Abstract
Background
Use of analgesics has been associated with lower risk of ovarian cancer, but to date, very few studies have explored the association between analgesics and ovarian cancer survival.
Methods
We examined the relationship between self-reported pre-diagnostic use of aspirin, ibuprofen, and acetaminophen and overall survival (OS), progression-free survival (PFS), ascites at the time of primary treatment, and persistence of disease after primary treatment among 699 women diagnosed with epithelial ovarian carcinoma. The associations between use of these medications and OS and PFS were estimated using Cox-proportional hazards models. We utilized unconditional logistic regression models to estimate associations between medication use and presence of ascites and persistence of disease.
Results
Pre-diagnostic intake of aspirin, both low-dose and regular-dose, ibuprofen, and acetaminophen were not associated with any of the outcomes of interest.
Conclusions
Our results indicate a lack of association between pre-diagnostic intake of selected analgesics and OS, PFS, presence of ascites at the time of primary treatment, and persistence of disease after primary treatment.
Impact
Pre-diagnostic intake of analgesics may not be associated with ovarian cancer outcomes.
Keywords: aspirin, acetaminophen, NSAIDs, ovarian, survival
Introduction
Chronic inflammation is suspected to be one of the etiological mechanisms of ovarian cancer initiation (1) and progression (2), with a majority of ovarian tumors overexpressing the pro-inflammatory mediator cyclooxygenase (COX)-2 (3). Analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) may reduce inflammation by inhibiting the COX enzyme, which may subsequently interfere with synthesis of prostaglandins and tumor cells growth and proliferation (4). Therefore, analgesic intake could potentially reduce risk of ovarian cancer and improve survival after the diagnosis. An extensive body of research has shown that intake of analgesics, especially aspirin, is associated with a lower ovarian cancer risk (5, 6), but there has been little study regarding the relationship with ovarian cancer survival.
We examined the association of self-reported pre-diagnostic intake of aspirin, ibuprofen, and acetaminophen on ovarian cancer survival. We hypothesized that among ovarian cancer patients, pre-diagnostic intake of aspirin and ibuprofen would be associated with a lower risk of death, disease progression, presence of ascites and persistent disease compared to non-users. We also investigated associations with acetaminophen as a comparison drug.
Materials and Methods
The Hormones and Ovarian cancer PrEdiction (HOPE) study, a population based case-control study, was conducted between February 2003 and November 2008 (7). Data on demographics, history of arthritis, diabetes, and intake of aspirin, non-aspirin NSAIDs, and acetaminophen were collected from study participants in an in-person interview. Data on disease characteristics and treatment were obtained from medical records which were collected until loss to follow up, death, or end of follow up on May 31, 2014. Vital status of the participants was determined from medical records abstraction or through National Death Index and Social Security Death Index search.
Out of the original sample of 902 patients, we excluded patients with non-epithelial (n=48) or low malignant potential (n=81) disease as well as those who did not receive surgery or chemotherapy (n=50), who had missing treatment information (n=9), and those who were lost to follow up immediately following the interview (n=15). We used chi-square or Student’s t-test to compare characteristics of deceased and alive patients.
Overall survival (OS) was defined as the number of days from the date of primary surgery to the date of death or date of last contact. Progression-free survival (PFS) was defined as the number of days between the date of diagnosis and the date when progression status (persistence, recurrence, or death) was determined.
Using Cox proportional hazards model adjusted for age and Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage, we examined the association between ever use, type of use (recent or past), average frequency and duration of use for regular strength aspirin (>81 mg, excluding those using low-dose aspirin), ibuprofen, and acetaminophen, and the OS and PFS after ovarian cancer diagnosis by calculating hazard ratios (HRs) and 95% confidence intervals (CIs) associated with survival. For low-dose aspirin, we examined ever use only due to small cell frequencies for the type and duration of use and no variation for average frequency of intake. Using unconditional logistic regression, we estimated odds ratios (ORs) and 95% CIs using age-, stage-, and histology-adjusted models for the presence of ascites, and age- and stage-adjusted models for persistence of disease as the outcomes. Those who reported no regular intake of any NSAIDs or acetaminophen were referent category for these analyses. We also conducted our analyses separately among patients with serous and advanced tumors.
