Japanese Journal of Clinical Oncology Advance Access originally published online on December 20, 2005
Japanese Journal of Clinical Oncology 2006 36(1):7-11; doi:10.1093/jjco/hyi208
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© 2005 Foundation for Promotion of Cancer Research
Second Primary Cancers in Patients with Stage III Non-Small Cell Lung Cancer Successfully Treated with Chemo-radiotherapy
1 National Hospital Study Group for Lung Cancer in Japan, 2 Department of Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Osaka, 3 Department of Surgery, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Osaka, 4 National Hospital Organization Okinawa Hospital, Ginowan, Okinawa, 5 National Hospital Organization Toneyama Hospital, Toyonaka, Osaka, 6 National Hospital Organization Ibaragi-Higashi Hospital, Naka-gun, Ibaraki and 7 National Hospital Organization Matsumoto Hospital, Matsumoto, Nagano, Japan
For reprints and all correspondence: Tomoya Kawaguchi, Department of Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center 1180 Nagasone-cho, Sakai, Osaka 591-8555, Japan. E-mail address: t-kawaguchi{at}kch.hosp.go.jp
Received August 11, 2005; accepted October 20, 2005
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Abstract |
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Background: Patients successfully treated for non-small cell lung cancer (NSCLC) remain at risk for developing second primary cancer (SPC). The purpose of the current study is to assess the incidence of SPC and the impact of smoking status on the SPC in long-term survivors with stage III NSCLC after chemo-radiotherapy.
Methods: Using the database from the Japan National Hospital Lung Cancer Study Group between 1985 and 1995, information was obtained on 62 patients who were more than 3 years disease-free survivors. Details of clinical information and most smoking history were available from the questionnaire.
Results: Nine of the 62 patients developed SPC 3.9–12.2 years (median, 6.2 years) after the initiation of the treatment. The site of SPC was 2 lung, 1 esophagus, 2 stomach, 1 colon, 1 breast, 1 skin and 1 leukemia. Among these nine, three cancers occurred inside the radiation field. The relative risk of any SPC was 2.8 [95% confidence interval (CI) 1.3–5.3]. The risk changed with the passage of time and it increased significantly (5.2 times at or beyond 7 years) after the treatment. In univariate analysis, the patients who were male, had more cumulative smoking and continued smoking, had an increased risk of SPC [relative risk (RR) 2.7, CI 1.1–5.3; RR 3.0, CI 1.2–6.2; RR 5.2, CI 1.6–11.7, respectively]. In multivariate analysis, factors including smoking status and histological type had no effect on the development of a SPC.
Conclusion: The patients with stage III NSCLC successfully treated with chemo-radiotherapy were at risk for developing SPC and this risk increased with time.
Key Words: second primary cancer • non-small cell lung cancer • chemo-radiotherapy
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INTRODUCTION |
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The introduction of combined modality therapy as chest radiotherapy (RT) and chemotherapy for patients with stage III non-small cell lung cancer (NSCLC) has resulted in achieving
15% long time survivors (12–3). However, patients successfully treated for NSCLC as well as small cell lung cancer (SCLC) remain at risk for developing second primary cancer (SPC) (4). The risk of SPC in patients with NSCLC has been studied mainly in cohorts of surgically resected patients for stage I NSCLC (567). These reports suggest that the risk of developing SPC and second primary lung cancer (SPLC) is 1–4% and 1–2% per patient per year, respectively, and it appears to increase with the passage of time. Another study including stages I and II patients treated with chest RT confirmed a similar trend that the risk of developing SPC and SPLC is 4.3 and 1.4% per patient per year, respectively (8). Unlike the studies of the patients with SCLC (9–11), these did not provide adequate follow-up information to determine relative risk. Also, there has been no report to date to evaluate the risk of SPC associated with the treatment of RT with chemotherapy as well as smoking status in stage III NSCLC patients.
PATIENTS AND METHODS
Information was obtained on 1643 patients with stage III NSCLC between 1985 and 1995, using the database from the National Hospital Study Group for Lung Cancer, including National Hospital Organization Kinki-chuo Chest Medical Center, National Hospital Organization Toneyama Hospital and National Hospital Organization Okinawa Hospital. Among them, 547 patients were treated with chemo-radiotherapy with or without surgery. Of the 547, the 62 patients were more than 3 years disease-free survivors. The patients who relapsed within the 3 years were excluded in this study. Details of clinical information after the treatment and smoking history of the patients were obtained by a questionnaire, which was completed by directly interviewing the patients or the relatives of deceased patients, or by checking the patient's medical records.
Smoking cessation was defined as completely stopping smoking within 6 months after initiation of treatment. Smoking-related cancers include cancer of the lung, larynx and oral cavity, including pharynx, esophagus, pancreas, bladder, kidney, stomach and uterine cervix. A second primary lung cancer was diagnosed according to the criteria provided by Martini and Melamed in 1975 (12). The period of the study was taken as starting from the first day of therapy, and the date of second cancer was taken as the day of histological or cytological documentation of cancer.
