Published Ahead of Print on February 2, 2015 as 10.1200/JCO.2014.58.3831 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.58.3831
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
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Active Smoking and Mortality Among Colorectal Cancer Survivors: The Cancer Prevention Study II Nutrition Cohort Baiyu Yang, Eric J. Jacobs, Susan M. Gapstur, Victoria Stevens, and Peter T. Campbell All authors: American Cancer Society; and Baiyu Yang, Emory University, Atlanta, GA. Published online ahead of print at www.jco.org on February 2, 2015. Supported by the American Cancer Society. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Peter T. Campbell, PhD, Epidemiology Research Program, American Cancer Society National Home Office, 250 Williams St NW, Atlanta, GA 30303; e-mail: peter. [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.58.3831
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Purpose Active smoking is associated with higher colorectal cancer risk, but its association with survival after colorectal cancer diagnosis is unclear. We investigated associations of smoking, before and after diagnosis, with all-cause and colorectal cancer–specific mortality among colorectal cancer survivors. Patients and Methods From a cohort of adults who were initially free of colorectal cancer, we identified 2,548 persons diagnosed with invasive, nonmetastatic colorectal cancer between baseline (1992 or 1993) and 2009. Vital status and cause of death were determined through 2010. Smoking was self-reported on the baseline questionnaire and updated in 1997 and every 2 years thereafter. Postdiagnosis smoking information was available for 2,256 persons (88.5%). Results Among the 2,548 colorectal cancer survivors, 1,074 died during follow-up, including 453 as a result of colorectal cancer. In multivariable-adjusted Cox proportional hazards regression models, prediagnosis current smoking was associated with higher all-cause mortality (relative risk [RR], 2.12; 95% CI, 1.65 to 2.74) and colorectal cancer–specific mortality (RR, 2.14; 95% CI, 1.50 to 3.07), whereas former smoking was associated with higher all-cause mortality (RR, 1.18; 95% CI, 1.02 to 1.36) but not with colorectal cancer–specific mortality (RR, 0.89; 95% CI, 0.72 to 1.10). Postdiagnosis current smoking was associated with higher all-cause (RR, 2.22; 95% CI, 1.58 to 3.13) and colorectal cancer–specific mortality (RR, 1.92; 95% CI, 1.15 to 3.21), whereas former smoking was associated with all-cause mortality (RR, 1.21; 95% CI, 1.03 to 1.42). Conclusion This study adds to the existing evidence that cigarette smoking is associated with higher all-cause and colorectal cancer–specific mortality among persons with nonmetastatic colorectal cancer. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
INTRODUCTION
Colorectal cancer was added to the list of smokingattributable cancers by the International Association for Research on Cancer in 20091,2 and by the US Surgeon General in 2014.3 According to several recent meta-analyses, the relationship between smoking and colorectal cancer incidence is likely dose dependent.4-7 Moreover, the association between smoking and colorectal cancer incidence seems strongest for three correlated molecular phenotypes of the disease: microsatellite instability (MSI) high,8-12 CpG island methylator phenotype (CIMP) high,12-14 and BRAF mutation positive.11-13 Less is known about the potential effect of smoking on overall or disease-specific survival rate after a diagnosis of colorectal cancer. A recent meta-
analysis of studies among patients with colorectal cancer who assessed smoking status before, at the time of, or after a cancer diagnosis showed higher risks of all-cause mortality among current smokers at all time points (summary hazard ratio [HR], 1.26) compared with never-smokers.15 Nevertheless, only six studies examined colorectal cancer–specific mortality,16-21 and only one study examined changes in smoking status from pre- to postdiagnosis (particularly quitting after diagnosis) in relation to mortality.18 Further research is needed to clarify the association between smoking and survival to better inform and support smoking-cessation efforts among colorectal cancer survivors. Herein, we report the associations of pre- and postdiagnosis active smoking with mortality resulting from all causes and from colorectal cancer © 2015 by American Society of Clinical Oncology
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Yang et al
specifically among persons diagnosed with invasive nonmetastatic colorectal cancer in a prospective cohort study of men and women in the United States. PATIENTS AND METHODS Study Cohort The Cancer Prevention Study II (CPS-II) nutrition cohort is a prospective study of cancer incidence and mortality that began in 1992.22 At baseline enrollment (1992 or 1993), approximately 184,000 men and women reported information regarding demographics, detailed smoking history, medical history, body size, diet, and other lifestyle factors on a 10-page, self-administered questionnaire. Follow-up questionnaires were mailed to participants in 1997 and every 2 years thereafter to update exposure information and document new cancer diagnoses. The CPS-II nutrition cohort was approved by the institutional review board of Emory University. We identified 3,832 men and women diagnosed with invasive colon or rectal cancer between enrollment in 1992 or 1993 and the end of incidence follow-up (June 30, 2009) from among the 181,293 participants with no previous history of colorectal cancer at baseline. A majority of these persons (n ⫽ 3,053) were first identified via self-report on a follow-up questionnaire and then verified either by review of medical records (n ⫽ 2,188) or linkage to state cancer registries (n ⫽ 865). The remaining 779 persons were initially identified as cancer deaths through linkage to the National Death Index (NDI),23 and 531 of them were subsequently verified through linkage to state cancer registries (n ⫽ 529) or by review of medical records (n ⫽ 2). Exclusions were made based on the following: deaths identified through NDI that were not verified through medical records or cancer registries (n ⫽ 248), prevalent cancers (except for nonmelanoma skin cancer) at baseline (n ⫽ 387), implausible diagnosis date (n ⫽ 11), missing stage at diagnosis (n ⫽ 136), TNM summary stage IV or distant SEER stage at diagnosis (n ⫽ 421), nonadenocarcinoma histology (n ⫽ 50), implausible death date (n ⫽ 2), and missing smoking status at baseline (n ⫽ 29). Consistent with our previous studies from this cohort,24-28 we chose a priori to exclude persons with distant metastatic disease in the main analyses, because this group has a poor 5-year relative survival that is unlikely to be substantially affected by risk behaviors and because this group is less likely to return a postdiagnosis survey; nonetheless, the impact of smoking on survival among persons with distant metastatic disease was examined separately. After exclusions, our final analytic cohort for prediagnosis analyses comprised 2,548 participants (1,416 men and 1,132 women). Among them, 1,887 were diagnosed with colon cancer (International Classification of Diseases for Oncology [ICD-O] codes C18.0 and C18.2 to C18.9), and 661 were diagnosed with rectal cancer (ICD-O codes C19.9 and C20.9). Stratified by SEER summary stage, 1,281 had localized disease (invasive tumors limited to colon or rectum), and 1,267 had regional disease (tumors that spread through bowel wall to adjacent tissues or organs or to regional lymph nodes). Study Outcomes Participants were observed through December 31, 2010, to ascertain their vital status through linkage to the NDI. Cause of death has been obtained for 99.3% of all known deaths in CPS-II. The primary outcome for this analysis was all-cause mortality. The secondary outcome was mortality specifically resulting from colorectal cancer (ICD ninth revision [ICD-9] codes 153 and 154; ICD 10th revision [ICD-10] coes C18, C19, and C20), defined from the singular underlying cause of death from NDI records. Pre- and Postdiagnosis Smoking Smoking status (never, former, or current) and dose were first ascertained at baseline and reassessed on each follow-up questionnaire (1997, 1999, 2001, 2003, 2005, 2007, and 2009). Smoking dose was categorized based on time since quitting for former smokers and cigarettes per day for current smokers (ie, never-smokers; former smokers who quit ⱖ 30, 20 to 29, and ⬍ 20 years ago; and current smokers who smoked ⬍ 15 or ⱖ 15 cigarettes per day). 2
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These categories were initially selected from an earlier analysis of the CPS-II cohort,29 with modification to account for the distributions in this analysis. Prediagnosis smoking status and dose were obtained from the last questionnaire completed before cancer diagnosis, or the penultimate questionnaire if the diagnosis was within 6 months of completing the last questionnaire, because smoking behaviors may be influenced by symptoms immediately preceding diagnosis. Postdiagnosis smoking information was obtained from the first questionnaire completed after diagnosis. Of the 2,548 patients included in the prediagnosis analysis, 2,256 (88.5%) reported postdiagnosis smoking information. A pre- to postdiagnosis change variable was constructed to include the four most common combinations of pre- and postdiagnosis smoking: never-never, former-former, current-former, and current-current. Statistical Analysis Cox proportional hazards regression was used to calculate relative risks (RRs) and 95% CIs. We assessed the proportional hazards assumption with a likelihood ratio test. The underlying time axis for all analyses was time since diagnosis. Delayed-entry Cox models were used for postdiagnosis smoking models so that person-time began on the date of return of the postdiagnosis questionnaire30; this procedure accounts for potential biases from immortal time.31 For all models, person-time ended at death or at the end of mortality follow-up (December 31, 2010), whichever came first. The mean follow-up was calculated by taking the mean of the observed follow-up time. All analyses were a priori adjusted for age at diagnosis, tumor stage at diagnosis, and sex. We evaluated other demographic, lifestyle, and clinical covariates, but none changed the RR estimates by ⬎ 10%. Nevertheless, for pre- and postdiagnosis multivariable models, we in addition adjusted for corresponding pre- or postdiagnosis alcohol intake, body mass index (BMI), and physical activity, because these variables are important predictors of survival in this cohort19,26,27 and/or because they may also correlate with smoking.19 We calculated P values for trend using Wald tests for time since quitting smoking from analyses restricted to former smokers and, separately, for cigarettes per day among current smokers. In sensitivity analyses, we excluded: participants with a history of lung disease, deaths within the first 2 years of follow-up, deaths within 2 years of returning the postdiagnosis survey, and participants who returned the postdiagnosis survey within 6 months of diagnosis. We conducted likelihood ratio tests to examine whether the associations between pre- or postdiagnosis smoking status and all-cause mortality were modified by the following prespecified potential effect modifiers: age at diagnosis, sex, tumor stage, tumor subsite, BMI, physical activity, and alcohol consumption. All analyses were performed using SAS software (version 9.3; SAS Institute, Cary, NC).