We had 80% power to detect risk estimates of 0.73, 0.68, and 0.68 for ever use of aspirin, ibuprofen, and acetaminophen correspondingly for OS, and 0.75, 0.71, and 0.71 respectively for PFS.
Results
Characteristics of participants by 5-year survival status are shown in Table 1. By the end of the fifth year of follow up, 343 patients were deceased. Median follow-up time was 1,759 days for OS and 540 days for PFS.
Table 1.
Characteristics of the HOPE study cases stratified by vital status after 5 years of follow upa.
| Characteristic | Deceased, n=343(%) | Alive, n=338 (%) | p-valueb |
|---|---|---|---|
|
| |||
| Age at diagnosis (years), mean (std) | 62.5(11.6) | 56.9(11.8) | <0.001 |
|
| |||
| Race | |||
| White | 328(95.6) | 325(96.1) | 0.73 |
| Non-white | 15(4.4) | 13(3.9) | |
|
| |||
| Education | |||
| High school or less | 154(44.9) | 144(42.6) | 0.54 |
| More than high school | 189(55.1) | 194(57.4) | |
|
| |||
| History of arthritis | |||
| No | 205(59.8) | 217(64.2) | 0.23 |
| Yes | 138(40.2) | 121(35.8) | |
|
| |||
| History of diabetes | |||
| No | 304(88.6) | 317(93.8) | 0.02 |
| Yes | 39(11.4) | 21(6.2) | |
|
| |||
| FIGO stage | |||
| I | 11(3.2) | 116(34.3) | <0.001 |
| II | 22(6.4) | 60(17.7) | |
| III | 245(71.4) | 140(41.4) | |
| IV | 63(18.4) | 17(5.0) | |
| Unknown | 2(0.6) | 5(1.5) | |
|
| |||
| Grade | |||
| Well differentiated | 6(1.8) | 40(11.8) | <0.001 |
| Moderately differentiated | 68(19.8) | 95(28.1) | |
| Poorly differentiated | 255(74.3) | 184(54.4) | |
| Unknown | 14(4.1) | 19(5.6) | |
|
| |||
| Histology | |||
| Serous | 253(74.0) | 176(52.1) | <0.001 |
| Mucinous | 5(1.5) | 16(4.7) | |
| Endometrioid | 19(5.5) | 58(17.2) | |
| Clear cell | 15(4.4) | 33(9.8) | |
| Mixed | 49(14.3) | 54(16.0) | |
| Other | 2(0.6) | 1(0.3) | |
|
| |||
| Presence of ascites | |||
| No | 76(22.2) | 165(49.4) | <0.001 |
| Yes | 266(77.8) | 169(50.6) | |
| Missing | 1 | 4 | |
|
| |||
| All gross disease removed during primary surgery | |||
| No | 231(67.5) | 96(28.4) | <0.001 |
| Yes | 96(28.1) | 231(68.3) | |
| Unknown | 16(4.4) | 11(3.3) | |
|
| |||
| Persistence of disease | |||
| No | 179(54.1) | 312 (92.6) | <0.001 |
| Yes | 152(45.9) | 25(7.4) | |
| Missing | 12 | 1 | |
|
| |||
| Recurrence of disease | |||
| No | 141(43.2) | 198(58.8) | <0.001 |
| Yes | 185(56.8) | 139(41.2) | |
| Missing | 17 | 1 | |
excluding 18 cases lost to follow up within the first 5 years of follow up
p-value for t-test for age at diagnosis and Chi-square test for categorical variables
No statistically significant association between use of these analgesics and any of the outcomes of interest were observed (Table 2). There was a weak suggestion of an inverse relationship for past intake of aspirin and ibuprofen, however, the estimated HR did not reach statistical significance. Results were not substantially changed when analyses were conducted separately among patients with serous and advanced tumors.
Table 2.
