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The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery
original articles
Annals of Oncology
Annals of Oncology 23: 2731–2737, 2012 doi:10.1093/annonc/mds101 Published online 2 May 2012
The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery Y. H. Yun1, Y. A. Kim2,3, Y. H. Min2, S. Park4, Y. J. Won4, D. Y. Kim2, I. J. Choi2, Y. W. Kim2, S. J. Park2, J. H. Kim5, D. H. Lee6, S. J. Yoon3, S. Y. Jeong7, D. Y. Noh7* & D. S. Heo8, † 1
Received 25 January 2012; revised 16 February 2012; accepted 17 February 2012
Background: We conducted a population-based retrospective cohort study to investigate the influence of hospital volume, delay of surgery, and both together on the long-term survival of postoperative cancer patients. Methods: Using information from the Korea Central Cancer Registry from 2001 through 2005 and the National Health Insurance claim database, we determined survival for 147 682 patients who underwent definitive surgery for any of six cancers. Results: Regardless of cancer site, surgical patients in low- to medium-volume hospitals showed significantly worse survival [adjusted hazard ratio (aHR) = 1.36–1.86] than those in high-volume hospitals in multivariable analyses. Among the latter, treatment delays > 1 month were not associated with worse survival for stomach, colon, pancreatic, or lung cancer but were for rectal [aHR = 1.28; 95% confidence interval (CI), 1.17–1.40] and breast (aHR = 1.59; 95% CI, 1.37–1.84) cancer. For patients in low- to medium-volume hospitals, treatment delay was associated with worse survival for all types of cancer (aHR = 1.78–3.81). Conclusion: Our findings suggest that the effect of hospital volume and surgical treatment delay on overall survival of cancer patients should be considered in formulating or revising national health policy. Key words: hospital volume, surgical treatment delay, survival
introduction Over the past 30 years, an association between high hospital volume and better outcomes for surgical cancer patients has been demonstrated [1] and reported specifically for oral, breast [2, 3], colon [4–6], esophageal [5, 6], lung [5, 6], liver [5], pancreatic [5–7], rectal [5], bladder [6], and gastric [5, 6] cancer. As a result, the past decade has seen extensive centralization of complex cancer surgery [1], and some countries have implemented policies to achieve this goal [1, 2, 8, 9]. Centralization, however, can substantially increase travel distance for patients [1, 10], particularly those living in rural areas, and might lead to therapeutic delay for many [10, 11]. That, in turn, could lead to treatment delay and thus decrease patient survival by enabling further tumor invasion [12, 13]. *Correspondence to: Dr D. Y. Noh, Department of Surgery, Seoul National University Hospital, 28 Yongon-dong, Chongro-gu, Seoul, 110-744, Republic of Korea. Tel: +822-2072-2921; Fax: +82-2-3673-4250; E-mail: [email protected] †
DSH contributed equally to this work as corresponding author.
Lengthy waits might also cause psychological distress [13]. Therefore, surgical wait times also have become a frequently targeted quality indicator in health care systems [14]. Despite the substantial body of literature investigating the effect of hospital volume or waiting time on cancer patient outcomes, to the best of our knowledge, no study has examined their concurrent effects. In a population-based retrospective cohort study, we used the Korea Central Cancer Registry (KCCR) data and National Health Insurance (NHI) data to investigate the influence of hospital volume, delay of surgery, and both together on the long-term survival of postoperative cancer patients.