RESULTS
The mean age of participants was 65 years at baseline and 73 years at diagnosis. Compared with never-smokers, former or current smokers were more likely to be men, less educated, and have ever consumed alcohol. Current smokers were more likely to be diagnosed with colorectal cancer at a younger age, less physically active, and leaner; former smokers were more likely to have a history of myocardial infarction (Table 1). On average, prediagnosis smoking was assessed 2.3 years before diagnosis, and postdiagnosis smoking was assessed 1.4 years after diagnosis. Among the 2,548 patients included in the prediagnosis analysis, 1,074 deaths occurred during a mean follow-up of 7.5 years (standard deviation, 4.6 years; range, 2 days to 18.1 years). The leading causes of death were colorectal cancer (n ⫽ 453), cardiovascular disease (n ⫽ 201), respiratory system disease (n ⫽ 66), and lung cancer (n ⫽ 55). In both pre- and postdiagnosis models, current smoking was associated with statistically significantly higher risks of all-cause and colorectal cancer–specific mortality, whereas former smoking was associated JOURNAL OF CLINICAL ONCOLOGY
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Smoking and Colorectal Cancer Survival
Table 1. Baseline Characteristics of Patients With Colorectal Cancer by Prediagnosis Smoking Status in CPS-II Nutrition Cohort Never (n ⫽ 993) Characteristic Age at colorectal cancer diagnosis, years ⬍ 65 65 to ⬍ 70 70 to ⬍ 75 75 to ⬍ 80 ⱖ 80 Year of colorectal cancer diagnosis 1992 to 1997 1998 to 2001 2002 to 2005 2006 to 2009 Sex Male Female Race/ethnicity White/white Hispanic Black/black Hispanic Other/missing Education Less than high school High school degree Some college/trade school College graduate SEER summary stage Localized Regional Tumor histologic grade at diagnosis Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Colorectal cancer diagnosis site Colon Rectum First course of cancer treatment Surgery No Yes Chemotherapy No Yes Radiation therapy No Yes First-degree family history of colorectal cancer in 1982 No Yes History of diabetes No Yes History of stroke No Yes History of myocardial infarction No Yes History of hypertension No Yes
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Former (n ⫽ 1,402)
Current (n ⫽ 153)
No.
%
No.
%
No.
%
111 201 254 249 178
11.2 20.2 25.6 25.1 17.9
146 277 394 367 218
10.4 19.8 28.1 26.2 15.5
35 39 41 31 7
22.9 25.5 26.8 20.3 4.6
288 291 261 153
29.0 29.3 26.3 15.4
405 425 349 223
28.9 30.3 24.9 15.9
66 49 22 16
43.1 32.0 14.4 10.5
389 604
39.2 60.8
942 460
67.2 32.8
85 68
55.6 44.4
964 19 10
97.1 1.9 1.0
1,378 10 14
98.3 0.7 1.0
149 2 2
97.4 1.3 1.3
59 328 274 328
5.9 33.0 27.6 33.0
115 342 430 508
8.2 24.4 30.7 36.2
19 45 49 38
12.4 29.4 32.0 24.8
487 506
49.0 51.0
721 681
51.4 48.6
73 80
47.7 52.3
123 601 184 12
12.4 60.5 18.5 1.2
171 879 205 18
12.2 62.7 14.6 1.3
17 84 33 0
11.1 54.9 21.6 0
751 242
75.6 24.4
1,028 374
73.3 26.7
108 45
70.6 29.4
25 708
2.5 71.3
24 1,033
1.7 73.7
4 94
2.6 61.4
434 299
43.7 30.1
617 440
44.0 31.4
54 44
35.3 28.8
665 68
67.0 6.8
962 95
68.6 6.8
85 13
55.6 8.5
933 60
94.0 6.0
1,314 88
93.7 6.3
143 10
93.5 6.5
901 92
90.7 9.3
1,263 139
90.1 9.9
148 5
96.7 3.3
975 18
98.2 1.8
1,365 37
97.4 2.6
151 2
98.7 1.3
941 52
94.8 5.2
1,261 141
89.9 10.1
144 9
94.1 5.9
594 59.8 841 399 40.2 561 (continued on following page)
60.0 40.0
109 44
71.2 28.8
Pⴱ ⬍ .01
⬍ .01
⬍ .01
.13
⬍ .01
.42
.04
.27
.02
.04
.03
.96
.03
.29
⬍ .01
.02
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Yang et al
Table 1. Baseline Characteristics of Patients With Colorectal Cancer by Prediagnosis Smoking Status in CPS-II Nutrition Cohort (continued) Never (n ⫽ 993) Characteristic History of lung disease No Yes Physical activity, MET-hours per week ⬍ 3.5 3.5 to ⬍ 8.75 ⱖ 8.75 BMI, kg/m2 ⬍ 18.5 18.5 to ⬍ 25 25 to ⬍ 30 ⱖ 30 Alcohol intake, drinks per day Nondrinker Former drinker ⬍1 1 to 2 ⬎2
Former (n ⫽ 1,402)
Current (n ⫽ 153)
No.
%
No.
%
No.
%
932 61
93.9 6.1
1,287 115
91.8 8.2
143 10
93.5 6.5
96 442 438
9.7 44.5 44.1
157 548 674
11.2 39.1 48.1
33 63 51
21.6 41.2 33.3
13 389 385 190
1.3 39.2 38.8 19.1
13 485 624 259
0.9 34.6 44.5 18.5
5 75 62 10
3.3 49.0 40.5 6.5
426 52 330 71 42
42.9 5.2 33.2 7.2 4.2
275 96 540 184 206
19.6 6.8 38.5 13.1 14.7
25 14 46 24 35
16.3 9.2 30.1 15.7 22.9
Pⴱ .15
⬍ .01
⬍ .01
⬍ .01
NOTE. Some percentages do not add up to 100% because of missing data or rounding. Abbreviations: BMI, body mass index; CPS, Cancer Prevention Study; MET, metabolic equivalent. ⴱ P values derived from 2 test for differences in frequencies across prediagnosis smoking status.
with all-cause mortality but not with colorectal cancer–specific mortality (Table 2). As summarized in Table 3, all-cause mortality RRs were higher for former smokers who had quit more recently than for those who had quit earlier (Ptrend ⬍ .01 in both pre- and postdiagnosis analyses), but no statistically significant differences were observed by cigarettes per day among current smokers. No statistically significant differences in colorectal cancer–specific mortality RRs were observed by time since quitting for former smokers or by cigarettes per day for current smokers. Table 4 lists associations between the four most common pre- to postdiagnosis smoking patterns and risk of mortality. For both mortality outcomes, RRs for current smokers who quit after diagnosis were lower than the RRs for current smokers who continued to smoke, but the RRs were not statistically significantly different (all-cause mortality, P ⫽ .37; colorectal cancer–specific mortality, P ⫽ .57).
Prediagnosis current (RR, 2.51; 95% CI, 1.70 to 3.70) and former smoking (RR, 1.59; 95% CI, 1.27 to 1.99) were associated with higher all-cause mortality for persons diagnosed with locally staged disease. Among persons diagnosed with regionally staged disease, current smoking was associated with higher risk of all-cause mortality (RR, 1.90; 95% CI, 1.36 to 2.64), whereas former smoking was not associated with all-cause mortality (RR, 0.95; 95% CI, 0.79 to 1.15). The interaction between smoking and stage was statistically significant (Appendix Table A1, online only). We detected an interaction between time and prediagnosis smoking with all-cause mortality. On the basis of visual inspection of the survival curves (Fig 1), this interaction occurred as a result of differences between the first 6 months of follow-up, during which time only two deaths occurred among current smokers, and later follow-up. When examined by follow-up period (0 to 6 months, 7 to 12 months, ⬎ 1 to 5 years, and ⬎ 5 years), the association between prediagnosis smoking and all-cause mortality
Table 2. All-Cause and Colorectal Cancer–Specific Mortality Among Patients With Nonmetastatic Colorectal Cancer by Smoking Status in CPS-II Nutrition Cohort Neverⴱ Mortality Prediagnosis smoking All cause Colorectal cancer specific Postdiagnosis smoking All cause Colorectal cancer specific
Former
Current
Deaths
PersonYears
Rate†
RR
Deaths
PersonYears
Rate†
RR
95% CI
Deaths
PersonYears
Rate†
RR
95% CI
367 174
7,610 7,610
4,280 2,566
1.00 1.00
618 231
10,454 10,454
4,871 2,150
1.18 0.89
1.02 to 1.36 0.72 to 1.10
89 48
1,123 1,123
7,528 4,336
2.12 2.14
1.65 to 2.74 1.50 to 3.07
263 115
5,563 5,563
4,287 2,504
1.00 1.00
554 187
8,940 8,940
5,117 2,128
1.21 0.91
1.03 to 1.42 0.71 to 1.18
48 22
540 540
8,393 4,148
2.22 1.92
1.58 to 3.13 1.15 to 3.21
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity. Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group. †Age-standardized rate, per 100,000 person-years, standardized to age distribution of men or women in CPS-II nutrition cohort.
4
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7,610
7,610
5,563
5,563
174
263
115
PersonYears
367
Deaths
1.00
1.00
1.00
1.00
RR
61
201
77
204
Deaths
3,400
3,400
3,442
3,442
PersonYears 95% CI
0.74 0.53 to 1.03
1.07 0.87 to 1.31
0.86 0.65 to 1.15
1.08 0.89 to 1.30
RR
Quit ⱖ 30 Years Ago
Deaths
46
104
63
148
Former
1,827
1,827
2,702
2,702
PersonYears 95% CI
1.29 0.88 to 1.87
1.21 0.94 to 1.55
0.92 0.67 to 1.26
1.08 0.88 to 1.34
RR
Quit 20 to 29 Years Ago
56
174
81
241
Deaths
2,792
2,792
3,846
3,846
PersonYears 95% CI
0.89 0.63 to 1.26
1.38 1.12 to 1.71
0.87 0.65 to 1.16
1.40 1.17 to 1.69
RR
Quit ⬍ 20 Years Ago
15
16
28
Deaths
153
360
360
PersonYears
95% CI
—†
2.08 1.17 to 3.67
2.10 1.22 to 3.61
22
28
57
294
672
672
PersonYears
95% CI
—†
2.19 1.35 to 3.55
2.08 1.32 to 3.28
2.41 1.76 to 3.30
RR
ⱖ 15 Cigarettes per Day
Deaths
Current
2.07 1.38 to 3.09
RR
⬍ 15 Cigarettes per Day
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity. Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group. †Data not shown because of small No. of deaths.