Intake of aspirin, ibuprofen, and acetaminophen and overall survival, progression-free survival, presence of ascites at the time of primary treatment, and persistence of disease after primary treatment among HOPE study casesa.
| Deceased | Progression | Ascites | Persistence | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||||
| Variables | Yes | No | HR (95%CI)b | Yes | No | HR (95%CI)b | Yes | No | OR (95%CI)c | Yes | No | OR (95%CI)d |
|
| ||||||||||||
| Aspirin | ||||||||||||
|
| ||||||||||||
| Non users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Regular users | 145 | 77 | 1.06(0.84–1.35) | 168 | 53 | 0.99(0.80–1.22) | 137 | 82 | 0.94(0.63–1.41) | 59 | 159 | 1.01(0.65–1.55) |
|
| ||||||||||||
| Type of userse | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Past | 48 | 29 | 0.88(0.64–1.21) | 59 | 17 | 1.00(0.75–1.34) | 49 | 26 | 1.10(0.61–1.99) | 23 | 54 | 1.12(0.62–2.04) |
| Recent | 93 | 45 | 1.19(0.92–1.55) | 104 | 34 | 0.98(0.77–1.25) | 83 | 54 | 0.89(0.56–1.42) | 34 | 100 | 0.93(0.56–1.54) |
|
| ||||||||||||
| Duration | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| 0.5–5 years | 62 | 41 | 0.94(0.70–1.27) | 71 | 31 | 0.92(0.70–1.21) | 63 | 39 | 1.01(0.60–1.70) | 31 | 71 | 1.33(0.77–2.29) |
| ≥5 years | 83 | 36 | 1.19(0.91–1.55) | 97 | 22 | 1.06(0.83–1.36) | 74 | 43 | 0.94(0.57–1.55) | 28 | 88 | 0.79(0.46–1.35) |
| p for trend | 0.28 | 0.72 | 0.83 | 0.54 | ||||||||
|
| ||||||||||||
| Aspirin: 81 mg | ||||||||||||
|
| ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.04(referent) |
| Regular users | 61 | 27 | 1.17(0.86–1.60) | 70 | 18 | 0.98(0.74–1.31) | 55 | 32 | 1.06(0.60–1.87) | 23 | 62 | 1.02(0.56–1.86) |
|
| ||||||||||||
| Aspirin: > 81 mg | ||||||||||||
|
| ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Regular users | 73 | 41 | 1.04(0.79–1.36) | 85 | 29 | 0.99(0.77–1.27) | 71 | 42 | 0.95(0.57–1.58) | 31 | 82 | 1.00(0.59–1.69) |
|
| ||||||||||||
| Tablets per weekf | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 239 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| ≤7 | 40 | 25 | 1.12(0.79–1.59) | 46 | 19 | 0.89(0.65–1.23) | 40 | 24 | 1.09(0.57–2.08) | 12 | 52 | 0.59(0.28–1.22) |
| >7 | 33 | 16 | 0.95(0.66–1.38) | 39 | 10 | 1.14(0.81–1.60) | 31 | 18 | 0.80(0.39–1.61) | 19 | 30 | 1.68(0.85–3.32) |
| p for trend | 0.99 | 0.73 | 0.66 | 0.40 | ||||||||
|
| ||||||||||||
| Type of userse | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Past | 39 | 18 | 0.83(0.53–1.29) | 46 | 11 | 1.03(0.75–1.42) | 35 | 21 | 0.85(0.44–1.66) | 20 | 37 | 1.27(0.66–2.41) |
| Recent | 33 | 22 | 1.05(0.68–1.64) | 38 | 17 | 0.97(0.69–1.37) | 35 | 20 | 1.08(0.55–2.14) | 11 | 43 | 0.76(0.36–1.63) |
|
| ||||||||||||
| Duration | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| 0.5–5 years | 24 | 15 | 0.99(0.65–1.52) | 27 | 12 | 0.95(0.64–1.41) | 26 | 13 | 1.18(0.54–2.61) | 13 | 26 | 1.34(0.61–2.92) |
| ≥5 years | 49 | 26 | 1.09(0.79–1.49) | 58 | 17 | 1.02(0.77–1.38) | 45 | 29 | 0.86(0.47–1.56) | 18 | 56 | 0.85(0.45–1.60) |
| p for trend | 0.67 | 0.91 | 0.71 | 0.76 | ||||||||
|
| ||||||||||||
| Ibuprofen | ||||||||||||
|
| ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Regular users | 69 | 68 | 0.97(0.74–1.28) | 84 | 53 | 0.86(0.67–1.11) | 81 | 55 | 0.98(0.61–1.56) | 28 | 108 | 0.99(0.58–1.69) |
|
| ||||||||||||