methods study patients and database We identified cancer patients who were registered in the KCCR from 2001 through 2005 and were followed up until the end of 2006. The KCCR is a nationwide population-based cancer registry that was first established in 1980 by the Minister of Health and Welfare in Korea. The number of participating hospitals and registered malignancies has been increasing year
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Cancer Research Institute, Seoul National University Hospital and College of Medicine, Seoul; 2Research Institute and Hospital, National Cancer Center, Goyang; Department of Preventive Medicine, Korea University, Seoul; 4The Korea Central Cancer Registry, Division of Cancer Registration and Surveillance, National Cancer Center, Goyang; 5Health Insurance Review and Assessment Service, Seoul; 6Department of Oncology, Asan Medical Center, Seoul; 7Department of Surgery, Cancer Research Institute, Seoul; 8Department of Medicine, Seoul National University College of Medicine, Seoul, Korea 3
original articles
insurance type (NHI, Medical Aid), adjuvant treatment (radiotherapy or chemotherapy), and comorbidities (Charlson index) [18]. We defined hospital volume as the mean number of procedures that each hospital carried out on NHI during each of the 5 years. First, we identified all patients who underwent a resection for cancer (stomach, colon, rectum, pancreas, lung, or breast) from 2001 through 2005. Then, we ranked hospitals by year according to the number of each of the procedures carried out on our cohort in order of increasing estimated total volume and defined tertiles of hospital volume (low, medium, and high) by selecting number cut-off points of each the procedures [2, 19, 20]. In sensitivity analysis, we recategorized hospital volume as a binary variable according to the criteria established by the Leapfrog Group for pancreatic resection (11 cases per year [21]) and the potential candidates of volumebased referral for breast (100 [3], 201 [2] per year), lung (25 [6], 67 [19], 84 [5] per year), colon (93 [19], 126 [5], 166 [4] per year), rectal (35 [5] per year), and stomach resection (17 [5, 6] per year). We defined treatment delay as the time between the date of cancer diagnosis and the date of the initiation of definitive treatment [22]. We based the 31-day standard for treatment delay on the UK’s National Health Service cancer waiting time target in the year 2000 [23].
statistical analysis We used the χ2 test to compare the characteristics of patients who underwent resection in a low-volume hospital with those who underwent resection in a high-volume hospital and of patients who waited > 1 month for treatment with those who waited ≤ 1 month. For multivariate multiple logistic regression, we used categorical indicator factors that showed significant association in univariate analysis. We carried out multivariable Cox proportional hazards modeling to assess the effects of waiting time and hospital volume for each procedure in each treatment year on overall survival, adjusting for age, sex, Charlson score, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institution, year of diagnosis, and waiting time. Five-year survival data are based on cases diagnosed in 2001 only. We used SAS software version 9.1 (SAS Institute
Figure 1. Flow of study population.
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by year, with > 180 hospitals currently participating in KCCR. It covers at least 95% of the newly diagnosed malignancies in Korea [15]. The KCCR has patient information including age, sex, region of residence, type of cancer, and date of diagnosis. Details of the history, objectives, and activities of the KCCR have been documented elsewhere [16]. We classified the conditions according to the International Classification of Diseases for Oncology, 3rd edition, and then converted them to the International Classification of Diseases 10th edition (ICD-10) [17]. We obtained the NHI database from the Health Insurance Review and Assessment Service and merged both sets of data using a unique patient identifier. We used the database to select patients aged ≥20 years who had been diagnosed with cancer of the stomach (ICD-10 code: C16), colon (C18), rectum (C19, C20), pancreas (C25), lung (C33 and C34), or breast (C50). Those sites were selected as major sites of interest in Korea at a focus meeting of health professionals that included medical oncologists and surgeons. We excluded patients with multiple cancers and patients who did not undergo cancer surgery as their first definitive treatment. We obtained patient characteristics (age, sex, region of residence, type of cancer, and date of diagnosis) from the KCCR, the date and cause of death from the Korea National Statistical Office database, and information about primary cancer, date of first treatment, insurance, type of hospital, type of treatment, and comorbidities from the Health Insurance Review and Assessment Service database, which covers almost all Koreans. We excluded from this merged database date-error cases and paper-claim cases. To simplify the presentation of our results, we present here the analyses for cancer surgery (± radiotherapy or chemotherapy); we excluded patients who had only radiotherapy, only chemotherapy, or radio and chemotherapy without cancer surgery. We identified 147 682 patients eligible for the study (Figure 1). We first categorized age group using the cut-off of 65 years as the criteria for the elderly. We then categorized according to the age distribution of the patients: under 50, from 50 to 64, and over 65 years of age. We grouped patients by sex, year of diagnosis, type of cancer, type of medical care institution ( private versus public hospital), hospital type (general, university), hospital volume (number of resections per year),
Annals of Oncology
original articles
Annals of Oncology Inc, Cary, NC) and SPSS 12.0 software (SPSS Inc., Chicago, IL) for statistical analysis and calculated P values for statistical significance.
results The mean patient age was 60.0 years (range, 20.0–98.0) for men and 54.4 years (range, 20.0–100.0) for women. The proportion of cancer patients who received surgery in a highvolume hospital changed slightly from 2001 (87.9%) to 2005 (88.7%).