For estimation of the expected values of SPC development, the period of risk began 3 years after initiation of treatment and ended with the date of death, date of last follow-up or date of diagnosis of a SPC, whichever occurred first. Age, gender and period-specific rates for cancer incidence within the period 1985–98 obtained from the Research Group for Population-based Cancer Registration in Japan were applied to the appropriate person-years of observation (13). Statistical methods for risk estimation were based on the assumption that observed number of second cancers followed a Poisson distribution (14). To calculate excess risks per 10 000 patients per year in subgroups with significant relative risks, the expected number of cases was subtracted from the number observed. The difference was divided by person-years of observation, and multiplied by 10 000. The risk of a SPC with a specific exposure as smoking was estimated by comparing the patients without the specific exposure, using Poisson regression methods adjusting for gender, histology (squamous cell carcinoma versus non-squamous cell carcinoma) and cumulative smoking amount before the treatment of NSCLC (40 pack-years > versus 
40 pack-years) (15).
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RESULTS |
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The 62 questionnaires completed for each patient showed that none of the patients had past history of cancer of any site nor received previous chemotherapy or RT. The patient characteristics are summarized in Table 1. The end of observation to count the person-years was 31 December 1998. The median follow-up from initiation of therapy was 6.2 years (range 3.1–12.2 years). Of the 62 patients, nine developed SPC in 435 person-years of follow-up. Forty-six patients have remained free of cancer since initial treatment. Three other patients relapsed with NSCLC and still remain alive receiving second line chemotherapy. Of the 62 patients, 13 have died: 5 from recurrent NSCLC, 4 from SPC, 4 from other causes. Regarding chemotherapy for initial treatment, 39 patients were treated with cisplatin (CDDP) + mitomycin (MMC) + vindesine (VDS), 16 with CDDP + VDS, 4 with carboplatin, 2 with CDDP + irinotecan, with 1 with CDDP + MMC + inorelbine. In the treatment of RT, 66 Gy were given to 5 patients, 60 Gy to10, 56 Gy to 28, 50 Gy to 15 and 40 Gy to 4. Of the 62 patients, surgery was performed in 24 patients after the chemo-radiotherapy.
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For smoking status, information was obtained for all the 62 patients before the treatment, but was available for 45 patients after the treatment. Of the 45 patients treated in the analysis, 16 patients continue to smoke and 19 patients stopped smoking. For assessment, 10 never smokers were also added to the 19 stopped patients, and the 29 patients were categorized to the stop smoking group.
Details of nine patients who developed SPC out of the 62 patients are shown in Table 2. There has been no SPC among the ten never smokers. Two patients (cases 5 and 9) developed a SPLC in different lobes from the original NSCLC. Both tumors arose from the ipsilateral side and both patients continued to smoke after the treatment. One of the two lung cancers developed inside the radiation field. The other malignancies consisted of carcinoma of the esophagus, stomach, colon, skin, breast and acute myelogenous leukemia. Two SPC with skin and breast cancer (cases 6 and 8) also developed inside the radiation field.
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Table 3 shows the relative and absolute risks of SPC after initiation of therapy for NSCLC. The risk for development of any SPC increased significantly to 2.8 [95% confidence interval (CI) 1.3–5.3]. In spite of the overall increase in risk, there was no significant increase in relative risk of developing a particular cancer. When smoking-related cancers are combined, there was still no significant increased relative risk in the development of SPC.
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Next, the effect of the passage of time was evaluated. The relative risk for 3–4 years after the treatment was 2.2 (95% CI 0.1–23.9) and 1.8 (95% CI 0.1–23.9) for 5–6 years, and 5.2 (95% CI 1.4–13.2) for at or beyond 7 years. The risk changed with the passage of time and it increased significantly (5.2 times at or beyond 7 years) after the treatment. The absolute risk was 600.1 per 10 000 persons per years.
Table 4 shows the results of univariate analysis on the relative risk for a SPC. The risk was significant but modestly increased relative to the general population in male and more cumulative smoking amount (2.7 times; 95% CI 1.1–5.3 and 3 times; 95% CI 1.2–6.2, respectively). Among those who continued to smoke, there was a significantly increased relative risk (5.2 times; 95% CI 1.6–11.7). In contrast, those who stopped smoking showed only a 1.8-fold increase (95% CI 0.3–5.9), which was not significantly different from the general population.
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Finally, we assessed multivariate analysis and examined the relationship between continued smoking habits and the risk of a SPC, adjusted for gender, histology type and cumulative smoking amount. The results are shown in Table 5. We could not demonstrate that factors such as continued smoking habits, gender, histology type and cumulative smoking amount had effect on the development of a SPC.