| Tablets per weekg | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| ≤14 | 47 | 49 | 0.98(0.71–1.35) | 59 | 37 | 0.94(0.70–1.25) | 59 | 361 | 1.21(0.70–2.08) | 17 | 78 | 0.91(0.48–1.72) |
| >14 | 22 | 19 | 0.97(0.62–1.51) | 25 | 16 | 0.72(0.48–1.10) | 22 | 19 | 0.62(0.30–1.28) | 11 | 30 | 1.15(0.51–2.60) |
| p for trend | 0.87 | 0.14 | 0.49 | 0.88 | ||||||||
|
| ||||||||||||
| Type of userse | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Past | 38 | 31 | 1.12(0.79–1.59) | 43 | 26 | 0.88(0.64–1.22) | 45 | 23 | 1.46(0.78–2.73) | 15 | 53 | 1.16(0.58–2.32) |
| Recent | 30 | 35 | 0.85(0.58–1.25) | 39 | 26 | 0.85(0.61–1.20) | 33 | 32 | 0.62(0.34–1.13) | 13 | 52 | 0.90(0.44–1.85) |
|
| ||||||||||||
| Duration | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| 0.5–5 years | 28 | 33 | 1.01(0.67–1.51) | 35 | 26 | 0.96(0.67–1.38) | 37 | 24 | 1.22(0.64–2.33) | 13 | 48 | 1.29(0.61–2.74) |
| ≥5 years | 40 | 35 | 0.94(0.67–1.33) | 48 | 27 | 0.81(0.59–1.11) | 44 | 30 | 0.87(0.48–1.55) | 15 | 59 | 0.84(0.43–1.65) |
| p for trend | 0.78 | 0.20 | 0.79 | 0.78 | ||||||||
|
| ||||||||||||
| Acetaminophen | ||||||||||||
|
| ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Regular users | 73 | 50 | 1.03(0.78–1.35) | 87 | 36 | 0.91(0.71–1.17) | 81 | 41 | 1.19(0.71–1.98) | 33 | 89 | 1.14(0.68–1.90) |
|
| ||||||||||||
| Tablets per weekh | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| ≤9 | 35 | 26 | 0.97(0.68–1.40) | 44 | 17 | 0.96(0.69–1.33) | 45 | 16 | 1.89(0.93–3.86) | 18 | 43 | 1.31(0.68–2.54) |
| >9 | 38 | 24 | 1.08(0.76–1.54) | 43 | 19 | 0.87(0.63–1.21) | 36 | 25 | 0.79(0.42–1.51) | 15 | 46 | 0.98(0.49–1.94) |
| p for trend | 0.71 | 0.40 | 0.93 | 0.83 | ||||||||
|
| ||||||||||||
| Type of userse | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| Past | 34 | 17 | 1.32(0.92–1.91) | 38 | 13 | 1.06(0.75–1.49) | 36 | 15 | 1.47(0.70–3.08) | 14 | 36 | 1.24(0.60–2.55) |
| Recent | 36 | 30 | 0.86(0.60–1.23) | 44 | 22 | 0.78(0.57–1.08) | 43 | 22 | 1.15(0.60–2.21) | 17 | 49 | 1.01(0.53–1.94) |
|
| ||||||||||||
| Duration | ||||||||||||
| Non-users | 190 | 130 | 1.00(referent) | 238 | 82 | 1.00(referent) | 207 | 111 | 1.00(referent) | 79 | 234 | 1.00(referent) |
| 0.5–5 years | 30 | 25 | 0.92(0.63–1.36) | 38 | 17 | 0.95(0.67–1.34) | 31 | 23 | 0.87(0.44–1.72) | 13 | 42 | 1.03(0.50–2.13) |
| ≥5 years | 43 | 25 | 1.12(0.80–1.56) | 49 | 19 | 0.89(0.65–1.21) | 50 | 18 | 1.57(0.80–3.04) | 20 | 47 | 1.23(0.65–2.30) |
| p for trend | 0.62 | 0.43 | 0.28 | 0.55 | ||||||||
those who reported no regular use of any medications were chosen as a referent category
Cox proportional hazards model adjusted for age and FIGO stage
unconditional logistic regression model adjusted for age, FIGO stage, and histology
unconditional logistic regression model adjusted for age and FIGO stage
Type of users: past users (stopped using medications at least 1 year before the reference date) and recent users (used medications for at least 1 year continuously through the reference date)
standardized as 325 mg
standardized as 200 mg
standardized as 500 mg
Discussion
In this study, we found no associations between ever use, frequency, type and duration of use of self-reported pre-diagnostic intake of analgesics and OS or PFS in women with epithelial ovarian cancer. These results are consistent with findings of a recent Australian study where aspirin, non-aspirin NSAIDs and acetaminophen use five years prior to diagnosis were not related to ovarian cancer survival (8).