hospital volume and surgical treatment delay
In sensitivity analysis of the concurrent effects of hospital volume and treatment delay according to recommended volume, overall survival changed only for breast cancer, showing that treatment delay was not associated with worse survival in high-volume hospitals (Table 2).
discussion In this study of the survival of patients with any of six types of cancer who were treated surgically in Korean hospitals from Table 1. Five-year survival of surgical cancer patients according to hospital volume and surgical treatment delay Variable
Hospital volumea HR (95% CI)
Surgical treatment delayb HR (95% CI)
70.5 1.66 (1.61–1.71) 1.38 (1.33–1.43)
1.10 (1.07–1.14) 1.10 (1.07–1.14)
68.9 1.63 (1.55–1.70) 1.36 (1.29–1.44)
0.94 (0.90–0.98) 1.03 (0.99–1.08)
66.0 1.47 (1.37–1.57) 1.41 (1.29–1.52)
1.08 (0.98–1.19) 1.10 (1.00–1.21)
66.3 1.52 (1.41–1.63) 1.39 (1.27–1.52)
1.29 (1.18–1.41) 1.28 (1.17–1.40)
16.2 1.49 (1.34–1.66) 1.26 (1.11–1.43)
1.33 (1.16–1.53) 1.23 (1.07–1.41)
50.1 1.69 (1.56–1.84) 1.60 (1.47–1.74)
1.12 (1.02–1.23) 1.16 (1.06–1.27)
90.5 2.12 (1.89–2.39) 1.86 (1.62–2.15)
1.57 (1.35–1.81) 1.59 (1.37–1.84)
survival by hospital volume and surgical treatment delay
Overall 5-year survival (%) Unadjusted HR Adjustedc Type of cancer Stomach (C16) 5-year survival (%) Unadjusted HR Adjustedc Colon (C18) 5-year survival (%) Unadjusted HR Adjustedc Rectal (C19, C20) 5-year survival (%) Unadjusted HR Adjustedc Pancreatic (C25) 5-year survival (%) Unadjusted HR Adjustedc Lung (C33, C34) 5-year survival (%) Unadjusted HR Adjustedc Breast (C50) 5-year survival (%) Unadjusted HR Adjustedc
Among cancer patients who received surgery in high-volume hospitals, treatment delays > 1 month were associated with worse survival for patients with rectal or breast cancer but not for those with stomach, colon, pancreatic, or lung cancer (Figure 2). All cancer patients who received surgery in low- to mediumvolume hospitals, regardless of the length of treatment delays, showed worse survival than patients who had treatment delays < 1 month in a high-volume hospital. Patients who had treatment delays > 1 month in low- to medium-volume hospital had the worst survival regardless of cancer site (Figure 2).
Derived from Cox proportional hazards models for crude (unadjusted) and adjusted analyses. a Low to medium (versus high). We recategorized hospital volume defined by number of operations/yr with cut-off points (tertiles) of low, medium, and high. The cut-off points are for high-volumes of stomach resection (≥56 per year), colon (≥24 per year), rectal (≥23 per year), pancreatic (≥5 per year), lung (≥15 per year), and breast (≥31 per year). b Surgical treatment delay > 31 days (versus ≤ 31 days). c Adjusted for age, sex, Charlson scale, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institution, year of diagnosis, and treatment delay or hospital volume. CI, confidence interval; HR, hazard ratio.
five-year survival according to hospital volume and surgical treatment delay The overall 5-year survival rate based on cases diagnosed in 2001 was 70.5%. Risk-adjusted long-term survival based on Cox proportional hazards modeling showed worse survival for patients who underwent surgery at low- to medium-volume hospitals than at high-volume hospitals (Table 1). Among surgery patients, treatment delays > 1 month were associated with worse survival for patients with rectal [adjusted hazard ratio (aHR) = 1.28], pancreatic (aHR = 1.23), lung (aHR = 1.16), or breast (aHR = 1.59) cancer than treatment delays <1 month (Table 1).
