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Keywords:

  • Chinese women;
  • epithelial ovarian carcinoma;
  • prognostic factor;
  • survival;
  • tubal ligation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Aim:  The aim of the present study was to investigate associations between ovarian cancer survival and reproductive, gynecological and hormone factors.

Material and Methods:  A prospective follow-up study was conducted in the Southeast of China. The cohort comprised 202 patients with histopathologically confirmed epithelial ovarian cancer who were enrolled during 1999–2000 and followed-up for 5 years subsequently. One hundred and ninety five (96.5%) of the cohort or their close relatives were traced. Information was obtained on reproductive, gynecological and hormone factors prior to diagnosis, actual survival time and number of deaths. Cox proportional models were used to estimate mortality hazard ratios (HR) and associated 95% confidence intervals (CI) for tubal ligation, adjusting for age at diagnosis, body mass index (BMI), menopausal status, International Federation of Gynaecology and Obstetrics (FIGO) stage, histological grade of differentiation, cytology of ascites, and chemotherapy status.

Results:  The HR was significantly increased and survival was worse in ovarian cancer patients with a previous tubal ligation, but not with any other reproductive, gynecological and hormone factor. Only 21 (38.9%) of 54 patients who had tubal ligation survived to the time of interview, in contrast to 95 women (67.4%) still alive among the 141 women without tubal ligation (P < 0.001). Compared to the patients who had no tubal ligation, the adjusted HR was 1.62 (95% CI 1.01–2.59; P = 0.04) for those who had tubal ligation. There was no association with age at menarche, menopausal status, parity, breastfeeding, hormone replacement therapy, oral contraceptive use, and hysterectomy.

Conclusion:  Previous tubal ligation was an independently adverse prognostic factor for epithelial ovarian cancer survival. Further studies that examine the relationship are warranted to confirm these results.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Ovarian cancer is a major contributor to cancer-related mortality in women, causing more annual deaths than any other gynecological malignancy in women worldwide.1 Reproductive, gynecological and hormonal factors have been shown to influence the development of epithelial ovarian cancer. Previous tubal ligation or hysterectomy, multiparity, oral contraceptive use and breastfeeding are all established protective factors, against the incidence of ovarian cancer, although the relevant epidemiological evidence may vary among histological subtypes.2–9

However, little is known about the influence of these reproductive and hormonal factors on survival from ovarian cancer. Naik et al. reported that previous tubal sterilization was an adverse independent prognostic indicator of cancer survival.10 Another study found that increasing lifetime number of ovulations had a negative impact on survival in women with Stage III ovarian carcinomas.11 One study reported that a possible survival advantage in women with a history of breastfeeding, but no association between survival and parity, use of oral contraceptives and history of tubal sterilization or hysterectomy.12 Furthermore, Yang et al. reported no clear association between reproductive and hormonal factors before diagnosis and ovarian cancer survival.13

In view of the likely role of reproductive, gynecological and hormonal factors in its etiology, it is plausible that these exposures may also influence tumor progression and survival. To investigate associations between ovarian cancer survival and previous tubal ligation, as well as other factors related to hormone and reproductive history, we conducted a follow-up study in China.

Material and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

Study design and participants

A detailed description of the study design has been provided elsewhere.14,15 A total of 202 incidence cases (non-response rate 0.4%) were identified during July 1999 to June 2000 from hospital medical records, who originally participated in our case-control study conducted during 1999–2000 in Hangzhou, Southeast China. The inclusion criteria required that each case was a woman aged younger than 75 years, who had been resident in Zhejiang Province for at least 10 years and was histologically diagnosed with epithelial ovarian cancer. The patients were recruited to the study shortly after they were diagnosed with an average interval of 3.7 months to baseline interviews. Baseline information was obtained by face-to-face interviews and hospital medical records, including data on tubal ligation, reproductive, gynecological and hormone factors prior to diagnosis.16 All diagnoses were histopathologically confirmed after surgery and classified using The International Histological Classification of Ovarian Tumours recommended by the International Federation of Gynaecology and Obstetrics (FIGO) was used.17 The distribution of pathological diagnoses in the ovarian cancer patients is shown in Table 1.