Prediagnosis smoking All cause Colorectal cancer specific Postdiagnosis smoking All cause Colorectal cancer specific
Mortality
Neverⴱ
Table 3. All-Cause and Colorectal Cancer–Specific Mortality Among Patients With Nonmetastatic Colorectal Cancer by Time Since Quitting Smoking and Cigarettes per Day in CPS-II Nutrition Cohort
Smoking and Colorectal Cancer Survival
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Yang et al
Table 4. All-Cause and Colorectal Cancer–Specific Mortality Among Patients With Nonmetastatic Colorectal Cancer by Pre- and Postdiagnosis Smoking Pattern in CPS-II Nutrition Cohort Never-Neverⴱ
Former-Former
Current-Former
Current-Current
Mortality
Deaths
PersonYears
RR
Deaths
PersonYears
RR
95% CI
Deaths
PersonYears
RR
95% CI
Deaths
PersonYears
RR
95% CI
All cause Colorectal cancer specific
263
5563
1.00
523
8477
1.18
1.00, 1.39
30
438
1.94
1.29, 2.91
43
454
2.33
1.62, 3.34
115
5563
1.00
172
8477
0.86
0.66, 1.11
15
438
1.85
1.02, 3.35
21
454
2.20
1.29, 3.76
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, and prediagnosis alcohol consumption, body mass index, and physical activity. Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group
in the first 6 months of follow-up differed from that in follow-up occurring ⱖ 6 months after diagnosis (Pinteraction ⬍ .05; Fig 1; Appendix Table A2, online only). There was no evidence of effect modification by age at diagnosis (⬍ 70 v ⱖ 70 years), sex, tumor site (colon v rectum), BMI (obese v not obese), physical activity (⬍ median v ⱖ median metabolic equivalent of task hours per week), and alcohol consumption (current v not current drinker; data not shown). In sensitivity analyses, associations between smoking and mortality were not materially different after we excluded: participants with a history of lung disease, deaths within the first 2 years of follow-up, deaths within 2 years of returning the postdiagnosis survey, and participants who returned the postdiagnosis survey within 6 months of diagnosis (data not shown). Among persons with distant metastatic colon or rectal cancer, smoking status before diagnosis was not associated with all-cause mortality (current v never-smoker: RR, 0.81; 95% CI, 0.52 to 1.25; former v never-smoker: RR, 1.00; 95% CI, 0.77 to 1.31). The association between postdiagnosis smoking and survival for survivors with distant metastatic disease could not be assessed, because of small numbers and limited study power (data not shown).
Overall Survival (proportion)
1.0
0.8
0.6
0.4
0.2
0
Never smoker Former smoker Current smoker
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Follow-Up After Colorectal Cancer Diagnosis (years) No. at risk Never smoker 993 Former smoker 1,402 Current smoker 153
654 905 89
306 432 51
75 95 9
Fig 1. Kaplan-Meier curves for overall survival by prediagnosis smoking status (never, former, and current) for 2,548 patients with nonmetastatic colorectal cancer in Cancer Prevention Study II nutrition cohort. 6
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DISCUSSION
In this cohort study of colorectal cancer survivors, smoking before or after cancer diagnosis was associated with higher risk of mortality resulting from all causes and from colorectal cancer specifically. These associations were independent of age at diagnosis, sex, and other important covariables. To our knowledge, this is one of the largest studies of smoking and colorectal cancer survival and the first study to prospectively collect both pre- and postdiagnosis smoking information. This study adds to the limited evidence of the adverse effect of smoking on survival for colorectal cancer survivors. According to a recent meta-analysis, smoking is associated with poorer long-term prognosis after colorectal cancer diagnosis; specifically, risk of allcause mortality was higher for current smoking at all time points (HR, 1.26; 95% CI, 1.15 to 1.37), with equivocal results reported for former smoking (HR, 1.11; 95% CI 0.93-1.33).15 We found a ⬎ two-fold higher risk of all-cause mortality for both pre- and postdiagnosis current smoking compared with never smoking, but lower, although still statistically significant, associations with both pre- and postdiagnosis former smoking. Only six other studies have examined the association between smoking and colorectal cancer–specific mortality16-21; of these, two studies with sample sizes comparable to ours18,19 found current, but not former, smoking to be associated with significantly higher colorectal cancer–specific mortality, consistent with our results. However, the previous RRs were lower than the RRs in our study, with prediagnosis current smoking associated with an RR of 1.30 in a study of patients with colorectal cancer in Washington state18 and an RR of 1.46 among patients with colon cancer in a large US cohort.19 Another study found a ⬎ two-fold higher risk of colorectal cancer–specific mortality comparing current smokers with former or never-smokers combined, and the remaining three studies found no association between pre- and postdiagnosis current and ever smoking with colorectal cancer–specific mortality; however, these analyses were based on relatively smaller sample sizes.16,17,20,21 Importantly, this study took advantage of prospectively collected exposure information to assess the association between change of smoking status from pre- to postdiagnosis and risk of mortality. We found that persons who quit smoking after diagnosis still experienced higher risks of all-cause and colorectal cancer–specific mortality than never-smokers. RRs for all-cause and colorectal cancer–specific mortality were slightly lower for persons who quit smoking after diagnosis JOURNAL OF CLINICAL ONCOLOGY
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Smoking and Colorectal Cancer Survival
than for those who continued smoking, although these RRs were not statistically significantly different. In the only comparable study, current smokers who quit after diagnosis were at slightly lower risk of colorectal cancer–specific mortality, but not all-cause mortality, than those who continued smoking.18 A limitation of both studies on this topic is that the reason for quitting smoking after diagnosis is unknown. If persons who are ill are more likely to quit smoking postdiagnosis, the RRs would be biased. The overall health benefits of smoking cessation are well documented32 and can be reasonably assumed to apply to colorectal cancer survivors, many of whom will die as a result of causes other than colorectal cancer. Whether smoking cessation after colorectal cancer diagnosis lowers colorectal cancer–specific mortality warrants further investigation, particularly in other large studies with prospectively collected smoking exposure information. The association between smoking and all-cause mortality among patients with colorectal cancer may be partially explained by the larger proportion of deaths among current smokers resulting from lung cancer or respiratory system diseases. However, smoking was also positively associated with colorectal cancer–specific mortality, and the biologic mechanisms underlying this association are not well understood. Smoking has been associated with risk of specific molecular phenotypes of colorectal cancer, including tumors characterized as MSI high8-12 or CIMP high12-14 or with BRAF mutations.11-13 Although MSI-high tumors generally demonstrate higher survival,33,34 BRAF mutation status is independently associated with higher risk of mortality,35 and CIMP-high status in microsatellite-stable tumors is also associated with lower survival.36,37 It is plausible that smokers have pathologically more-aggressive tumors, which in part explains the lower survival in this group. Three studies reported that the impact of smoking on colorectal cancer survival differs according to tumor molecular phenotype, although the patterns of association across tumor molecular phenotypes varied, and more research is needed to determine if smoking specifically affects certain molecular phenotypes of colorectal carcinogenesis to influence prognosis.18,38,39 Other mechanisms for the adverse impact of smoking on colorectal cancer–specific survival may include decreased efficacy of colorectal cancer treatment among smokers. Patients who smoked during cetuximab-based treatment had statistically significant lower response rates and shorter time to progression.40 Nicotine interferes with chemotherapeutic drugs in vitro by inhibiting drug-induced apoptosis.41 Also, in mice bearing human lung cancer xenografts, nicotine may decrease responses to radiotherapy and chemoradiotherapy through upregulating HIF-1␣ expression, but this effect is reversible with nicotine removal.42 In addition, smoking may result in higher risk of tumor recurrence. It has been reported that nicotine increases REFERENCES 1. Secretan B, Straif K, Baan R, et al: A review of human carcinogens: Part E: Tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 10:1033-1034, 2009 2. International Agency for Research on Cancer: IARC Monograph on the Evaluation of Carcinogenic Risks to Humans. Lyon, France, International Agency for Research on Cancer, 2012 3. US Department of Health and Human Services: The Health Consequences of Smoking: 50 www.jco.org
proliferation and angiogenesis and suppresses apoptosis in colon cancer cells.43-45 Thus, smoking could promote growth and metastasis of residual cancer cells that escaped the colon during treatment. Because we had limited treatment data in CPS-II, we could not address these issues. This study has several strengths. It was a large study on smoking and long-term survival in patients with colorectal cancer, with sufficient power to examine associations of both pre- and postdiagnosis smoking with all-cause and colorectal cancer–specific mortality. Information on smoking and other important covariates was prospectively collected and updated in all follow-up questionnaires, with postdiagnosis data available for 88% of the original sample. Limitations of this study include a lack of information on tumor molecular phenotype, treatment efficacy, and tumor recurrence, which may be important for elucidating mechanisms for the adverse impact of smoking on colorectal cancer survival. There was limited power to assess the potential influence of pre- to postdiagnosis smoking change. Statistical power to examine the influence of changes in smoking status between the first postdiagnosis and subsequent postdiagnosis smoking assessments was also limited. In conclusion, results from this study of colorectal cancer survivors suggest that smoking is associated with a nearly two-fold higher risk of death compared with never smoking. Further research is needed to understand mechanisms whereby smoking may increase colorectal cancer–specific mortality and determine if quitting smoking after diagnosis lowers the risk of colorectal cancer– specific mortality. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR CONTRIBUTIONS Conception and design: Baiyu Yang, Susan M. Gapstur, Peter T. Campbell Financial support: Susan M. Gapstur, Peter T. Campbell Administrative support: Susan M. Gapstur, Peter T. Campbell Provision of study materials or patients: Susan M. Gapstur, Peter T. Campbell Collection and assembly of data: Eric J. Jacobs, Susan M. Gapstur, Peter T. Campbell Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors
Years of Progress—A Report of the Surgeon General. Atlanta, GA, US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014 4. Tsoi KK, Pau CY, Wu WK, et al: Cigarette smoking and the risk of colorectal cancer: A metaanalysis of prospective cohort studies. Clin Gastroenterol Hepatol 7:682-688, e1-e5, 2009 5. Huxley RR, Ansary-Moghaddam A, Clifton P, et al: The impact of dietary and lifestyle risk factors on risk of colorectal cancer: A quantitative overview
of the epidemiological evidence. Int J Cancer 125: 171-180, 2009 6. Liang PS, Chen TY, Giovannucci E: Cigarette smoking and colorectal cancer incidence and mortality: Systematic review and meta-analysis. Int J Cancer 124:2406-2415, 2009 7. Botteri E, Iodice S, Bagnardi V, et al: Smoking and colorectal cancer: A meta-analysis. JAMA 300: 2765-2778, 2008 8. Slattery ML, Curtin K, Anderson K, et al: Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst 92:1831-1836, 2000
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9. Chia VM, Newcomb PA, Bigler J, et al: Risk of microsatellite-unstable colorectal cancer is associated jointly with smoking and nonsteroidal anti-inflammatory drug use. Cancer Res 66:6877-6883, 2006 10. Poynter JN, Haile RW, Siegmund KD, et al: Associations between smoking, alcohol consumption, and colorectal cancer, overall and by tumor microsatellite instability status. Cancer Epidemiol Biomarkers Prev 18:2745-2750, 2009 11. Curtin K, Samowitz WS, Wolff RK, et al: Somatic alterations, metabolizing genes and smoking in rectal cancer. Int J Cancer 125:158-164, 2009 12. Limsui D, Vierkant RA, Tillmans LS, et al: Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst 102:1012-1022, 2010 13. Samowitz WS, Albertsen H, Sweeney C, et al: Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst 98:1731-1738, 2006 14. Nishihara R, Morikawa T, Kuchiba A, et al: A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification. Am J Epidemiol 178:84-100, 2013 15. Walter V, Jansen L, Hoffmeister M, et al: Smoking and survival of colorectal cancer patients: Systematic review and meta-analysis. Ann Oncol 25:1517-1525, 2014 16. Warren GW, Kasza KA, Reid ME, et al: Smoking at diagnosis and survival in cancer patients. Int J Cancer 132:401-410, 2013 17. Boyle T, Fritschi L, Platell C, et al: Lifestyle factors associated with survival after colorectal cancer diagnosis. Br J Cancer 109:814-822, 2013 18. Phipps AI, Baron J, Newcomb PA: Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival. Cancer 117:4948-4957, 2011 19. Pelser C, Arem H, Pfeiffer RM, et al: Prediagnostic lifestyle factors and survival after colon and rectal cancer diagnosis in the National Institutes of Health (NIH)-AARP Diet and Health Study. Cancer 120:1540-1547, 2014 20. Richards CH, Leitch EF, Horgan PG, et al: The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer. Br J Cancer 103:1356-1361, 2010 21. Munro AJ, Bentley AH, Ackland C, et al: Smoking compromises cause-specific survival in
patients with operable colorectal cancer. Clin Oncol (R Coll Radiol) 18:436-440, 2006 22. Calle EE, Rodriguez C, Jacobs EJ, et al: The American Cancer Society Cancer Prevention Study II nutrition cohort: Rationale, study design, and baseline characteristics. Cancer 94:2490-2501, 2002 23. Calle EE, Terrell DD: Utility of the National Death Index for ascertainment of mortality among Cancer Prevention Study II participants. Am J Epidemiol 137:235-241, 1993 24. McCullough ML, Gapstur SM, Shah R, et al: Association between red and processed meat intake and mortality among colorectal cancer survivors. J Clin Oncol 31:2773-2782, 2013 25. Dehal AN, Newton CC, Jacobs EJ, et al: Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: The Cancer Prevention Study-II nutrition cohort. J Clin Oncol 30:53-59, 2012 26. Campbell PT, Patel AV, Newton CC, et al: Associations of recreational physical activity and leisure time spent sitting with colorectal cancer survival. J Clin Oncol 31:876-885, 2013 27. Campbell PT, Newton CC, Dehal AN, et al: Impact of body mass index on survival after colorectal cancer diagnosis: The Cancer Prevention Study-II nutrition cohort. J Clin Oncol 30:42-52, 2012 28. Yang B, McCullough ML, Gapstur SM, et al: Calcium, vitamin D, dairy products, and mortality among colorectal cancer survivors: The Cancer Prevention Study-II nutrition cohort. J Clin Oncol 32: 2335-2343, 2014 29. Chao A, Thun MJ, Jacobs EJ, et al: Cigarette smoking and colorectal cancer mortality in the cancer prevention study II. J Natl Cancer Inst 92:18881896, 2000 30. Allison PD: Survival Analysis Using the SAS System: A Practical Guide. Cary, NC, SAS Institute, 1995 31. Lash TL, Cole SR: Immortal person-time in studies of cancer outcomes. J Clin Oncol 27:e55e56, 2009 32. US Department of Health and Human Services: The Health Benefits of Smoking Cessation: A Report of the Surgeon General. Rockville, MD, US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 1990 33. Guastadisegni C, Colafranceschi M, Ottini L, et al: Microsatellite instability as a marker of prog-
nosis and response to therapy: A meta-analysis of colorectal cancer survival data. Eur J Cancer 46: 2788-2798, 2010 34. Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609-618, 2005 35. Safaee Ardekani G, Jafarnejad SM, Tan L, et al: The prognostic value of BRAF mutation in colorectal cancer and melanoma: A systematic review and meta-analysis. PLoS ONE 7:e47054, 2012 36. Ogino S, Meyerhardt JA, Kawasaki T, et al: CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch 450:529-537, 2007 37. Ward RL, Cheong K, Ku SL, et al: Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21:3729-3736, 2003 38. Zhu Y, Yang SR, Wang PP, et al: Influence of pre-diagnostic cigarette smoking on colorectal cancer survival: Overall and by tumour molecular phenotype. Br J Cancer 110:1359-1366, 2014 39. Phipps AI, Shi Q, Newcomb PA, et al: Associations between cigarette smoking status and colon cancer prognosis among participants in North Central Cancer Treatment Group phase III trial N0147. J Clin Oncol 31:2016-2023, 2013 40. Vincenzi B, Santini D, Loupakis F, et al: Cigarettes smoking habit may reduce benefit from cetuximab-based treatment in advanced colorectal cancer patients. Expert Opin Biol Ther 9:945-949, 2009 41. Dinicola S, Morini V, Coluccia P, et al: Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs. Toxicol In Vitro 27:2256-2263, 2013 42. Warren GW, Romano MA, Kudrimoti MR, et al: Nicotinic modulation of therapeutic response in vitro and in vivo. Int J Cancer 131:2519-2527, 2012 43. Wong HP, Yu L, Lam EK, et al: Nicotine promotes colon tumor growth and angiogenesis through -adrenergic activation. Toxicol Sci 97:279287, 2007 44. Cucina A, Dinicola S, Coluccia P, et al: Nicotine stimulates proliferation and inhibits apoptosis in colon cancer cell lines through activation of survival pathways. J Surg Res 178:233-241, 2012 45. Ye YN, Wu WK, Shin VY, et al: A mechanistic study of colon cancer growth promoted by cigarette smoke extract. Eur J Pharmacol 519:52-57, 2005
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GLOSSARY TERMS
BRAF: an isoform of RAF. CIMP: The CpG island methylator phenotype is characterized by widespread, concordant promoter CpG island methylation resulting in silencing of many tumor suppressor genes. CIMPhigh (high degree of CIMP) in colorectal cancer is associated with old age, female sex, proximal colon, BRAF mutation and microsatellite instability, and inversely with chromosomal instability, TP53 mutation, WNT/-catenin (CTNNB1) activation, and genome-wide DNA hypomethylation.
Cox proportional hazards regression model: a statistical model for regression analysis of censored survival data, examining the relationship of censored survival distribution to one or more covariates. This model produces a baseline survival curve, covariate coefficient estimates with their standard errors, risk ratios, 95% CIs, and significance levels.
disease-specific survival rate: the percentage of people in a study who have not died from a specific disease since diagnosis
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or treatment. Patients who died as a result of some other cause are not counted.
first-degree family history: the record of a recurring medical condition occurring in family members who share about 50% of their genes, including parents, offspring, and siblings.
histologic grade: provides prognostic information in many tumors, including ovarian cancer. Histologic grade is based on a combination of cellular features (nuclear, cytologic, and architectural). The more nuclear atypia and mitotic figures, the higher the grade.
microsatellite instability (MSI): an alteration in the length of the microsatellites from cell to cell.
overall survival: the duration between random assignment and death.
Surveillance, Epidemiology, and End Results (SEER): a national cancer registry that collects information from all incident malignancies in multiple geographic areas of the United States.
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Active Smoking and Mortality Among Colorectal Cancer Survivors: The Cancer Prevention Study II Nutrition Cohort The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Baiyu Yang No relationship to disclose
Victoria Stevens No relationship to disclose
Eric J. Jacobs No relationship to disclose
Peter T. Campbell No relationship to disclose
Susan M. Gapstur No relationship to disclose
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Smoking and Colorectal Cancer Survival
Appendix
Table A1. Prediagnosis Smoking and All-Cause Mortality Among Patients With Nonmetastatic Colorectal Cancer by Tumor Stage in CPS-II Nutrition Cohort Neverⴱ Stage
Former
Deaths Person-Years RR Deaths Person-Years RR
All-cause mortality Localized Regional Colorectal cancer–specific mortality Localized Regional
Current 95% CI
Deaths Person-Years RR
95% CI
Pinteraction ⬍ .01
139 228
4,138 3,472
1.00 1.00
289 329
5,734 4,721
1.59 1.27 to 1.99 0.95 0.79 to 1.15
37 52
640 483
2.51 1.70 to 3.70 1.90 1.36 to 2.64
29 145
4,138 3,472
1.00 1.00
61 170
5,734 4,721
1.48 0.93 to 2.36 0.77 0.61 to 0.99
12 36
640 483
3.21 1.56 to 6.60 1.92 1.27 to 2.89
.04
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group.
Table A2. Prediagnosis Smoking Status and All-Cause Mortality Stratified by Follow-Up Period Neverⴱ
Former
Current
Follow-Up
Deaths
Person-Years
RR
Deaths
Person-Years
RR
95% CI
Deaths
Person-Years
RR
95% CI
0 to 6 months 7 to 12 months ⬎ 1 to 5 years ⬎ 5 years
34 14 168 151
486 476 3,228 3,420
1.00 1.00 1.00 1.00
39 25 258 296
688 675 4,501 4,590
0.90 1.43 0.99 1.49
0.53 to 1.53 0.67 to 3.04 0.80 to 1.22 1.19 to 1.87
2 6 42 39
76 74 460 513
0.57 5.11 1.99 2.38
0.13 to 2.52 1.70 to 15.37 1.37 to 2.87 1.61 to 3.54
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity. Abbreviation: RR, relative risk. ⴱ Reference group.