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Supplemental Table S1 (available at Annals of Oncology online) shows the results of χ2 analysis of the association of treatment delay and hospital volume with patient characteristics. Patients within low- to medium-volume hospitals were significantly older, had medical aid, had fewer comorbidities, received radiotherapy or chemotherapy, and were admitted to a private hospital. Patients within low- to medium-volume hospitals were more likely to have rectal, lung, or pancreatic cancer and less likely to have stomach or breast cancer. Patients with treatment delays of over 1 month were significantly older, male, received medical aid, had fewer comorbidities, did not receive chemotherapy, and were admitted to a public highvolume hospital. Patients with treatment delays were more likely to have rectal, breast, pancreatic, lung, and stomach cancer than colon cancer. Delays of > 1 month were experienced by 13.6% of the subjects over the study period.
sensitivity analysis of overall survival by hospital volume and surgical treatment delay
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Annals of Oncology
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Annals of Oncology
2001 through 2005, we showed that the effects of hospital volume and treatment delay varied. Table 2. Sensitivity analysis of hazard ratios for overall survival in patients who had resection for each type of cancer according to surgical treatment delaya and hospital volumeb as a binary variable according to previously established criteria aHRc (95% CI)
Type of cancer Stomach (C16) High and 31 day High and > 31 day Low and ≤ 31 day Low and > 31 day Colon (C18) High and ≤ 31 day High and > 31 day Low and ≤ 31 day Low and > 31 day Rectal (C19, C20) High and ≤ 31 day High and > 31 day Low and 31 day Low and > 31 day Pancreatic (C25) High and 31 day High and > 31 day Low and 31 day Low and > 31 day Lung (C33, C34) High and 31 day High and > 31 day Low and 31 day Low and > 31 day Breast (C50) High and 31 day High and > 31 day Low and 31 day Low and > 31 day
≤ 17 1 1.01 (0.96–1.05) 1.54 (1.41–1.68) 2.42 (2.05–2.84) ≤ 93 1 1.04 (0.89–1.22) 1.27 (1.18–1.36) 1.48 (1.30–1.67) ≤ 35 1 1.20 (1.08–1.34) 1.21 (1.11–1.32) 1.84 (1.57–2.16) ≤ 11 1 1.07 (0.84–1.36) 1.21 (1.08–1.36) 1.60 (1.33–1.92) ≤ 25 1 1.00 (0.89–1.13) 1.30 (1.20–1.41) 1.94 (1.69–2.23) ≤ 100 1 1.21 (0.97–1.51) 1.28 (1.13–1.44) 2.66 (2.18–3.24)
aHRc (95% CI)
aHRc (95% CI)
≤ 126 1 1.04 (0.88–1.24) 1.32 (1.22–1.41) 1.53 (1.35–1.73)
≤ 166 1 1.08 (0.87–1.33) 1.37 (1.26–1.48) 1.55 (1.36–1.76)
≤ 67 1 1.04 (0.90–1.20) 1.43 (1.31–1.55) 1.83 (1.62–2.08) ≤ 201 1 1.03 (0.77–1.36) 1.17 (1.03–1.33) 2.37 (1.96–2.87)
≤ 84 1 1.07 (0.90–1.26) 1.45 (1.33–1.58) 1.82 (1.61–2.07)
a
Delay of cancer surgery > 31 day versus 31 day. The bold values mean the criteria for hospital volume category. In sensitivity analyses, we recategorized hospital volume as a binary variable according to the criteria established by the Leapfrog Group for pancreatic resection (≥11 per year [21]) and the potential candidates of volume-based referral for stomach resection (≥17 per year), lung (25 [6], 67 [19], and 84 [5] per year), and breast (100 [3] and 201 [2] > per year). c Adjusted for age, sex, Charlson scale, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institution and year of diagnosis. aHR, adjusted hazard ratio; CI, confidence interval. b
Figure 2. Survival of patients who had resection of each cancers according to hospital volumea and surgical treatment delayb (adjusted HR, 95% CI). aHR, adjusted hazard ratio; CI, confidence interval. All types of P < 0.01. aWe recategorized hospital volume defined by number of operations per year with cut-off points (tertiles) of low, medium, and high as a binary variable (low–medium versus high). The cut-off points are for high volumes of stomach resection (≥56 per year), colon (≥24 per year), rectal (≥23 per year), pancreatic (≥56 per year), lung (≥15 per year), and breast [≥31 per year]. bSurgical treatment delay > 31 days (versus ≤ 31 days). Adjusted age, sec, Charlson scale, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institutions, year of diagnosis.