Table 1.  Distribution of diagnoses of ovarian cancer patients
Pathological diagnosis of epithelial ovarian cancerFrequency (%)
Serous cystadenocarcinoma88 (43.6)
Mucinous cystadenocarcinoma26 (12.9)
Endometrioid cystadenocarcinoma15 (7.4)
Mixed epithelial cystadenocarcinoma9 (4.5)
Undifferentiated carcinoma27 (13.4)
Borderline malignancy31 (15.3)
Clear cell carcinoma3 (1.5)
Transitional cell carcinoma2 (1.0)
Malignant Brenner tumor1 (0.5)
Total202 (100.0)

The vital status of cases was confirmed by telephone interviews at 3–5 years post-diagnosis. Participants who had changed their telephone number were located with the assistance of local community and village committees. These committees in Zhejiang Province maintain registers of individual residents, which include personal details such as date of birth and death, and contact phone numbers. The remaining participants without home telephones were contacted through a telephone in the office of a community or village committee. A total of 195 patients of the original cohort of 202 were located and included in the study, representing a response rate of 96.5%.

Questionnaire and interview

The research methods were approved by the Human Research Ethics Committee of Curtin University and informed consent was obtained from each participant after they were briefed regarding the study aims, and confidentiality and anonymity issues. An appointment for interview was then made after obtaining their verbal consent by initial telephone contact. Of the 195 participants, 114 women were interviewed by telephone. For the remaining 81 cases, their next of kin were interviewed instead, because the patients were either deceased (78 deaths) or too ill to be interviewed (three women). These 81 proxies comprised husbands (69.1%), children (21.0%), siblings (2.5%), parents (2.5%), and other relatives (4.9%). All interviews were conducted by the first author and usually took 10–15 min. A test-retest study was undertaken on 30 pairs of living patients and proxies recruited only for validation purposes to assess the information bias and discrepancy in responses between the two groups.

A structured questionnaire was used to collect individual information on survival status and date of death (if deceased), as well as smoking, alcohol drinking, and tea consumption post-diagnosis. To ascertain all ovarian cancer-related deaths, information was sought from the community registration files and/or hospital medical records. Data on the following variables were retrieved from medical records in the participating hospitals: FIGO stage, histological type, grade of differentiation, cytology of ascites, residual disease after surgery, and regime and frequency of chemotherapy. Baseline data were also utilized from our previous case-control study.16

Statistical analysis

The data were coded and analyzed using the SPSS package (SPSS, Chicago, IL, USA). Survival time (in years) was calculated from the date of diagnosis to the date of death (event) or date of interview (censored). The Kaplan–Meier technique was applied to characterize the survival experiences according to tubal ligation status pre-diagnosis. The intraclass correlation coefficient (ICC) and Kappa statistic were used to examine the agreement in reported smoking, alcohol consumption, and tea drinking post-diagnosis between the patients and their next of kin.

Univariate analysis was first undertaken to screen for potentially important variables for subsequent multivariate analysis. Separate Cox regression models were fitted to each categorical or quantitative variable in the study, and the corresponding linear trend test was performed. The effects of tubal ligation, reproductive and hormonal factors on ovarian cancer survival were assessed using adjusted hazard ratios (HR) and associated 95% confidence intervals (CI), accounting for age at diagnosis, usual body mass index (BMI), FIGO stage, grade of histopathological differentiation, ascites, and chemotherapy status. These variables had been reported to influence ovarian cancer survival or were significant confounders according to the univariate results.18–20

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

By 5 years after diagnosis, 79 patients of the 195 cases in the original cohort were deceased. The details of their causes of death, obtained from hospital records, showed that all 79 patients died from ovarian cancer. Seventy-seven patients died from spread of their cancer, while two deaths were recorded as being related to the side-effects of chemotherapy. In 30 cases in the questionnaire was administered to both the patient and a close relative, there were no important differences in smoking, alcohol consumption, and tea drinking post-diagnosis between the patients and their corresponding next of kin. The ICC ranged from 0.88 for the quantity of dried tea-leaf consumed to 0.96 for the frequency of new batches brewed. The agreement was high for smoking and tea drinking (Kappa = 0.99 and 0.93 respectively) and moderate for alcohol consumption (Kappa = 0.46), further supporting the reliability of information provided by the proxies.

Selected characteristics of ovarian cancer patients by survival status are shown in Table 2. Compared with survivors, the deceased patients were older, had a higher BMI and greater menopausal status at diagnosis, were more likely to have reported tubal ligation prior to diagnosis, and had higher parity and ever breastfeeding. A higher proportion of deceased patients was diagnosed at an advanced stage, with ascites and poorly differentiated histopathological grade, and chemotherapy after surgery. There were no significant differences in age at menarche, hysterectomy, hormone replacement therapy, oral contraceptive use, and family history of ovarian cancer between the living and deceased patients.