Limitations of our study include reliance on self-reported pre-diagnostic analgesics intake; they do not provide information as to the impact on survival of post-diagnostic intake.
In conclusion, we found no evidence that pre-diagnostic intake of commonly used analgesics influence OS, PFS, presence of ascites at diagnosis, and persistence of disease after primary treatment.
Acknowledgments
Financial support:
All authors were supported by NIH/NCI P50CA159981
J L. Freudenheim and K.B. Moysich were supported by NIH/NCI 2R25CA113951
W.H Lo-Ciganic, B. Diergaarde, F. Modugno, G. Friel and K.B. Moysich were supported by NIH/NCI R01CA095023 and NIH/NCI, R01CA126841
K.H. Eng, K. Odunsi and K.B. Moysich were supported by the Roswell Park Alliance Foundation
F. Modugno was supported by the US Army Medical Research and Materiel Command DAMD17-02-01-0669
J.B. Szender and K. Grzankowski were supported by NIH/NCI 5T32CA108456
Footnotes
Conflict of interest: R. Ness has disclosed support from the Beasley Allen Law Firm
References
- 1.Ness RB, Cottreau C. Possible role of ovarian epithelial inflammation in ovarian cancer. Journal of the National Cancer Institute. 1999;91:1459–67. doi: 10.1093/jnci/91.17.1459. [DOI] [PubMed] [Google Scholar]
- 2.Macciò A, Madeddu C. Inflammation and ovarian cancer. Cytokine. 2012;58:133–47. doi: 10.1016/j.cyto.2012.01.015. [DOI] [PubMed] [Google Scholar]
- 3.Lee JS, Choi YD, Lee JH, Nam JH, Choi C, Lee MC, et al. Expression of cyclooxygenase-2 in epithelial ovarian tumors and its relation to vascular endothelial growth factor and p53 expression. Int J Gynecol Cancer. 2006;16 (Suppl 1):247–53. doi: 10.1111/j.1525-1438.2006.00477.x. [DOI] [PubMed] [Google Scholar]
- 4.Rodriguez-Burford C, Barnes MN, Oelschlager DK, Myers RB, Talley LI, Partridge EE, et al. Effects of nonsteroidal anti-inflammatory agents (NSAIDs) on ovarian carcinoma cell lines: preclinical evaluation of NSAIDs as chemopreventive agents. Clinical cancer research: an official journal of the American Association for Cancer Research. 2002;8:202–9. [PubMed] [Google Scholar]
- 5.Trabert B, Ness RB, Lo-Ciganic WH, Murphy MA, Goode EL, Poole EM, et al. Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst. 2014;106:djt431. doi: 10.1093/jnci/djt431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Baandrup L, Faber MT, Christensen J, Jensen A, Andersen KK, Friis S, et al. Nonsteroidal anti-inflammatory drugs and risk of ovarian cancer: systematic review and meta-analysis of observational studies. Acta Obstet Gynecol Scand. 2013;92:245–55. doi: 10.1111/aogs.12069. [DOI] [PubMed] [Google Scholar]
- 7.Ness RB, Dodge RC, Edwards RP, Baker JA, Moysich KB. Contraception methods, beyond oral contraceptives and tubal ligation, and risk of ovarian cancer. Ann Epidemiol. 2011;21:188–96. doi: 10.1016/j.annepidem.2010.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Nagle CM, Ibiebele TI, DeFazio A, Protani MM, Webb PM. Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival. Cancer Epidemiol. 2015;39:196–9. doi: 10.1016/j.canep.2014.12.010. [DOI] [PubMed] [Google Scholar]