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Variable
Our finding that risk-adjusted long-term conditional survival was better for patients who underwent surgery at high-volume hospitals than at low- to medium-volume hospitals regardless of cancer site is consistent with several earlier studies [2–7, 19], but not with other studies of patients with lung [24], rectal [25], or gastric cancer [26], wherein hospital volume appeared to have no effect on overall survival. The relationships between hospital volume and long-term survival after cancer surgery could not be fully explained by volume-related differences in the patient characteristics identified in this study (age, sex, hospital type, type of insurance, type of cancer, and Charlson index). Numerous quality-of-care factors may contribute to improved long-term outcomes at high-volume hospitals, including completeness of resection [27], number of lymph nodes harvested [3], utilization of multimodality therapy (such as administration of adjuvant systemic therapy) [7], more intensive surveillance with follow-up treatment of recurrent cancer [5, 6], and better treatment of comorbidities [6], all good prognostic factors. In the present study, however, addition of adjuvant chemotherapy and radiotherapy to Cox proportional hazards modeling as independent variables did not alter the main outcomes. Despite the general recommendation that the waiting time from diagnosis to surgery should not exceed 4 weeks [28] or 31 days, we found that 13.6% of surgery patients in Korea waited > 31 days and that patients at high-volume hospitals waited longer for treatment than those in low- to mediumvolume hospitals, We showed that many factors, both personal and institutional, influenced wait time, which is consistent with the findings of others [10, 13]. Others have also reported that patients at high-volume hospitals wait longer for treatment than those at low- to medium-volume hospitals [13]. This can be attributed to hospital crowding due to centralization and to an increased travel burden [1, 11]. Although earlier studies reported no effect of therapeutic delay on 5-year survival for breast [14], colorectal [13], lung [29], or pancreatic cancer [12] patients, we did find an effect. Our results were in agreement, however, with another study that looked at wait times of 6 and 12 weeks for breast cancer patients [30]. Thus, the effect of therapeutic delay on prognosis is still not clear, but it differs with type of cancer, stage of disease, and delay duration [13]. Study inconsistencies can be due to variations in study populations, cancer stage, and time frames. Furthermore, some studies are inconclusive due to methodological limitations, such as a failure to perform multivariate analyses with risk adjustment. Surprisingly, there are too few population-based studies with sample sizes large enough to lead to definitive conclusions [13]. The kind of large prospective randomized trial needed to conclusively answer this question would be ethically unacceptable. This study also showed that the effect of treatment delay on survival for
original articles
acknowledgements We thank Miriam Bloom (SciWrite Biomedical Writing & Editing Services) for professional editing.
funding National Cancer Center (1010081).
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disclosure The authors have declared no conflicts of interest.
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patients with each type of cancer differs according to hospital volume, but if the stage is right for surgery, a 1-month delay might put patients at risk for micro metastases. Our findings support the recommendations of the Canadian Society of Surgical Oncology, the American College of Chest Physicians (ACCP) [31], and the British Thoracic Society [28]. As part of its National Health Service Cancer Plan published in 2000, the UK government introduced cancer waiting time targets, stipulating that the overall time from referral of a patient with suspected cancer to diagnosis and treatment initiation should not exceed 62 days and that patients with confirmed cancer should be treated within 31 days. Furthermore, noncompliance could lead to financial penalties [12]. As of 2007, excellent progress had been reported toward achievement of the 31-day goal [32]. Together with earlier studies, the present study suggests that policymakers should consider strategies for centralization by volume-based referral without subjecting patients to therapeutic delays or unreasonable travel burdens and indicates a need to monitor wait times closely [1, 4, 11]. To accommodate more patients at high-volume hospitals without increasing wait times, either existing high-volume hospitals must increase their capacity or new high-volume hospitals must be developed [1]. Our study had several limitations. First, nonrandomized studies should be interpreted with caution because of the potential for confounding. Second, despite our adjustment of variables known to affect patient outcomes, we could not differentiate the confounding effect of variables such as cancer stage that may have impacted patient outcomes, at least for some of the less frequently carried out operations, such as pancreatic and lung resection. Third, the reason for treatment delay was unknown in these cases. The patients with greater delay may have been more ill or presented with more advanced disease, which required greater preoperative intervention, but these factors could not be controlled in our analysis. Fourth, we cannot exclude the possibility that the threshold for the impact of therapeutic delay on survival might differ with type of cancer and treatment. Evidence for maximum acceptable wait times is not adequate, and further studies are needed. Finally, our definitions of high-volume and medium- to lowvolume hospitals were arbitrary and did not necessarily reflect thresholds for optimal performance [6, 7]. Sensitivity analysis based on minimal volume standards, however, supports our conclusions. Despite its limitations, our study suggests that the combined effect of hospital volume and therapeutic delay on overall survival should be considered when formulating or revising national health policy on quality cancer care. Continuous monitoring of the impact of centralization and treatment delay is crucial for evaluating policy at the national level.