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JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Active Smoking and Mortality Among Colorectal Cancer Survivors: The Cancer Prevention Study II Nutrition Cohort Baiyu Yang, Eric J. Jacobs, Susan M. Gapstur, Victoria Stevens, and Peter T. Campbell All authors: American Cancer Society; and Baiyu Yang, Emory University, Atlanta, GA. Published online ahead of print at www.jco.org on February 2, 2015. Supported by the American Cancer Society. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Peter T. Campbell, PhD, Epidemiology Research Program, American Cancer Society National Home Office, 250 Williams St NW, Atlanta, GA 30303; e-mail: peter. [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.58.3831
A
B
S
T
R
A
C
T
Purpose Active smoking is associated with higher colorectal cancer risk, but its association with survival after colorectal cancer diagnosis is unclear. We investigated associations of smoking, before and after diagnosis, with all-cause and colorectal cancer–specific mortality among colorectal cancer survivors. Patients and Methods From a cohort of adults who were initially free of colorectal cancer, we identified 2,548 persons diagnosed with invasive, nonmetastatic colorectal cancer between baseline (1992 or 1993) and 2009. Vital status and cause of death were determined through 2010. Smoking was self-reported on the baseline questionnaire and updated in 1997 and every 2 years thereafter. Postdiagnosis smoking information was available for 2,256 persons (88.5%). Results Among the 2,548 colorectal cancer survivors, 1,074 died during follow-up, including 453 as a result of colorectal cancer. In multivariable-adjusted Cox proportional hazards regression models, prediagnosis current smoking was associated with higher all-cause mortality (relative risk [RR], 2.12; 95% CI, 1.65 to 2.74) and colorectal cancer–specific mortality (RR, 2.14; 95% CI, 1.50 to 3.07), whereas former smoking was associated with higher all-cause mortality (RR, 1.18; 95% CI, 1.02 to 1.36) but not with colorectal cancer–specific mortality (RR, 0.89; 95% CI, 0.72 to 1.10). Postdiagnosis current smoking was associated with higher all-cause (RR, 2.22; 95% CI, 1.58 to 3.13) and colorectal cancer–specific mortality (RR, 1.92; 95% CI, 1.15 to 3.21), whereas former smoking was associated with all-cause mortality (RR, 1.21; 95% CI, 1.03 to 1.42). Conclusion This study adds to the existing evidence that cigarette smoking is associated with higher all-cause and colorectal cancer–specific mortality among persons with nonmetastatic colorectal cancer. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
INTRODUCTION
Colorectal cancer was added to the list of smokingattributable cancers by the International Association for Research on Cancer in 20091,2 and by the US Surgeon General in 2014.3 According to several recent meta-analyses, the relationship between smoking and colorectal cancer incidence is likely dose dependent.4-7 Moreover, the association between smoking and colorectal cancer incidence seems strongest for three correlated molecular phenotypes of the disease: microsatellite instability (MSI) high,8-12 CpG island methylator phenotype (CIMP) high,12-14 and BRAF mutation positive.11-13 Less is known about the potential effect of smoking on overall or disease-specific survival rate after a diagnosis of colorectal cancer. A recent meta-
analysis of studies among patients with colorectal cancer who assessed smoking status before, at the time of, or after a cancer diagnosis showed higher risks of all-cause mortality among current smokers at all time points (summary hazard ratio [HR], 1.26) compared with never-smokers.15 Nevertheless, only six studies examined colorectal cancer–specific mortality,16-21 and only one study examined changes in smoking status from pre- to postdiagnosis (particularly quitting after diagnosis) in relation to mortality.18 Further research is needed to clarify the association between smoking and survival to better inform and support smoking-cessation efforts among colorectal cancer survivors. Herein, we report the associations of pre- and postdiagnosis active smoking with mortality resulting from all causes and from colorectal cancer © 2015 by American Society of Clinical Oncology
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Yang et al
specifically among persons diagnosed with invasive nonmetastatic colorectal cancer in a prospective cohort study of men and women in the United States. PATIENTS AND METHODS Study Cohort The Cancer Prevention Study II (CPS-II) nutrition cohort is a prospective study of cancer incidence and mortality that began in 1992.22 At baseline enrollment (1992 or 1993), approximately 184,000 men and women reported information regarding demographics, detailed smoking history, medical history, body size, diet, and other lifestyle factors on a 10-page, self-administered questionnaire. Follow-up questionnaires were mailed to participants in 1997 and every 2 years thereafter to update exposure information and document new cancer diagnoses. The CPS-II nutrition cohort was approved by the institutional review board of Emory University. We identified 3,832 men and women diagnosed with invasive colon or rectal cancer between enrollment in 1992 or 1993 and the end of incidence follow-up (June 30, 2009) from among the 181,293 participants with no previous history of colorectal cancer at baseline. A majority of these persons (n ⫽ 3,053) were first identified via self-report on a follow-up questionnaire and then verified either by review of medical records (n ⫽ 2,188) or linkage to state cancer registries (n ⫽ 865). The remaining 779 persons were initially identified as cancer deaths through linkage to the National Death Index (NDI),23 and 531 of them were subsequently verified through linkage to state cancer registries (n ⫽ 529) or by review of medical records (n ⫽ 2). Exclusions were made based on the following: deaths identified through NDI that were not verified through medical records or cancer registries (n ⫽ 248), prevalent cancers (except for nonmelanoma skin cancer) at baseline (n ⫽ 387), implausible diagnosis date (n ⫽ 11), missing stage at diagnosis (n ⫽ 136), TNM summary stage IV or distant SEER stage at diagnosis (n ⫽ 421), nonadenocarcinoma histology (n ⫽ 50), implausible death date (n ⫽ 2), and missing smoking status at baseline (n ⫽ 29). Consistent with our previous studies from this cohort,24-28 we chose a priori to exclude persons with distant metastatic disease in the main analyses, because this group has a poor 5-year relative survival that is unlikely to be substantially affected by risk behaviors and because this group is less likely to return a postdiagnosis survey; nonetheless, the impact of smoking on survival among persons with distant metastatic disease was examined separately. After exclusions, our final analytic cohort for prediagnosis analyses comprised 2,548 participants (1,416 men and 1,132 women). Among them, 1,887 were diagnosed with colon cancer (International Classification of Diseases for Oncology [ICD-O] codes C18.0 and C18.2 to C18.9), and 661 were diagnosed with rectal cancer (ICD-O codes C19.9 and C20.9). Stratified by SEER summary stage, 1,281 had localized disease (invasive tumors limited to colon or rectum), and 1,267 had regional disease (tumors that spread through bowel wall to adjacent tissues or organs or to regional lymph nodes). Study Outcomes Participants were observed through December 31, 2010, to ascertain their vital status through linkage to the NDI. Cause of death has been obtained for 99.3% of all known deaths in CPS-II. The primary outcome for this analysis was all-cause mortality. The secondary outcome was mortality specifically resulting from colorectal cancer (ICD ninth revision [ICD-9] codes 153 and 154; ICD 10th revision [ICD-10] coes C18, C19, and C20), defined from the singular underlying cause of death from NDI records. Pre- and Postdiagnosis Smoking Smoking status (never, former, or current) and dose were first ascertained at baseline and reassessed on each follow-up questionnaire (1997, 1999, 2001, 2003, 2005, 2007, and 2009). Smoking dose was categorized based on time since quitting for former smokers and cigarettes per day for current smokers (ie, never-smokers; former smokers who quit ⱖ 30, 20 to 29, and ⬍ 20 years ago; and current smokers who smoked ⬍ 15 or ⱖ 15 cigarettes per day). 2
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These categories were initially selected from an earlier analysis of the CPS-II cohort,29 with modification to account for the distributions in this analysis. Prediagnosis smoking status and dose were obtained from the last questionnaire completed before cancer diagnosis, or the penultimate questionnaire if the diagnosis was within 6 months of completing the last questionnaire, because smoking behaviors may be influenced by symptoms immediately preceding diagnosis. Postdiagnosis smoking information was obtained from the first questionnaire completed after diagnosis. Of the 2,548 patients included in the prediagnosis analysis, 2,256 (88.5%) reported postdiagnosis smoking information. A pre- to postdiagnosis change variable was constructed to include the four most common combinations of pre- and postdiagnosis smoking: never-never, former-former, current-former, and current-current. Statistical Analysis Cox proportional hazards regression was used to calculate relative risks (RRs) and 95% CIs. We assessed the proportional hazards assumption with a likelihood ratio test. The underlying time axis for all analyses was time since diagnosis. Delayed-entry Cox models were used for postdiagnosis smoking models so that person-time began on the date of return of the postdiagnosis questionnaire30; this procedure accounts for potential biases from immortal time.31 For all models, person-time ended at death or at the end of mortality follow-up (December 31, 2010), whichever came first. The mean follow-up was calculated by taking the mean of the observed follow-up time. All analyses were a priori adjusted for age at diagnosis, tumor stage at diagnosis, and sex. We evaluated other demographic, lifestyle, and clinical covariates, but none changed the RR estimates by ⬎ 10%. Nevertheless, for pre- and postdiagnosis multivariable models, we in addition adjusted for corresponding pre- or postdiagnosis alcohol intake, body mass index (BMI), and physical activity, because these variables are important predictors of survival in this cohort19,26,27 and/or because they may also correlate with smoking.19 We calculated P values for trend using Wald tests for time since quitting smoking from analyses restricted to former smokers and, separately, for cigarettes per day among current smokers. In sensitivity analyses, we excluded: participants with a history of lung disease, deaths within the first 2 years of follow-up, deaths within 2 years of returning the postdiagnosis survey, and participants who returned the postdiagnosis survey within 6 months of diagnosis. We conducted likelihood ratio tests to examine whether the associations between pre- or postdiagnosis smoking status and all-cause mortality were modified by the following prespecified potential effect modifiers: age at diagnosis, sex, tumor stage, tumor subsite, BMI, physical activity, and alcohol consumption. All analyses were performed using SAS software (version 9.3; SAS Institute, Cary, NC).
