Abstract The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60–15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC. second primary cancer, chemoradiotherapy, surgical resection, non-small-cell lung cancer, cancer survivor Introduction Second primary cancers (SPCs) have been detected in survivors of non-metastatic non-small-cell lung cancer (NSCLC) (1). Kawaguchi et al. reported that 62 of 547 patients treated with chemoradiotherapy (CRT) were disease-free for more than 3 years, but nine developed SPC, with an estimated incidence of 2.9 per 100 patient-years (2). Previously, we reported that the 5-year survival rate of patients with locally advanced (LA)-NSCLC treated with CRT (cisplatin + docetaxel + radiotherapy (RT)) was 23.5% (3). Moreover, seven of 92 patients developed SPC after CRT, for an estimated incidence of 2.4 per 100 patient-years (4). Although induction CRT followed by surgery for LA-NSCLC patients did not show survival benefits compared with CRT alone in large-scale clinical trials, the possibility of long-term survival was shown in a limited number of patients who had undergone lobectomy excluding pneumonectomy (5). In our institute, trimodal therapy for LA-NSCLC yielded a much longer survival, with a 5-year overall survival (OS) rate of 67.1% (6). Although the risk of SPC in cancer survivors is expected to increase with the prolonged survival time, to our knowledge, there are no data concerning SPC after trimodal treatment. Therefore, it is necessary to determine the risk of SPC after trimodal treatment. Patients and methods Patients Between October 1997 and October 2013, 112 Stage III NSCLC patients were treated with CRT followed by surgery. The data available as on 31 October 2015 were analysed. Patients had histologically or cytologically confirmed NSCLC, previously untreated disease, measurable lesions, and no history of malignancy within 5 years of enrolment. Patients who had previously undergone chemotherapy or RT were excluded. The study protocol was approved by the Okayama University institutional review board. Most patients received docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on Days 1, 8, 29 and 36 with concurrent RT (2 Gy daily, total 46 Gy) (DP-RT). Following induction CRT, the patients’ responses were evaluated by chest radiography and computed tomography (CT). Patients with no progressive disease were scheduled to undergo surgery within 6 weeks of completing the induction therapy. Postoperative adjuvant treatment was left to the physician’s discretion. For the first 2 years postoperatively, patients were monitored by chest radiography every month and by CT every 3 months, and were examined for brain metastasis by magnetic resonance imaging (MRI) every 3 months. After 2 years, brain MRI and CT were performed twice a year and annually after 3 years. SPC in the lung was defined according to the method of Martini and Melamed (7). Statistical analysis All statistical analyses were conducted using STATA/SE ver. 14.0 (College Station, TX, USA). Survival time was defined from the time of initiating CRT to the last follow-up evaluation or death. The SPC rate was calculated as the number of SPC cases over 100 patient-years of follow-up (8, 9). The interval from the initial NSCLC to SPC was measured from the initiation of CRT to the diagnosis of SPC. Survival rates and cumulative risks of developing SPC were calculated using the Kaplan–Meier method. Data from the patients still alive at the last follow-up or who died without SPC development were censored when calculating the cumulative risks. The risk of SPC in survivors of LA-NSCLC treated with concurrent CRT followed by surgery was compared with the general population in Japan, using standardized incidence ratio (SIR). Values of SIRs (analogous to the relative risk of developing SPC) were estimated by taking the ratio of the observed to the expected number of patients with SPC. The expected number of SPC was determined using sex, age and calendar-year specific incidence rate from the data of Cancer Registry and Statistics from 1997 to 2013 (Cancer Information Service, National Cancer Center, Japan) (10), and applied to the corresponding person-years at risk. Results In this study, 112 patients (86 men, 26 women; median age 61 (range 31–78) years), 105 of whom were treated with DP-RT, were analysed. At treatment initiation, 79 patients had Stage IIIA and 33 patients had Stage IIIB disease (seventh edition of the TNM staging system). Smoking status was as follows: 51 current smokers, 41 former smokers and 20 never smokers (median 40 pack-year (range: 0–138)). Almost all current smokers stopped smoking before trimodal therapy. The majority of the patients (n = 78, 70%) received total radiation dose of 46 