lung cancers (nine squamous; one adenocarcinoma, one large cell carcinoma, and one sarcoma; and one suspected second primary cancer without histologic confirmation) (Table 2). A patient who developed an adenocarcinoma of the lung 12 years after the initial diagnosis of small-cell lung cancer had an initial biopsy specimen with predominant small-cell lung cancer histologic features and an adenocarcinoma component. The patient who developed a squamous cell cancer of the head and neck 8.9 years after the initiation of treatment for small-cell lung cancer had mixed small-cell/large-cell histologic features. The other 53 patients had only small-cell lung cancer in their biopsy specimens at presentation. Seven cancers developed in the lung contralateral to the original small-cell lung cancer, two in a different lobe of the ipsilateral lung, three in the same lobe, and one site could not be accurately determined because of the presence of massive bilateral pleural effusions. The relative risk for a second primary non-small-cell lung cancer compared with that in the general population increased significantly over time from 6 times at 2 to 4 years to 36 t