Annals of Oncology
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Annals of Oncology 23: 2737–2742, 2012 doi:10.1093/annonc/mds212 Published online 16 August 2012
A. Tavani1*, S. Malerba1, C. Pelucchi1, L. Dal Maso2, A. Zucchetto2, D. Serraino2, F. Levi3, M. Montella4, S. Franceschi5, A. Zambon6 & C. La Vecchia1,7 1 Department of Epidemiology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan; 2Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, Aviano (Pordenone), Italy; 3Cancer Epidemiology Unit and Registre Vaudois des Tumeurs, Institut universitaire de médecine sociale et préventive, Lausanne, Switzerland; 4Unit of Epidemiology, Istituto Tumori ‘Fondazione Pascale’, Naples, Italy; 5International Agency for Research on Cancer, Lyon, France; 6Department of Statistics, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Milan; 7Department of Clinical Sciences and Public Health, University of Milan, Milan, Italy
Received 18 May 2012; accepted 24 May 2012
Background: Folate deficiency leads to DNA damage and inadequate repair, caused by a decreased synthesis of thymidylate and purines. We analyzed the relationship between dietary folate intake and the risk of several cancers. Patients and methods: The study is based on a network of case–control studies conducted in Italy and Switzerland in 1991–2009. The odds ratios (ORs) for dietary folate intake were estimated by multiple logistic regression models, adjusted for major identified confounding factors. Results: For a few cancer sites, we found a significant inverse relation, with ORs for an increment of 100 μg/day of dietary folate of 0.65 for oropharyngeal (1467 cases), 0.58 for esophageal (505 cases), 0.83 for colorectal (2390 cases), 0.72 for pancreatic (326 cases), 0.67 for laryngeal (851 cases) and 0.87 for breast (3034 cases) cancers. The risk estimates were below unity, although not significantly, for cancers of the endometrium (OR = 0.87, 454 cases), ovary (OR = 0.86, 1031 cases), prostate (OR = 0.91, 1468 cases) and kidney (OR = 0.88, 767 cases), and was 1.00 for stomach cancer (230 cases). No material heterogeneity was found in strata of sex, age, smoking and alcohol drinking. Conclusions: Our data support a real inverse association of dietary folate intake with the risk of several common cancers. Key words: cancer risk, case–control study, diet, folates
introduction Folates, the water-soluble vitamin B9, play a central role as cofactors in nucleotide synthesis and have been involved in both prevention and promotion of cancer [1]. Many epidemiological studies have shown that dietary folate intake is inversely related with cancer at several sites [2]. A meta-analysis of 18 case–control studies of colorectal cancer *Correspondence to: Dr A. Tavani, Department of Epidemiology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via G. La Masa 19, 20156 Milan, Italy. Tel: +39-02-39014722; Fax: +39-02-3320-0231; E-mail: [email protected]
found an overall odds ratio (OR) for high versus low intake of folates of 0.85 [95% confidence interval (CI) 0.74–0.99] [3], and a pooled analysis of 13 prospective studies found a relative risk (RR) of colon cancer for highest versus lowest intake of folate of 0.92 (95% CI 0.84–1.00) [4]. As for other cancers of the digestive tract, a meta-analysis found overall RRs for the highest versus the lowest intake of dietary folates of 0.66 (95% CI 0.53–0.83) for esophageal squamous cell carcinoma (based on four case–control studies), 0.50 (95% CI 0.39–0.65) for esophageal adenocarcinoma (three case–control studies) and 0.90 (95% CI 0.72–1.13) for gastric cancer (two cohort and
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Dietary folates and cancer risk in a network of case–control studies
Annals of Oncology
Annals of Oncology 23: 2731–2737, 2012 doi:10.1093/annonc/mds101 Published online 2 May 2012
The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery Y. H. Yun1, Y. A. Kim2,3, Y. H. Min2, S. Park4, Y. J. Won4, D. Y. Kim2, I. J. Choi2, Y. W. Kim2, S. J. Park2, J. H. Kim5, D. H. Lee6, S. J. Yoon3, S. Y. Jeong7, D. Y. Noh7* & D. S. Heo8, † 1
Received 25 January 2012; revised 16 February 2012; accepted 17 February 2012
