Abstract
We investigated the impact of smoking on overall survival (OS) in testicular germ cell cancer (TC) patients receiving first-line combination chemotherapy (bleomycin-etoposide-cisplatin [BEP]). Patients who received BEP for metastatic TC were identified in the Danish Testicular Cancer database. Information on smoking status at the time of diagnosis was obtained by medical record review. OS and cause of death were compared between current smokers and never-smokers. Of 1883 eligible patients, information on smoking status was available in 1156 patients, of whom 602 were current smokers. The 10-year OS was 92% in never-smokers compared with 83% in current smokers (P < .001) (hazard ratio for death = 1.85, 95% confidence interval = 1.29 to 2.66, P = .001). A higher proportion of current smokers died of TC compared with nonsmokers (P < .01). Smoking negatively affects survival after BEP in patients with disseminated TC. Vigorous smoking cessation programs are advocated in TC patients.
Testicular germ cell cancer (TC) is a rare disease with an annual incidence of 8.7 cases per 100 000 in Western Europe; however, it is the most common malignant disease among men aged 15-35 years (1). Even with metastatic disease, TC is highly curable, with a 5-year overall survival (OS) of approximately 90% (2). Although tobacco smoking at diagnosis is a poor prognostic factor for survival in several cancers (3-9), the prognostic importance of tobacco smoking remains unknown in patients with metastatic TC.
The aim in this study was to investigate the impact of tobacco smoking on OS after bleomycin-etoposide-cisplatin (BEP) in patients with metastatic TC treated in Denmark between 1984 and 2007. Secondly, we wanted to investigate causes of death in current smokers vs never smokers. The cohort in this Danish nationwide and population-based study was obtained from the Danish Testicular Cancer database, which is the most detailed database concerning TC worldwide (10).
Until 2001, the first-line standard chemotherapy for disseminated disease was 4 cycles of BEP; after 2001, patients with International Germ Cell Cancer Collaborative Group (IGCCCG) good prognosis received 3 cycles of BEP, and patients with intermediate or poor prognosis continued to receive 4 cycles (11,12). Bleomycin was administered to all patients independently of smoking status as described in detail elsewhere (13). Smoking status at the time of diagnosis was obtained from medical records as registered by the treating physician. For analytic purposes, we divided smoking into groups of current smokers and never-smokers. Patients classified as former smokers were excluded because the group of patients was small (n = 59), heterogenic, and poorly defined.
Cause and time of death were obtained by review of medical records for all included individuals and pooled into fitting groups (14-16). OS was calculated from date of start of BEP to date of death. Patients were censored at emigration or loss to or end of follow-up (December 1, 2014), whichever came first. Crude survival curves for OS were calculated using the Kaplan–Meier method, and the log-rank (Mantel–Cox) test was used for statistical testing of differences between groups. Multivariable Cox proportional hazard analysis was used to determine the independent association of the covariates smoking status, age, IGCCCG prognostic group, and decade of treatment on OS. Interactions between all covariates and outcome were tested. The proportional hazard assumption was tested with the use of Schoenfeld residuals.
A total of 1883 patients were identified to have received a BEP regime as first-line treatment for metastatic TC. In total, 668 patients were excluded because smoking status was not available. A further 59 patients were excluded as former smokers, which led to a total of 1156 patients eligible for analysis (flowchart, Supplementary Figure 1, available online). No difference in treatment intensity was observed between current smokers and never-smokers (Table 1). Smoking statistically significantly reduced 10-year OS (92% in never-smokers vs 83% in current smokers) (P < .005) (Figure 1).
Table 1.