Table 2.  Selected characteristics of ovarian cancer patients by survival status
Selected characteristicsAlive (n = 116)Dead (n = 79)P-value
  1. Values expressed as mean ± SD or number (%). †Two-sided; t-test for continuous variables and χ2 test for categorical variables.

  2. BMI, body mass index; FIGO, International Federation of Gynaecology and Obstetrics.

Age at diagnosis (years)44.3 ± 14.151.6 ± 8.9<0.001
 <4046 (39.7)5 (6.3) 
 40–4930 (25.9)35 (44.3) 
 50–5920 (17.2)23 (29.1) 
 ≥6020 (17.2)16 (20.3) 
BMI (kg/m2)21.9 ± 2.622.7 ± 3.00.03
 <25104 (89.7)63 (79.7) 
 ≥2512 (10.3)16 (20.3) 
Age at menarche (years)16.3 ± 7.916.2 ± 2.10.90
 ≤123 (2.6)2 (2.5) 
 >12110 (97.4)72 (97.5) 
Menopausal status  <0.01
 Premenopausal85 (73.3)41 (51.9) 
 Postmenopausal31 (26.7)38 (48.1) 
Parity (full-term pregnancy)  <0.001
 024 (20.7)8 (10.1) 
 148 (41.4)17 (21.5) 
 ≥244 (37.9)54 (68.4) 
Breastfeeding  0.03
 Never24 (20.7)7 (8.9) 
 Ever92 (79.3)72 (91.1) 
Hormone replacement therapy  0.52
 Never113 (97.4)78 (98.7) 
 Ever3 (2.6)1 (1.3) 
Oral contraceptive use  0.23
 Never95 (81.9)59 (74.7) 
 Ever21 (18.1)20 (25.3) 
Hysterectomy  0.58
 No112 (96.5)75 (94.9) 
 Yes4 (3.5)4 (5.1) 
Tubal ligation  <0.001
 No95 (81.9)46 (58.2) 
 Yes21 (18.1)33 (41.8) 
Ovarian cancer in first degree relatives  0.98
 No113 (97.4)77 (97.5) 
 Yes3 (2.6)2 (2.5) 
FIGO stage  <0.001
 I68 (58.6)2 (2.5) 
 II10 (8.6)0 (0) 
 III36 (31.0)65 (82.3) 
 IV2 (1.7)12 (15.2) 
Histopathological grade  <0.001
 Well differentiated67 (57.8)6 (7.6) 
 Moderately differentiated12 (10.3)15 (18.9) 
 Poorly differentiated26 (22.4)54 (69.4) 
 Not available11 (9.5)4 (5.1) 
Ascites  <0.001
 No105 (90.5)62 (78.5) 
 Yes11 (9.5)17 (21.5) 
Chemotherapy status  <0.01
 No24 (20.7)4 (5.1) 
 Yes92 (79.3)75 (94.9) 

The survival curves in the ovarian cancer patients according to tubal ligation status were distinctly different visually (see Fig. 1) and, based on the log-rank test for equality of survival distributions, the difference was not a chance occurrence (P < 0.001). Only 21 (38.9%) of 54 patients who had tubal ligation survived to the time of interview, in contrast to 95 women (67.4%) still alive among the 141 women without tubal ligation.

image

Figure 1. Crude survival time curves by tubal ligation status. inline image, no; inline image, yes.

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Table 3 shows the crude and adjusted mortality hazard ratios and 95% CI for epithelial ovarian cancer according to selected factors. Compared with patients in FIGO stage I, the adjusted HR were 12.25 (95% CI 2.47–60.78; P < 0.001) and 24.54 (4.50–133.8; P < 0.001) for those who were diagnosed at FIGO stage III and IV. An insignificant increased HR was observed for ascites 1.27 (95% CI 1.00–1.60; P = 0.05). There was no significant association between cancer survival and age, BMI, World Health Organization (WHO) grade of differentiation, and chemotherapy status.

Table 3.  Crude and adjusted mortality hazard ratios and 95% confidence intervals (CI) for epithelial ovarian cancer according to selected factors
 Cases (n = 195)Deaths n (%)Crude HR (95% CI)Adjusted HR (95% CI)
  • Estimates from Cox regression models included terms for age at diagnosis (in years, continuous), body mass index (BMI) (continuous), menopausal status (no, yes), International Federation of Gynaecology and Obstetrics (FIGO) stage (I, II, III, and IV), histopathological grade (well, moderately, poorly differentiated, not available), ascites (no, yes), chemotherapy status (no, yes);

  • ‡Two-sided test for trend.