Gy, 14 patients (13%) received more than 46 Gy and 20 patients (18%) received less than 46 Gy. Over a median follow-up of 5.2 (range 0.37–16.4) years, the observed 5-year OS rate was 71.8%, with 49 of 112 patients surviving more than 5 years. The median survival time was 13.0 years (95% confidence interval [CI] 9.7 years–not reached (NR)). Of the 112 patients, 47 (42%) eventually developed disease progression. The progression patterns included local progression only (n = 15), local plus distant progression (n = 10), distant progression only (n = 19) and unspecified (n = 3). Brain metastases were observed in 15 patients, and the brain was the only site of relapse in 12 patients. Grade 3 or more severe radiation pneumonitis was observed in nine patients (Grade 3 in seven patients, Grade 4 in two patients). Of the 112 patients, 10 (8.9%) developed SPC (Table 1). No patient developed leukaemia or myelodysplastic syndrome. The SPC developed in three never smokers (colon carcinoma, thyroid cancer and urinary bladder cancer). Of the 10 patients who developed SPC, nine (90%) had continued smoking cessation after trimodal therapy. There were no significant differences between never and ever smokers in SPC development (P = 0.293, chi-square test). In three patients, the SPC developed in the RT treatment field for the initial NSCLC. Of the 49 patients who survived more than 5 years, eight (16.3%) developed SPC: colon cancer in two, gastric cancer in two, and lung cancer, thyroid cancer, sarcoma and urinary bladder cancer in one patient each. Of the 49 patients who survived more than 5 years, two died of progression of primary NSCLC, two died of SPC, four died of other diseases, and 41 were still alive. Table 1. Characteristics of 10 patients with SPC Type of SPC Age Sex First to second cancer (years) RT field Treatment of SPC Survival after SPC (years) Gastric 59 M 0.6 Outside Endoscopic resection 8.3 (alive) Oesophagus 76 F 2.5 Inside Endoscopic resection 0.60 (alive) Lung (SCLC) 62 M 3.7 Outside Chemotherapy + radiotherapy 0.89 (alive) Gastric 65 F 4.3 Outside Surgical resection 2.1 (alive) Urinary bladder 64 M 5.5 Outside Surgical resection 0.77 (alive) Colon 69 M 5.6 Outside Surgical resection 0.15 (alive) Lung (SCLC) 59 M 8.7 Inside Chemotherapy 1.2 (died of SPC) Thyroid 55 F 10.3 Outside Surgical resection 1.7 (alive) Colon 62 M 14.8 Outside Endoscopic resection 0.82 (alive) Sarcoma 50 M 15 Inside Chemotherapy 0.58 (died of SPC) Type of SPC Age Sex First to second cancer (years) RT field Treatment of SPC Survival after SPC (years) Gastric 59 M 0.6 Outside Endoscopic resection 8.3 (alive) Oesophagus 76 F 2.5 Inside Endoscopic resection 0.60 (alive) Lung (SCLC) 62 M 3.7 Outside Chemotherapy + radiotherapy 0.89 (alive) Gastric 65 F 4.3 Outside Surgical resection 2.1 (alive) Urinary bladder 64 M 5.5 Outside Surgical resection 0.77 (alive) Colon 69 M 5.6 Outside Surgical resection 0.15 (alive) Lung (SCLC) 59 M 8.7 Inside Chemotherapy 1.2 (died of SPC) Thyroid 55 F 10.3 Outside Surgical resection 1.7 (alive) Colon 62 M 14.8 Outside Endoscopic resection 0.82 (alive) Sarcoma 50 M 15 Inside Chemotherapy 0.58 (died of SPC) Age; at the age of surgical resection of NSCLC. FP, 5-FU and cisplatin; DP, docetaxel and cisplatin; RT, radiation; SPC, second primary cancer. View Large The observed incidence rate of SPC was 1.8 per 100 patient-years. The cumulative incidences were 1.9% (95% CI 0.4–6.1%), 4.5% (95% CI 1.4–10.3%), 7.8% (95% CI 3.0–15.4%) and 10.9% (95% CI 4.2–21.2%) at 3, 5, 8 and 10 years, respectively (Fig. 1). The median time from the start of CRT to the diagnosis of SPC was 5.0 years (95% CI 4.3–5.7 years). Two patients with SPC (thyroid and oesophageal carcinomas) showed progression of the primary NSCLC, brain metastasis treated by CyberKnife in both cases, and are alive. SIR of SPC in LA-NSCLC patients after trimodal therapy compared with that in the age-, sex- and calender-year-matched general population in Japan was 1.30 (95% CI 0.66–2.49). Figure 1. View largeDownload slide Cumulative incidence of SPC from the initiation of concurrent CRT. The observed incidence rate of SPC was 1.8 per 100 patient-years. The cumulative incidence was 1.9% (95% CI 0.4–6.1%) at 3 years, 4.5% (95% CI 1.4–10.3%) at 5 years, 7.8% (95% CI 3.0–15.4%) at 8 years and 10.9% (95% CI 4.2–21.2%) at 10 years. Figure 1. View largeDownload slide Cumulative incidence of SPC from the initiation of concurrent CRT. The observed incidence rate of SPC was 1.8 per 100 patient-years. The cumulative incidence was 1.9% (95% CI 0.4–6.1%) at 3 years, 4.5% (95% CI 1.4–10.3%) at 5 years, 7.8% (95% CI 3.0–15.4%) at 8 years and 10.9% (95% CI 4.2–21.2%) at 10 years. Discussion This is the first report to investigate the incidence of SPC after CRT