Patient demographics and clinical characteristics stratified by smoking status (n = 1156)a
| Characteristics | Total | Never-smokers | Current smokers | P |
|---|---|---|---|---|
| (n = 1156) | (n = 554) | (n = 602) | ||
| Age, median (IQR), y | 32.4 (26.1 - 40.5) | 30.0 (24.7-38.4) | 34.2 (27.2-42.8) | <.001 |
| Follow-up, median (IQR), y | 18.0 (17.3-18.6) | 17.7 (16.8-18.7) | 18.1 (17.1-19.1) | .678 |
| Decade of treatment, no. (%) | .367 | |||
| 1980s | 306 (26) | 144 (26) | 162 (27) | |
| 1990s | 456 (40) | 210 (38) | 246 (41) | |
| 2000s | 394 (34) | 200 (36) | 194 (32) | |
| Histology, no. (%) | .681 | |||
| Seminoma | 282 (24) | 132 (24) | 150 (25) | |
| Nonseminoma | 874 (76) | 422 (76) | 452 (75) | |
| Prognostic groupb, no. (%) | .949 | |||
| Good | 845 (73) | 403 (73) | 442 (74) | |
| Intermediate | 185 (16) | 89 (16) | 96 (16) | |
| Poor | 126 (11) | 62 (11) | 64 (10) | |
| Primary stage, no. (%) | .383 | |||
| Localized | 353 (31) | 176 (32) | 177 (30) | |
| Disseminated | 803 (69) | 378 (68) | 425 (70) | |
| Pulmonary metastases | .567 | |||
| No | 907 (40) | 439 (79) | 468 (78) | |
| Yes | 249 (20) | 115 (21) | 134 (22) | |
| First-line chemotherapy regimen, no. (%) | .381 | |||
| BEP | 1050 (90) | 499 (90) | 551 (91) | |
| Double dose EP + standard dose B | 106 (10) | 55 (10) | 51 (9) | |
| No. of cycles, no. (%) | .114 | |||
| ≤2 | 17 (1) | 6 (1) | 11 (2) | |
| 3 | 289 (25) | 151 (27) | 138 (23) | |
| 4 | 651 (56) | 296 (53) | 355 (59) | |
| 5 | 45 (4) | 25 (5) | 20 (3) | |
| ≥6 | 53 (5) | 30 (6) | 23 (4) | |
| N/A | 101 (9) | 46 (8) | 55 (9) | |
| Cumulative dose, median (IQR)c | ||||
| Cisplatin, mg | 800 (654-865) | 800 (630-880) | 800 (675-840) | .718 |
| Bleomycin, kIE | 270 (231-300) | 270 (240-300) | 270 (225-300) | .656 |
| Etoposide, mg | 3875 (3200-4200) | 3900 (3150-4281) | 3850 (3300-4113) | .994 |
| Relapse after first-line treatment | 138 (12) | 62 (11) | 76 (13) | .564 |
| Second-line chemotherapy regimen, no. (%) | .740 | |||
| BEP | 14 (10) | 6 (10) | 8 (11) | |
| Paclitaxel, cisplatin, gemcitabine | 33 (24) | 17 (27) | 16 (21) | |
| HDCTd and stem-cell transplantation | 20 (14) | 9 (15) | 11 (15) | |
| Carboplatin and ifosfamide | 9 (7) | 6 (10) | 3 (4) | |
| Surgery only | 31 (22) | 13 (21) | 18 (24) | |
| Radiotherapy only | 9 (7) | 3 (5) | 6 (8) | |
| Other chemotherapy regimen | 22 (16) | 8 (12) | 14 (17) | |
| Tobacco consumption, no. of cigarettes daily (%) | N/A | |||
| ≤10 | — | — | 159 (26) | |
| 11-20 | — | — | 317 (53) | |
| >20 | — | — | 105 (17) | |
| Unknown | — | — | 21 (3) |
BEP = bleomycin-etoposide-cisplatin; IQR = interquartile range; N/A = not applicable.
According to the definition of the International Germ-Cell Cancer Collaborative Group prognostic group.
Median chemotherapy doses were calculated for patients with information available (666, 331, and 345, respectively).
High-dose chemotherapy.
Figure 1.
The 10-year overall survival for patients with metastatic testicular cancer who received first-line bleomycin-etoposide-cisplatin (BEP) stratified by smoking status.
In the good prognostic group, the 10-year OS was 97% in never-smokers compared with 87% in current smokers (P < .001), (Supplementary Figure 2, available online). In the intermediate prognostic group, the 10-year OS was 91% in never-smokers compared with 77% in current smokers (P = .033). In the poor prognostic group, there was no difference between the groups.