  • WHO, World Health Organization.

Age at diagnosis (years)    
 <40515 (9.8)1.0 (referent)1.0 (referent)
 40–496535 (53.8)7.04 (2.75–17.98)1.37 (0.50–3.75)
 50–594323 (53.5)7.73 (2.94–20.36)1.32 (0.42–4.15)
 ≥603616 (44.4)5.58 (2.04–15.24)0.66 (0.19–2.32)
 Ptrend  <0.0010.17
BMI (kg/m2)    
 <2516763 (37.7)1.0 (referent)1.0 (referent)
 ≥252816 (57.1)1.67 (0.96–2.89)1.36 (0.75–2.47)
 Ptrend  0.080.32
FIGO stage    
 I702 (2.9)1.0 (referent)1.0 (referent)
 II100 (0)
 III10165 (64.4)34.48 (8.43–141.0)12.25 (2.47–60.78)
 IV1412 (85.7)64.02 (14.26–287.5)24.54 (4.50–133.8)
 Ptrend  <0.001<0.001
WHO grade of differentiation    
 Well differentiated736 (8.2)1.0 (referent)1.0 (referent)
 Moderately differentiated2715 (55.6)9.36 (3.63–24.16)1.83 (0.63–5.31)
 Poorly differentiated8054 (67.5)13.06 (5.60–30.43)2.25 (0.84–6.07)
 Not available154 (26.7)3.94 (1.11–13.96)1.01 (0.24–4.23)
 Ptrend  <0.0010.15
Ascites    
 No16762 (37.1)1.0 (referent)1.0 (referent)
 Yes2817 (60.7)2.05 (1.68–2.50)1.27 (1.00–1.60)
 Ptrend  <0.0010.05
Chemotherapy status    
 No284 (14.3)1.0 (referent)1.0 (referent)
 Yes16775 (44.9)3.64 (1.33–9.95)0.46 (0.15–1.40)
 Ptrend  0.010.21

Adjusted HR and 95% CI for reproductive, gynecological and hormone factors are shown in Table 4. HR significantly increased with tubal ligation prior to diagnosis. Compared to patients without tubal ligation, the adjusted HR was 1.62 (95% CI 1.01–2.59; P = 0.04) for patients who had tubal ligation. There was no significant association found with age at menarche, menopausal status, parity, breastfeeding, hormone replacement therapy, oral contraceptive use, and hysterectomy.

Table 4.  Adjusted hazard ratios and 95% confidence intervals (CI) of epithelial ovarian cancer for reproductive factors
 Cases (n = 195)Deaths n (%)Adjusted HR (95% CI)
  • Estimates from Cox regression models included terms for age at diagnosis (in years, continuous), body mass index (BMI) (continuous), menopausal status (no, yes), International Federation of Gynaecology and Obstetrics (FIGO) stage (I, II, III, and IV), histopathological grade (well, moderately, poorly differentiated, not available), ascites (no, yes), chemotherapy status (no, yes);

  • ‡Two-sided test for trend. HR hazards ratio.

Age at menarche (years)   
 ≤1252 (40.0)1.0 (referent)
 >1219077 (40.5)0.22 (0.05–1.01)
 Ptrend  0.10
Menopausal status   
 No12641 (32.5)1.0 (referent)
 Yes6938 (55.1)2.04 (0.99–4.16)
 Ptrend  0.05
Parity (full-term pregnancy)   
 0328 (25.0)1.0 (referent)
 16517 (26.2)0.43 (0.18–1.07)
 ≥29854 (55.1)0.74 (0.32–1.68)
 Ptrend  0.10
Breastfeeding   
 Never317 (22.6)1.0 (referent)
 Ever16472 (43.9)1.00 (0.43–2.34)
 Ptrend  0.99
Hormone replacement therapy   
 Never19178 (41.4)1.0 (referent)
 Ever41 (25.0)0.23 (0.03–1.73)
 Ptrend  0.15
Oral contraceptive use   
 Never15459 (38.1)1.0 (referent)
 Ever4120 (48.8)0.88 (0.52–1.49)
 Ptrend  0.62
Hysterectomy   
 No18775 (38.1)1.0 (referent)
 Yes84 (50.0)1.02 (0.35–3.00)
 Ptrend  0.97
Tubal ligation   
 No14146 (32.6)1.0 (referent)
 Yes5433 (61.1)1.62 (1.01–2.59)
 Ptrend  0.04