followed by surgical resection. The estimated incidence of SPC in our trimodal therapy cohort was 1.8 per 100 patient-years, which was slightly lower than that of our previous CRT alone cohort (2.4 per 100 patient-years), although it was not statistically significant (P = 0.602, Gray’s test) (4). Despite patients who receive trimodal therapy may live longer, the estimated incidence of SPC does not increase. Several reports have evaluated the risk of SPC in patients with NSCLC. The calculated incidence of SPC ranged from 1.7 to 4.3 per 100 patient-years after treatment with surgery or RT alone (8, 9, 11, 12). When limiting the data to LA-NSCLC cases, the risk of SPC was reported to be 2.4 and 2.9 per 100 patient-years (2, 4). In this study, the incidence of SPC after trimodal therapy was slightly lower than that observed in our previous CRT alone cohort (4). One difference among these studies was the radiation dose used. Takigawa et al. (2006) (4) used a total radiation dose of 60 Gy (cisplatin and docetaxel arm) or 62.5–70 Gy (cisplatin and 5-fluorouracil arm), while Kawaguchi et al. (2006) (2) used a median radiation dose of 56 Gy. In comparison, our median radiation dose was 46 Gy. However, there is no clear evidence of a relationship between the RT dose and SPC rate, because the SPC was present in the RT field in only 1/7 (14.3%) patients in Takigawa et al. (2006) (4), 3/9 (33.3%) patients in Kawaguchi et al. (2006) (2) and 3/10 (30.0%) patients in our report. In our study, 9/112 (8%) patients occurred Grade 3 or more severe RT pneumonitis, which was not different clearly compared with previous reports (3). Age-, sex- and period-specific cancer incidence rates in Japan were applied to the appropriate person-years of observation. The relative risk of SPC in LA-NSCLC patients after trimodal therapy compared with that in the general population was 1.30 (95% CI 0.66–2.49), which means that patients tend to have a relatively high risk of SPC after trimodal therapy. In this study, SPC developed in spite of the high smoking cessation rate, and it would be better to follow up these patients by using routine CT imaging, tumour markers, and additional examinations such as ultrasonic abdominal imaging, occult blood stool tests and endoscopy to detect SPC. In the present study, eight of 49 patients survived more than 5 years. Such patients may accept non-consultant follow-up if compensated with changes elsewhere (13). Further investigation of follow-up methods, including cost–benefit analysis and survivors’ preferences, is necessary. There are several limitations to this study. First, the relatively small sample size and rarity of SPC resulted in large CIs for the estimates. Second, the chemotherapy regimen differed somewhat between our series and previous reports, which may have influenced the difference in SPC rates. Conclusion The 5-year OS rate was 71.8% in LA-NSCLC patients treated with trimodal therapy. Although these long-term survivors were suggested to be at high risk of developing SPC, trimodal therapy may not increase this risk. This result indicates another advantage for reducing the RT dose by combined surgical resection with CRT. A large prospective study with a longer follow-up is required to determine the effect of trimodal therapy, including the development of SPC. Studies to determine appropriate methods to prevent SPC in such patients are warranted. Conflict of interest statement Dr Hotta received personal fees from Nihon Kayaku, Sanofi-Aventis, during the conduct of the study; grants and personal fees from Merck, Chugai Pharmaceutical, Lilly, personal fees from AstraZeneca, Daiichi-Sankyo Pharmaceutical, Boehringer-Ingelheim, Taiho Pharmaceutical, Kyowa-Kirin, Ono, BMS, Novartis and Pfizer, outside the submitted work. Dr Takigawa received grants and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer-Ingelheim, Ono Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd and Takeda Pharmaceutical Co. Ltd, outside the submitted work. Dr Kiura received grants and personal fees from Eli Lilly Japan, AstraZeneca, Chugai Pharmaceutical, Boehringer-Ingelheim, Kyowa Hakko Kirin, personal fees from Taiho Pharmaceutical, Pfizer Inc. Japan, grants from Ono Pharmaceutical, Astellas Pharmaceutical, outside the submitted work. Funding No external funding received for this study. References 1 Duchateau CS, Stokkel MP. Second primary tumors involving non-small cell lung cancer: prevalence and its influence on survival. Chest 2005; 127: 1152– 8. Google Scholar PubMed 2 Kawaguchi T, Matsumura A, Iuchi K, et al. . 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Japanese Journal of Clinical Oncology – Oxford University Press
Published: Mar 1, 2018
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