RESULTS
The mean age of participants was 65 years at baseline and 73 years at diagnosis. Compared with never-smokers, former or current smokers were more likely to be men, less educated, and have ever consumed alcohol. Current smokers were more likely to be diagnosed with colorectal cancer at a younger age, less physically active, and leaner; former smokers were more likely to have a history of myocardial infarction (Table 1). On average, prediagnosis smoking was assessed 2.3 years before diagnosis, and postdiagnosis smoking was assessed 1.4 years after diagnosis. Among the 2,548 patients included in the prediagnosis analysis, 1,074 deaths occurred during a mean follow-up of 7.5 years (standard deviation, 4.6 years; range, 2 days to 18.1 years). The leading causes of death were colorectal cancer (n ⫽ 453), cardiovascular disease (n ⫽ 201), respiratory system disease (n ⫽ 66), and lung cancer (n ⫽ 55). In both pre- and postdiagnosis models, current smoking was associated with statistically significantly higher risks of all-cause and colorectal cancer–specific mortality, whereas former smoking was associated JOURNAL OF CLINICAL ONCOLOGY
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Smoking and Colorectal Cancer Survival
Table 1. Baseline Characteristics of Patients With Colorectal Cancer by Prediagnosis Smoking Status in CPS-II Nutrition Cohort Never (n ⫽ 993) Characteristic Age at colorectal cancer diagnosis, years ⬍ 65 65 to ⬍ 70 70 to ⬍ 75 75 to ⬍ 80 ⱖ 80 Year of colorectal cancer diagnosis 1992 to 1997 1998 to 2001 2002 to 2005 2006 to 2009 Sex Male Female Race/ethnicity White/white Hispanic Black/black Hispanic Other/missing Education Less than high school High school degree Some college/trade school College graduate SEER summary stage Localized Regional Tumor histologic grade at diagnosis Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Colorectal cancer diagnosis site Colon Rectum First course of cancer treatment Surgery No Yes Chemotherapy No Yes Radiation therapy No Yes First-degree family history of colorectal cancer in 1982 No Yes History of diabetes No Yes History of stroke No Yes History of myocardial infarction No Yes History of hypertension No Yes
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Former (n ⫽ 1,402)
Current (n ⫽ 153)
No.
%
No.
%
No.
%
111 201 254 249 178
11.2 20.2 25.6 25.1 17.9
146 277 394 367 218
10.4 19.8 28.1 26.2 15.5
35 39 41 31 7
22.9 25.5 26.8 20.3 4.6
288 291 261 153
29.0 29.3 26.3 15.4
405 425 349 223
28.9 30.3 24.9 15.9
66 49 22 16
43.1 32.0 14.4 10.5
389 604
39.2 60.8
942 460
67.2 32.8
85 68
55.6 44.4
964 19 10
97.1 1.9 1.0
1,378 10 14
98.3 0.7 1.0
149 2 2
97.4 1.3 1.3
59 328 274 328
5.9 33.0 27.6 33.0
115 342 430 508
8.2 24.4 30.7 36.2
19 45 49 38
12.4 29.4 32.0 24.8
487 506
49.0 51.0
721 681
51.4 48.6
73 80
47.7 52.3
123 601 184 12
12.4 60.5 18.5 1.2
171 879 205 18
12.2 62.7 14.6 1.3
17 84 33 0
11.1 54.9 21.6 0
751 242
75.6 24.4
1,028 374
73.3 26.7
108 45
70.6 29.4
25 708
2.5 71.3
24 1,033
1.7 73.7
4 94
2.6 61.4
434 299
43.7 30.1
617 440
44.0 31.4
54 44
35.3 28.8
665 68
67.0 6.8
962 95
68.6 6.8
85 13
55.6 8.5
933 60
94.0 6.0
1,314 88
93.7 6.3
143 10
93.5 6.5
901 92
90.7 9.3
1,263 139
90.1 9.9
148 5
96.7 3.3
975 18
98.2 1.8
1,365 37
97.4 2.6
151 2
98.7 1.3
941 52
94.8 5.2
1,261 141
89.9 10.1
144 9
94.1 5.9
594 59.8 841 399 40.2 561 (continued on following page)
60.0 40.0
109 44
71.2 28.8
Pⴱ ⬍ .01
⬍ .01
⬍ .01
.13
⬍ .01
.42
.04
.27
.02
.04
.03
.96
.03
.29
⬍ .01
.02
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Yang et al
Table 1. Baseline Characteristics of Patients With Colorectal Cancer by Prediagnosis Smoking Status in CPS-II Nutrition Cohort (continued) Never (n ⫽ 993) Characteristic History of lung disease No Yes Physical activity, MET-hours per week ⬍ 3.5 3.5 to ⬍ 8.75 ⱖ 8.75 BMI, kg/m2 ⬍ 18.5 18.5 to ⬍ 25 25 to ⬍ 30 ⱖ 30 Alcohol intake, drinks per day Nondrinker Former drinker ⬍1 1 to 2 ⬎2
Former (n ⫽ 1,402)
Current (n ⫽ 153)
No.
%
No.
%
No.
%
932 61
93.9 6.1
1,287 115
91.8 8.2
143 10
93.5 6.5
96 442 438
9.7 44.5 44.1
157 548 674
11.2 39.1 48.1
33 63 51
21.6 41.2 33.3
13 389 385 190
1.3 39.2 38.8 19.1
13 485 624 259
0.9 34.6 44.5 18.5
5 75 62 10
3.3 49.0 40.5 6.5
426 52 330 71 42
42.9 5.2 33.2 7.2 4.2
275 96 540 184 206
19.6 6.8 38.5 13.1 14.7
25 14 46 24 35
16.3 9.2 30.1 15.7 22.9
Pⴱ .15
⬍ .01
⬍ .01
⬍ .01
NOTE. Some percentages do not add up to 100% because of missing data or rounding. Abbreviations: BMI, body mass index; CPS, Cancer Prevention Study; MET, metabolic equivalent. ⴱ P values derived from 2 test for differences in frequencies across prediagnosis smoking status.
with all-cause mortality but not with colorectal cancer–specific mortality (Table 2). As summarized in Table 3, all-cause mortality RRs were higher for former smokers who had quit more recently than for those who had quit earlier (Ptrend ⬍ .01 in both pre- and postdiagnosis analyses), but no statistically significant differences were observed by cigarettes per day among current smokers. No statistically significant differences in colorectal cancer–specific mortality RRs were observed by time since quitting for former smokers or by cigarettes per day for current smokers. Table 4 lists associations between the four most common pre- to postdiagnosis smoking patterns and risk of mortality. For both mortality outcomes, RRs for current smokers who quit after diagnosis were lower than the RRs for current smokers who continued to smoke, but the RRs were not statistically significantly different (all-cause mortality, P ⫽ .37; colorectal cancer–specific mortality, P ⫽ .57).
Prediagnosis current (RR, 2.51; 95% CI, 1.70 to 3.70) and former smoking (RR, 1.59; 95% CI, 1.27 to 1.99) were associated with higher all-cause mortality for persons diagnosed with locally staged disease. Among persons diagnosed with regionally staged disease, current smoking was associated with higher risk of all-cause mortality (RR, 1.90; 95% CI, 1.36 to 2.64), whereas former smoking was not associated with all-cause mortality (RR, 0.95; 95% CI, 0.79 to 1.15). The interaction between smoking and stage was statistically significant (Appendix Table A1, online only). We detected an interaction between time and prediagnosis smoking with all-cause mortality. On the basis of visual inspection of the survival curves (Fig 1), this interaction occurred as a result of differences between the first 6 months of follow-up, during which time only two deaths occurred among current smokers, and later follow-up. When examined by follow-up period (0 to 6 months, 7 to 12 months, ⬎ 1 to 5 years, and ⬎ 5 years), the association between prediagnosis smoking and all-cause mortality
Table 2. All-Cause and Colorectal Cancer–Specific Mortality Among Patients With Nonmetastatic Colorectal Cancer by Smoking Status in CPS-II Nutrition Cohort Neverⴱ Mortality Prediagnosis smoking All cause Colorectal cancer specific Postdiagnosis smoking All cause Colorectal cancer specific
Former
Current
Deaths
PersonYears
Rate†
RR
Deaths
PersonYears
Rate†
RR
95% CI
Deaths
PersonYears
Rate†
RR
95% CI
367 174
7,610 7,610
4,280 2,566
1.00 1.00
618 231
10,454 10,454
4,871 2,150
1.18 0.89
1.02 to 1.36 0.72 to 1.10
89 48
1,123 1,123
7,528 4,336
2.12 2.14
1.65 to 2.74 1.50 to 3.07
263 115
5,563 5,563
4,287 2,504
1.00 1.00
554 187
8,940 8,940
5,117 2,128
1.21 0.91
1.03 to 1.42 0.71 to 1.18
48 22
540 540
8,393 4,148
2.22 1.92
1.58 to 3.13 1.15 to 3.21
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity. Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group. †Age-standardized rate, per 100,000 person-years, standardized to age distribution of men or women in CPS-II nutrition cohort.
4
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7,610
7,610
5,563
5,563
174
263
115
PersonYears
367
Deaths
1.00
1.00
1.00
1.00
RR
61
201
77
204
Deaths
3,400
3,400
3,442
3,442
PersonYears 95% CI
0.74 0.53 to 1.03
1.07 0.87 to 1.31
0.86 0.65 to 1.15
1.08 0.89 to 1.30
RR
Quit ⱖ 30 Years Ago
Deaths
46
104
63
148
Former
1,827
1,827
2,702
2,702
PersonYears 95% CI
1.29 0.88 to 1.87
1.21 0.94 to 1.55
0.92 0.67 to 1.26
1.08 0.88 to 1.34
RR
Quit 20 to 29 Years Ago
56
174
81
241
Deaths
2,792
2,792
3,846
3,846
PersonYears 95% CI
0.89 0.63 to 1.26
1.38 1.12 to 1.71
0.87 0.65 to 1.16
1.40 1.17 to 1.69
RR
Quit ⬍ 20 Years Ago
15
16
28
Deaths
153
360
360
PersonYears
95% CI
—†
2.08 1.17 to 3.67
2.10 1.22 to 3.61
22
28
57
294
672
672
PersonYears
95% CI
—†
2.19 1.35 to 3.55
2.08 1.32 to 3.28
2.41 1.76 to 3.30
RR
ⱖ 15 Cigarettes per Day
Deaths
Current
2.07 1.38 to 3.09
RR
⬍ 15 Cigarettes per Day
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity. Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group. †Data not shown because of small No. of deaths.