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DISCUSSION |
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TOPAbstractINTRODUCTIONRESULTSDISCUSSIONReferences |
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There has been a large body of work that evaluated the risk of SPC in the patients with NSCLC in the treatment of surgery or RT alone (5678). Although the number of survivors in patients with stage III NSCLC has increased by combined modality therapy as chemotherapy and RT, there has been no report to date to evaluate the risk of SPC in these patients. Additionally, Ng and co-workers (16) reported that the relative risk of SPC was 6.1 with the combined chemotherapy and RT and 4.0 with the RT alone, showing a significant difference (P = 0.03) in the surviving patients in Hodgkin's disease. Given that, we focused on the NSCLC patients treated with chemo-radiotherapy.
In our study, 9 patients out of 62 long-term survivors of stage III NSCLC treated with chemo-radiotherapy had a SPC. The relative risk for any SPC (2.8; 95% CI 1.3–5.3) compared with the general population was significantly increased. Instead of many reports examining the risk, these do not provide adequate follow-up information to determine relative risk in the patients with NSCLC. Most studies only show a percent risk per patient per year (5–8). In the current study, the overall rate of developing SPC is estimated at 2.9% per patient per year, which is in agreement with the rates in most surgical series. Ginsberg and Rubinstein (5) reported that SPC occurrence rate was 1.7% per patient per year on 247 patients operated for T1 N0 NSCLC. Other studies showed the rate of 2.8% by Martini et al. (6) and 2.4–3.6% by Thomas and Rubinstein (7). In the current study, we also confirmed the effect of the passage of time on developing SPC. Thomas and Rubinstein (7) reported that the rate of SPC increased from 2.4% for the first 5 years after surgical resection to 3.6% after the fifth year.
We previously studied the relative risk of SPC in the SCLC patient successfully treated with chemotherapy with or without RT (9). Our results showed a similar trend as previous studies (10,11) and demonstrated that the patient had a significantly increased relative risk of 3.6 (95% CI 2.0–5.9) and that the patients who continued to smoke demonstrated a significantly increased risk for a SPC (4.3, 95% CI 1.1–15.9, P = 0.03) compared with those who stopped smoking.
Unlike the results of SCLC patients study, the risk of SPC in NSCLC patients was lower, and the impact of continued smoking on developing SPC in the patients was less significant, but the reason for this observation is not completely understood. According to the case–control study from Japan (17), lung cancer risk reduction due to smoking cessation appeared to be greater in SCLC than squamous cell carcinoma or adenocarcinoma, and SCLC seems to be more smoking-related than NSCLC. However, there have been a couple of germline polymorphism as cytochrome P 450 1A1 (CYP1A1) and glutathione S-transferase class mu (GSTM1), reported, which is implicated in smoking-related carcinogenesis (18,19). Therefore, SCLC patients are speculated to have a higher potential to develop a SPC, particularly smoking-related cancers.
Among NSCLC patients, there seems to be a special group of roentgenographically occult early stage squamous cell carcinoma of the lung. In this patient group, the rate of occurrence of SPC, particularly SPLC was estimated at 3–4% per patient per year (20,21). The risk for SPLC seemed to be substantially higher than that of 1–2% in the NSCLC patients treated with surgery or RT from the previous study and treated with chemo-radiotherapy from our study. Therefore, the group should be given a special focus and be divided from the general population of NSCLC patients in the research of risk of SPC. Most of the patients can be cured by surgery, photodynamic therapy, brachytherapy and chest RT because of its early clinical stage (22), and are not included in our study. Roentgenographically occult early stage squamous cell carcinoma of the lung is associated with the concept of field cancerization (23), and smoking status seems to be very important to evaluate the risk of SPC, which awaits further examination.
A relatively small sample size and rare events such as SPC in this study resulted in large confidence intervals for the estimates. It is still difficult to conclude the effect of continued smoking on the development of SPC. Cigarette smoking causes not only developing cancers but also cardiovascular and lung damage as well (24,25). It may be speculated that continued smokers died off early when interpreting the results. The cessation of smoking is still warranted among patients with stage III NSCLC treated by chemo-radiotherapy.
In conclusion, stage III NSCLC patients treated with chemo-radiotherapy were at risk of developing SPC and this risk increased with time. A large sample size study in a longer follow-up period may be required in further research to conclude the effect of continued smoking on the development of SPC. SPC in another particular group such as roentgenographically occult early stage squamous cell carcinoma of bronchus also awaits further studies.
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Acknowledgments |
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We thank Mrs Chihiro Horii, Mr Toshiyuki Ijima and Dr Satoshi Teramukai for their statistical assistance; Dr Mitsumasa Ogawara, Dr Toshi Hashizume and Dr Yuka Fujita for their support of the study; Dr Minoru Takada for his comments on the manuscript. This work was supported in part by a Grand-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.
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References |
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