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

The study found that tubal ligation prior to diagnosis had an independently adverse influence on epithelial ovarian cancer survival in Chinese women. The study had a relatively small sample size and exposures to some factors were uncommon (e.g. only four cases were exposed to estrogens). There was no relationship found between other reproductive, gynecological, and hormone factors and survival of ovarian cancer, in contrast to substantial effects of these factors on the incidence of the disease reported elsewhere.2–9 In addition to the evidence presented here, previous tubal ligation or hysterectomy, multiparity, oral contraceptive use and breastfeeding have been reported as protective factors against ovarian cancer incidence in several others studies.2–9,16 Chinese women are characterized by a relatively high prevalence of tubal ligation due to implementation of a national policy of strict family planning over past three decades. The prevalence of tubal ligation was 27% in the study participants.

Little is known about the influence of reproductive, gynecological and hormonal factors on survival of ovarian cancer and very few studies have investigated the influence of tubal ligation on ovarian cancer survival. The results from our study confirm a finding in a UK study that reported a past history of surgical sterilization to be an adverse independent prognostic indicator in women presenting with stage III epithelial ovarian cancer.10 However, another study reported that previous tubal sterilization was associated with improved survival and a decrease the cancer death risk in Danish women with Stage III ovarian carcinomas, although the association was not statistically significant.11 Two other studies, conducted in Australia and the UK respectively, reported no association of ovarian cancer survival with tubal ligation or hysterectomy.12,13

Tubal ligation has consistently been reported to predict a reduced risk of ovarian cancer incidence in epidemiological studies and is recognized as an established protective factor,2–6 which is in contrast to the observation in our study that previous tubal ligation was an independently adverse prognostic factor for survival from the same cancer. Serous carcinoma is the most common epithelial ovarian malignancy.17 Most cases in the subtype present at an advanced stage and the overall prognosis is poor.21–23 The proportions of serous carcinoma accounted for 57% and 34% of the participants with and without a tubal sterilization prior to diagnosis, respectively. A higher proportion of the serous carcinoma subtype in the patients who previously had a tubal sterilization may partially explain its adverse influence on survival of the cancer, because that subtype of histopathology is associated with poor prognosis.21–23 A recent review and meta-analysis reported that a higher risk reduction was found for endometrioid invasive cancers in comparison with the other types. A less apparent reduction was found for serous-invasive cancers, whereas the results did not reach statistical significance for mucinous-invasive cancers.24 The hypothesis that chronic inflammation in the fallopian tube resulting from a tubal ligation may explain its adverse influence on ovarian cancer survival was proposed in other studies. One study reported that chronic inflammation in the fallopian tube was a possible risk factor for mutagenesis leading to serous carcinoma.25 Another study found that in situ epithelial lesions of the fallopian tube show gene copy abnormalities consistent with these being early lesions of serous carcinoma.26 Further studies that examine the relationship are warranted to support the hypothesis.

Several issues should be taken into consideration when interpreting our results. A high follow-up response rate of 97% was attained, and the cohort was not related to their tubal ligation status when recruited in the original case-control study.16 The survival status of each patient was confirmed by independent sources. Another feature of this study was the effort made to ensure the accuracy of exposure information (e.g. reproductive, gynecological, and hormone factors), which were collected by face-to-face interviews with the patients during 1999–2000 and recorded as baseline information. Clinical data on cancer stage, histologic type, grade, cytology, and regime of chemotherapy were sought from medical records in the participating hospitals. Test-retest results of survivors and their next of kin confirmed the reproducibility of the questionnaire and the reliability of next of kin's proxy report. The associations between tubal ligation and ovarian cancer survival found in the study might be a chance occurrence because of the modest sample size, or misleading due to the inclusion of borderline malignancy. However, the observed association was strong and similar results were obtained in separate analyses of the women with invasive diseases only and all participants together.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

In the present study there was a significant adverse influence of previous tubal ligation on survival of ovarian cancer, which may be associated with a higher proportion of serous carcinoma in the patients with tubal ligation compare with those who had no tubal ligation. These findings have biological plausibility, being supported by evidence from experiments studies. Future studies are required to examine the relationship between ovarian cancer survival and tubal ligation to fully understand the complex effects of tubal ligation on the incidence and mortality of ovarian cancer.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References

The authors acknowledge with gratitude the participation of patients in Hangzhou. We are grateful for the collaboration received from the participating hospitals and their staff. In particular, we thank Chief Pathologist Chen Xiao Duan of Women's Hospital, School of Medicine, Zhejiang University, for her kind assistance.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. References