In multivariable analysis, smoking statistically significantly affected 5-year OS (hazard ratio [HR] = 2.53, 95% confidence interval [CI] = 1.32 to 4.84, P = .005) and 10-year OS (HR = 3.08, 95% CI = 1.71 to 5.55, P < .001) (Supplementary Table 1, available online). We identified a statistically significant interaction between prognostic group and impact of smoking (P < .05) and further conducted stratified analyses per IGCCCG group as presented in Supplementary Table 2 (available online). Current smoking was associated with inferior survival in the good prognostic group within both 5 years (HR = 2.52, 95% CI = 1.31 to 4.83, P = .005) and 10 years (HR = 3.04, 95% CI = 1.69 to 5.47, P < .001). No interaction between cumulative cisplatin doses or cycles and smoking was observed.
A higher proportion of current smokers died of TC compared with nonsmokers at both 5 years and 10 years (P < .05 and P < .01, respectively; Supplementary Table 3, available online).
OS in patients smoking more than 20 daily cigarettes was inferior to patients smoking 20 and less cigarettes per day, indicating a dose–response relationship (Supplementary Figure 3, available online).
Based on these analyses, current smoking at the time of diagnosis was an independent poor prognostic factor for survival in TC patients treated with BEP. The increased mortality in smokers was likely caused by decreased treatment efficacy as shown by an increased number of TC-related deaths in smokers; treatment intensity was similar between smokers and never-smokers.
In the good prognostic group, current smokers suffered a more than 2 times increased risk of dying compared with nonsmokers during the first 5 years after treatment. The detrimental effect of smoking was not present in the poor prognostic group, probably due to the preexisting high mortality from well-known poor prognostic factors for survival in this subgroup of TC patients.
This is a very large nationwide study established in a health system with free access to all medical services and thereby includes cases in a population-based fashion excluding selection bias. This contributes to the reliability of the results.
Smoking status was analyzed as registered by the treating physician and may thus be influenced by information bias. Furthermore, no information on past smoking history and smoking habits after TC treatment was available. The clear effect of current smoking on survival with a cumulative dose–response relationship suggests a causal relation, although prospective studies with detailed information on tobacco consumption and lifestyle factors are needed to further clarify the association between smoking and survival in TC patients.
In conclusion, smoking is an independent poor prognostic factor for survival in metastatic TC. Smoking cessation programs are cost-effective (17,18), and clinicians should vigorously safeguard that patients quit smoking prior to the beginning of treatment. Studies are needed to test the efficacy of smoking cessation programs specifically tailored for this group of young cancer patients. Intensified follow-up of smokers should be considered.
Supplementary Material
Contributor Information
Mikkel Bandak, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Kristine Skovly Nielsen, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Michael Kreiberg, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Thomas Wagner, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Josephine Rosenvilde, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Charlotta Pisinger, Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region of Denmark, Copenhagen, Denmark; Faculty of Health Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark; Danish Heart Foundation, Copenhagen, Denmark.
Christoffer Johansen, Late Effect Research Unit (CASTLE), Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark.
Gedske Daugaard, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Jakob Lauritsen, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Data availability
The data underlying this article cannot be shared publicly due to ethical and privacy reasons.
Author contributions
Mikkel Bandak, MD (conceptualization; methodology; writing—original draft); Kristine Skovly Nielsen, MD (methodology; visualization; writing—original draft); Michael Kreiberg, PhD (conceptualization; methodology; writing—review and editing); Thomas Wagner, MD (methodology; writing—review and editing); Josephine Rosenvilde, MD (writing—review and editing); Charlotta Pisinger, PhD (supervision; writing—review and editing); Christoffer Johansen, DMSc (supervision; writing—review and editing); Gedske Daugaard, DMSc (methodology; supervision; writing—review and editing); Jakob Lauritsen, MD (conceptualization; formal analysis; methodology; supervision; visualization; writing—review and editing).
Funding
No funding was used for this study.
Conflicts of interest
The authors declared no conflicts of interest.
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Data Availability Statement
The data underlying this article cannot be shared publicly due to ethical and privacy reasons.