Prediagnosis smoking All cause Colorectal cancer specific Postdiagnosis smoking All cause Colorectal cancer specific
Mortality
Neverⴱ
Table 3. All-Cause and Colorectal Cancer–Specific Mortality Among Patients With Nonmetastatic Colorectal Cancer by Time Since Quitting Smoking and Cigarettes per Day in CPS-II Nutrition Cohort
Smoking and Colorectal Cancer Survival
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Yang et al
Table 4. All-Cause and Colorectal Cancer–Specific Mortality Among Patients With Nonmetastatic Colorectal Cancer by Pre- and Postdiagnosis Smoking Pattern in CPS-II Nutrition Cohort Never-Neverⴱ
Former-Former
Current-Former
Current-Current
Mortality
Deaths
PersonYears
RR
Deaths
PersonYears
RR
95% CI
Deaths
PersonYears
RR
95% CI
Deaths
PersonYears
RR
95% CI
All cause Colorectal cancer specific
263
5563
1.00
523
8477
1.18
1.00, 1.39
30
438
1.94
1.29, 2.91
43
454
2.33
1.62, 3.34
115
5563
1.00
172
8477
0.86
0.66, 1.11
15
438
1.85
1.02, 3.35
21
454
2.20
1.29, 3.76
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, and prediagnosis alcohol consumption, body mass index, and physical activity. Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group
in the first 6 months of follow-up differed from that in follow-up occurring ⱖ 6 months after diagnosis (Pinteraction ⬍ .05; Fig 1; Appendix Table A2, online only). There was no evidence of effect modification by age at diagnosis (⬍ 70 v ⱖ 70 years), sex, tumor site (colon v rectum), BMI (obese v not obese), physical activity (⬍ median v ⱖ median metabolic equivalent of task hours per week), and alcohol consumption (current v not current drinker; data not shown). In sensitivity analyses, associations between smoking and mortality were not materially different after we excluded: participants with a history of lung disease, deaths within the first 2 years of follow-up, deaths within 2 years of returning the postdiagnosis survey, and participants who returned the postdiagnosis survey within 6 months of diagnosis (data not shown). Among persons with distant metastatic colon or rectal cancer, smoking status before diagnosis was not associated with all-cause mortality (current v never-smoker: RR, 0.81; 95% CI, 0.52 to 1.25; former v never-smoker: RR, 1.00; 95% CI, 0.77 to 1.31). The association between postdiagnosis smoking and survival for survivors with distant metastatic disease could not be assessed, because of small numbers and limited study power (data not shown).
Overall Survival (proportion)
1.0
0.8
0.6
0.4
0.2
0
Never smoker Former smoker Current smoker
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Follow-Up After Colorectal Cancer Diagnosis (years) No. at risk Never smoker 993 Former smoker 1,402 Current smoker 153
654 905 89
306 432 51
75 95 9
Fig 1. Kaplan-Meier curves for overall survival by prediagnosis smoking status (never, former, and current) for 2,548 patients with nonmetastatic colorectal cancer in Cancer Prevention Study II nutrition cohort. 6
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DISCUSSION
In this cohort study of colorectal cancer survivors, smoking before or after cancer diagnosis was associated with higher risk of mortality resulting from all causes and from colorectal cancer specifically. These associations were independent of age at diagnosis, sex, and other important covariables. To our knowledge, this is one of the largest studies of smoking and colorectal cancer survival and the first study to prospectively collect both pre- and postdiagnosis smoking information. This study adds to the limited evidence of the adverse effect of smoking on survival for colorectal cancer survivors. According to a recent meta-analysis, smoking is associated with poorer long-term prognosis after colorectal cancer diagnosis; specifically, risk of allcause mortality was higher for current smoking at all time points (HR, 1.26; 95% CI, 1.15 to 1.37), with equivocal results reported for former smoking (HR, 1.11; 95% CI 0.93-1.33).15 We found a ⬎ two-fold higher risk of all-cause mortality for both pre- and postdiagnosis current smoking compared with never smoking, but lower, although still statistically significant, associations with both pre- and postdiagnosis former smoking. Only six other studies have examined the association between smoking and colorectal cancer–specific mortality16-21; of these, two studies with sample sizes comparable to ours18,19 found current, but not former, smoking to be associated with significantly higher colorectal cancer–specific mortality, consistent with our results. However, the previous RRs were lower than the RRs in our study, with prediagnosis current smoking associated with an RR of 1.30 in a study of patients with colorectal cancer in Washington state18 and an RR of 1.46 among patients with colon cancer in a large US cohort.19 Another study found a ⬎ two-fold higher risk of colorectal cancer–specific mortality comparing current smokers with former or never-smokers combined, and the remaining three studies found no association between pre- and postdiagnosis current and ever smoking with colorectal cancer–specific mortality; however, these analyses were based on relatively smaller sample sizes.16,17,20,21 Importantly, this study took advantage of prospectively collected exposure information to assess the association between change of smoking status from pre- to postdiagnosis and risk of mortality. We found that persons who quit smoking after diagnosis still experienced higher risks of all-cause and colorectal cancer–specific mortality than never-smokers. RRs for all-cause and colorectal cancer–specific mortality were slightly lower for persons who quit smoking after diagnosis JOURNAL OF CLINICAL ONCOLOGY
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than for those who continued smoking, although these RRs were not statistically significantly different. In the only comparable study, current smokers who quit after diagnosis were at slightly lower risk of colorectal cancer–specific mortality, but not all-cause mortality, than those who continued smoking.18 A limitation of both studies on this topic is that the reason for quitting smoking after diagnosis is unknown. If persons who are ill are more likely to quit smoking postdiagnosis, the RRs would be biased. The overall health benefits of smoking cessation are well documented32 and can be reasonably assumed to apply to colorectal cancer survivors, many of whom will die as a result of causes other than colorectal cancer. Whether smoking cessation after colorectal cancer diagnosis lowers colorectal cancer–specific mortality warrants further investigation, particularly in other large studies with prospectively collected smoking exposure information. The association between smoking and all-cause mortality among patients with colorectal cancer may be partially explained by the larger proportion of deaths among current smokers resulting from lung cancer or respiratory system diseases. However, smoking was also positively associated with colorectal cancer–specific mortality, and the biologic mechanisms underlying this association are not well understood. Smoking has been associated with risk of specific molecular phenotypes of colorectal cancer, including tumors characterized as MSI high8-12 or CIMP high12-14 or with BRAF mutations.11-13 Although MSI-high tumors generally demonstrate higher survival,33,34 BRAF mutation status is independently associated with higher risk of mortality,35 and CIMP-high status in microsatellite-stable tumors is also associated with lower survival.36,37 It is plausible that smokers have pathologically more-aggressive tumors, which in part explains the lower survival in this group. Three studies reported that the impact of smoking on colorectal cancer survival differs according to tumor molecular phenotype, although the patterns of association across tumor molecular phenotypes varied, and more research is needed to determine if smoking specifically affects certain molecular phenotypes of colorectal carcinogenesis to influence prognosis.18,38,39 Other mechanisms for the adverse impact of smoking on colorectal cancer–specific survival may include decreased efficacy of colorectal cancer treatment among smokers. Patients who smoked during cetuximab-based treatment had statistically significant lower response rates and shorter time to progression.40 Nicotine interferes with chemotherapeutic drugs in vitro by inhibiting drug-induced apoptosis.41 Also, in mice bearing human lung cancer xenografts, nicotine may decrease responses to radiotherapy and chemoradiotherapy through upregulating HIF-1␣ expression, but this effect is reversible with nicotine removal.42 In addition, smoking may result in higher risk of tumor recurrence. It has been reported that nicotine increases REFERENCES 1. Secretan B, Straif K, Baan R, et al: A review of human carcinogens: Part E: Tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 10:1033-1034, 2009 2. International Agency for Research on Cancer: IARC Monograph on the Evaluation of Carcinogenic Risks to Humans. Lyon, France, International Agency for Research on Cancer, 2012 3. US Department of Health and Human Services: The Health Consequences of Smoking: 50 www.jco.org
proliferation and angiogenesis and suppresses apoptosis in colon cancer cells.43-45 Thus, smoking could promote growth and metastasis of residual cancer cells that escaped the colon during treatment. Because we had limited treatment data in CPS-II, we could not address these issues. This study has several strengths. It was a large study on smoking and long-term survival in patients with colorectal cancer, with sufficient power to examine associations of both pre- and postdiagnosis smoking with all-cause and colorectal cancer–specific mortality. Information on smoking and other important covariates was prospectively collected and updated in all follow-up questionnaires, with postdiagnosis data available for 88% of the original sample. Limitations of this study include a lack of information on tumor molecular phenotype, treatment efficacy, and tumor recurrence, which may be important for elucidating mechanisms for the adverse impact of smoking on colorectal cancer survival. There was limited power to assess the potential influence of pre- to postdiagnosis smoking change. Statistical power to examine the influence of changes in smoking status between the first postdiagnosis and subsequent postdiagnosis smoking assessments was also limited. In conclusion, results from this study of colorectal cancer survivors suggest that smoking is associated with a nearly two-fold higher risk of death compared with never smoking. Further research is needed to understand mechanisms whereby smoking may increase colorectal cancer–specific mortality and determine if quitting smoking after diagnosis lowers the risk of colorectal cancer– specific mortality. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR CONTRIBUTIONS Conception and design: Baiyu Yang, Susan M. Gapstur, Peter T. Campbell Financial support: Susan M. Gapstur, Peter T. Campbell Administrative support: Susan M. Gapstur, Peter T. Campbell Provision of study materials or patients: Susan M. Gapstur, Peter T. Campbell Collection and assembly of data: Eric J. Jacobs, Susan M. Gapstur, Peter T. Campbell Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors
Years of Progress—A Report of the Surgeon General. Atlanta, GA, US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014 4. Tsoi KK, Pau CY, Wu WK, et al: Cigarette smoking and the risk of colorectal cancer: A metaanalysis of prospective cohort studies. Clin Gastroenterol Hepatol 7:682-688, e1-e5, 2009 5. Huxley RR, Ansary-Moghaddam A, Clifton P, et al: The impact of dietary and lifestyle risk factors on risk of colorectal cancer: A quantitative overview
of the epidemiological evidence. Int J Cancer 125: 171-180, 2009 6. Liang PS, Chen TY, Giovannucci E: Cigarette smoking and colorectal cancer incidence and mortality: Systematic review and meta-analysis. Int J Cancer 124:2406-2415, 2009 7. Botteri E, Iodice S, Bagnardi V, et al: Smoking and colorectal cancer: A meta-analysis. JAMA 300: 2765-2778, 2008 8. Slattery ML, Curtin K, Anderson K, et al: Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst 92:1831-1836, 2000
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7
Yang et al
9. Chia VM, Newcomb PA, Bigler J, et al: Risk of microsatellite-unstable colorectal cancer is associated jointly with smoking and nonsteroidal anti-inflammatory drug use. Cancer Res 66:6877-6883, 2006 10. Poynter JN, Haile RW, Siegmund KD, et al: Associations between smoking, alcohol consumption, and colorectal cancer, overall and by tumor microsatellite instability status. Cancer Epidemiol Biomarkers Prev 18:2745-2750, 2009 11. Curtin K, Samowitz WS, Wolff RK, et al: Somatic alterations, metabolizing genes and smoking in rectal cancer. Int J Cancer 125:158-164, 2009 12. Limsui D, Vierkant RA, Tillmans LS, et al: Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst 102:1012-1022, 2010 13. Samowitz WS, Albertsen H, Sweeney C, et al: Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst 98:1731-1738, 2006 14. Nishihara R, Morikawa T, Kuchiba A, et al: A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification. Am J Epidemiol 178:84-100, 2013 15. Walter V, Jansen L, Hoffmeister M, et al: Smoking and survival of colorectal cancer patients: Systematic review and meta-analysis. Ann Oncol 25:1517-1525, 2014 16. Warren GW, Kasza KA, Reid ME, et al: Smoking at diagnosis and survival in cancer patients. Int J Cancer 132:401-410, 2013 17. Boyle T, Fritschi L, Platell C, et al: Lifestyle factors associated with survival after colorectal cancer diagnosis. Br J Cancer 109:814-822, 2013 18. Phipps AI, Baron J, Newcomb PA: Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival. Cancer 117:4948-4957, 2011 19. Pelser C, Arem H, Pfeiffer RM, et al: Prediagnostic lifestyle factors and survival after colon and rectal cancer diagnosis in the National Institutes of Health (NIH)-AARP Diet and Health Study. Cancer 120:1540-1547, 2014 20. Richards CH, Leitch EF, Horgan PG, et al: The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer. Br J Cancer 103:1356-1361, 2010 21. Munro AJ, Bentley AH, Ackland C, et al: Smoking compromises cause-specific survival in
patients with operable colorectal cancer. Clin Oncol (R Coll Radiol) 18:436-440, 2006 22. Calle EE, Rodriguez C, Jacobs EJ, et al: The American Cancer Society Cancer Prevention Study II nutrition cohort: Rationale, study design, and baseline characteristics. Cancer 94:2490-2501, 2002 23. Calle EE, Terrell DD: Utility of the National Death Index for ascertainment of mortality among Cancer Prevention Study II participants. Am J Epidemiol 137:235-241, 1993 24. McCullough ML, Gapstur SM, Shah R, et al: Association between red and processed meat intake and mortality among colorectal cancer survivors. J Clin Oncol 31:2773-2782, 2013 25. Dehal AN, Newton CC, Jacobs EJ, et al: Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: The Cancer Prevention Study-II nutrition cohort. J Clin Oncol 30:53-59, 2012 26. Campbell PT, Patel AV, Newton CC, et al: Associations of recreational physical activity and leisure time spent sitting with colorectal cancer survival. J Clin Oncol 31:876-885, 2013 27. Campbell PT, Newton CC, Dehal AN, et al: Impact of body mass index on survival after colorectal cancer diagnosis: The Cancer Prevention Study-II nutrition cohort. J Clin Oncol 30:42-52, 2012 28. Yang B, McCullough ML, Gapstur SM, et al: Calcium, vitamin D, dairy products, and mortality among colorectal cancer survivors: The Cancer Prevention Study-II nutrition cohort. J Clin Oncol 32: 2335-2343, 2014 29. Chao A, Thun MJ, Jacobs EJ, et al: Cigarette smoking and colorectal cancer mortality in the cancer prevention study II. J Natl Cancer Inst 92:18881896, 2000 30. Allison PD: Survival Analysis Using the SAS System: A Practical Guide. Cary, NC, SAS Institute, 1995 31. Lash TL, Cole SR: Immortal person-time in studies of cancer outcomes. J Clin Oncol 27:e55e56, 2009 32. US Department of Health and Human Services: The Health Benefits of Smoking Cessation: A Report of the Surgeon General. Rockville, MD, US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 1990 33. Guastadisegni C, Colafranceschi M, Ottini L, et al: Microsatellite instability as a marker of prog-
nosis and response to therapy: A meta-analysis of colorectal cancer survival data. Eur J Cancer 46: 2788-2798, 2010 34. Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609-618, 2005 35. Safaee Ardekani G, Jafarnejad SM, Tan L, et al: The prognostic value of BRAF mutation in colorectal cancer and melanoma: A systematic review and meta-analysis. PLoS ONE 7:e47054, 2012 36. Ogino S, Meyerhardt JA, Kawasaki T, et al: CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch 450:529-537, 2007 37. Ward RL, Cheong K, Ku SL, et al: Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21:3729-3736, 2003 38. Zhu Y, Yang SR, Wang PP, et al: Influence of pre-diagnostic cigarette smoking on colorectal cancer survival: Overall and by tumour molecular phenotype. Br J Cancer 110:1359-1366, 2014 39. Phipps AI, Shi Q, Newcomb PA, et al: Associations between cigarette smoking status and colon cancer prognosis among participants in North Central Cancer Treatment Group phase III trial N0147. J Clin Oncol 31:2016-2023, 2013 40. Vincenzi B, Santini D, Loupakis F, et al: Cigarettes smoking habit may reduce benefit from cetuximab-based treatment in advanced colorectal cancer patients. Expert Opin Biol Ther 9:945-949, 2009 41. Dinicola S, Morini V, Coluccia P, et al: Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs. Toxicol In Vitro 27:2256-2263, 2013 42. Warren GW, Romano MA, Kudrimoti MR, et al: Nicotinic modulation of therapeutic response in vitro and in vivo. Int J Cancer 131:2519-2527, 2012 43. Wong HP, Yu L, Lam EK, et al: Nicotine promotes colon tumor growth and angiogenesis through -adrenergic activation. Toxicol Sci 97:279287, 2007 44. Cucina A, Dinicola S, Coluccia P, et al: Nicotine stimulates proliferation and inhibits apoptosis in colon cancer cell lines through activation of survival pathways. J Surg Res 178:233-241, 2012 45. Ye YN, Wu WK, Shin VY, et al: A mechanistic study of colon cancer growth promoted by cigarette smoke extract. Eur J Pharmacol 519:52-57, 2005
■ ■ ■
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GLOSSARY TERMS
BRAF: an isoform of RAF. CIMP: The CpG island methylator phenotype is characterized by widespread, concordant promoter CpG island methylation resulting in silencing of many tumor suppressor genes. CIMPhigh (high degree of CIMP) in colorectal cancer is associated with old age, female sex, proximal colon, BRAF mutation and microsatellite instability, and inversely with chromosomal instability, TP53 mutation, WNT/-catenin (CTNNB1) activation, and genome-wide DNA hypomethylation.
Cox proportional hazards regression model: a statistical model for regression analysis of censored survival data, examining the relationship of censored survival distribution to one or more covariates. This model produces a baseline survival curve, covariate coefficient estimates with their standard errors, risk ratios, 95% CIs, and significance levels.
disease-specific survival rate: the percentage of people in a study who have not died from a specific disease since diagnosis
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or treatment. Patients who died as a result of some other cause are not counted.
first-degree family history: the record of a recurring medical condition occurring in family members who share about 50% of their genes, including parents, offspring, and siblings.
histologic grade: provides prognostic information in many tumors, including ovarian cancer. Histologic grade is based on a combination of cellular features (nuclear, cytologic, and architectural). The more nuclear atypia and mitotic figures, the higher the grade.
microsatellite instability (MSI): an alteration in the length of the microsatellites from cell to cell.
overall survival: the duration between random assignment and death.
Surveillance, Epidemiology, and End Results (SEER): a national cancer registry that collects information from all incident malignancies in multiple geographic areas of the United States.
© 2015 by American Society of Clinical Oncology
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9
Yang et al
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Active Smoking and Mortality Among Colorectal Cancer Survivors: The Cancer Prevention Study II Nutrition Cohort The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Baiyu Yang No relationship to disclose
Victoria Stevens No relationship to disclose
Eric J. Jacobs No relationship to disclose
Peter T. Campbell No relationship to disclose
Susan M. Gapstur No relationship to disclose
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Smoking and Colorectal Cancer Survival
Appendix
Table A1. Prediagnosis Smoking and All-Cause Mortality Among Patients With Nonmetastatic Colorectal Cancer by Tumor Stage in CPS-II Nutrition Cohort Neverⴱ Stage
Former
Deaths Person-Years RR Deaths Person-Years RR
All-cause mortality Localized Regional Colorectal cancer–specific mortality Localized Regional
Current 95% CI
Deaths Person-Years RR
95% CI
Pinteraction ⬍ .01
139 228
4,138 3,472
1.00 1.00
289 329
5,734 4,721
1.59 1.27 to 1.99 0.95 0.79 to 1.15
37 52
640 483
2.51 1.70 to 3.70 1.90 1.36 to 2.64
29 145
4,138 3,472
1.00 1.00
61 170
5,734 4,721
1.48 0.93 to 2.36 0.77 0.61 to 0.99
12 36
640 483
3.21 1.56 to 6.60 1.92 1.27 to 2.89
.04
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity Abbreviations: CPS, Cancer Prevention Study; RR, relative risk. ⴱ Reference group.
Table A2. Prediagnosis Smoking Status and All-Cause Mortality Stratified by Follow-Up Period Neverⴱ
Former
Current
Follow-Up
Deaths
Person-Years
RR
Deaths
Person-Years
RR
95% CI
Deaths
Person-Years
RR
95% CI
0 to 6 months 7 to 12 months ⬎ 1 to 5 years ⬎ 5 years
34 14 168 151
486 476 3,228 3,420
1.00 1.00 1.00 1.00
39 25 258 296
688 675 4,501 4,590
0.90 1.43 0.99 1.49
0.53 to 1.53 0.67 to 3.04 0.80 to 1.22 1.19 to 1.87
2 6 42 39
76 74 460 513
0.57 5.11 1.99 2.38
0.13 to 2.52 1.70 to 15.37 1.37 to 2.87 1.61 to 3.54
NOTE. All RRs and 95% CIs obtained from multivariable models, adjusted for age at diagnosis, sex, tumor stage at diagnosis, alcohol consumption, body mass index, and physical activity. Abbreviation: RR, relative risk. ⴱ Reference group.
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