Background: We conducted a population-based retrospective cohort study to investigate the influence of hospital volume, delay of surgery, and both together on the long-term survival of postoperative cancer patients. Methods: Using information from the Korea Central Cancer Registry from 2001 through 2005 and the National Health Insurance claim database, we determined survival for 147 682 patients who underwent definitive surgery for any of six cancers. Results: Regardless of cancer site, surgical patients in low- to medium-volume hospitals showed significantly worse survival [adjusted hazard ratio (aHR) = 1.36–1.86] than those in high-volume hospitals in multivariable analyses. Among the latter, treatment delays > 1 month were not associated with worse survival for stomach, colon, pancreatic, or lung cancer but were for rectal [aHR = 1.28; 95% confidence interval (CI), 1.17–1.40] and breast (aHR = 1.59; 95% CI, 1.37–1.84) cancer. For patients in low- to medium-volume hospitals, treatment delay was associated with worse survival for all types of cancer (aHR = 1.78–3.81). Conclusion: Our findings suggest that the effect of hospital volume and surgical treatment delay on overall survival of cancer patients should be considered in formulating or revising national health policy. Key words: hospital volume, surgical treatment delay, survival
introduction Over the past 30 years, an association between high hospital volume and better outcomes for surgical cancer patients has been demonstrated [1] and reported specifically for oral, breast [2, 3], colon [4–6], esophageal [5, 6], lung [5, 6], liver [5], pancreatic [5–7], rectal [5], bladder [6], and gastric [5, 6] cancer. As a result, the past decade has seen extensive centralization of complex cancer surgery [1], and some countries have implemented policies to achieve this goal [1, 2, 8, 9]. Centralization, however, can substantially increase travel distance for patients [1, 10], particularly those living in rural areas, and might lead to therapeutic delay for many [10, 11]. That, in turn, could lead to treatment delay and thus decrease patient survival by enabling further tumor invasion [12, 13]. *Correspondence to: Dr D. Y. Noh, Department of Surgery, Seoul National University Hospital, 28 Yongon-dong, Chongro-gu, Seoul, 110-744, Republic of Korea. Tel: +822-2072-2921; Fax: +82-2-3673-4250; E-mail: [email protected] †
DSH contributed equally to this work as corresponding author.
Lengthy waits might also cause psychological distress [13]. Therefore, surgical wait times also have become a frequently targeted quality indicator in health care systems [14]. Despite the substantial body of literature investigating the effect of hospital volume or waiting time on cancer patient outcomes, to the best of our knowledge, no study has examined their concurrent effects. In a population-based retrospective cohort study, we used the Korea Central Cancer Registry (KCCR) data and National Health Insurance (NHI) data to investigate the influence of hospital volume, delay of surgery, and both together on the long-term survival of postoperative cancer patients.
methods study patients and database We identified cancer patients who were registered in the KCCR from 2001 through 2005 and were followed up until the end of 2006. The KCCR is a nationwide population-based cancer registry that was first established in 1980 by the Minister of Health and Welfare in Korea. The number of participating hospitals and registered malignancies has been increasing year
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Cancer Research Institute, Seoul National University Hospital and College of Medicine, Seoul; 2Research Institute and Hospital, National Cancer Center, Goyang; Department of Preventive Medicine, Korea University, Seoul; 4The Korea Central Cancer Registry, Division of Cancer Registration and Surveillance, National Cancer Center, Goyang; 5Health Insurance Review and Assessment Service, Seoul; 6Department of Oncology, Asan Medical Center, Seoul; 7Department of Surgery, Cancer Research Institute, Seoul; 8Department of Medicine, Seoul National University College of Medicine, Seoul, Korea 3
original articles
insurance type (NHI, Medical Aid), adjuvant treatment (radiotherapy or chemotherapy), and comorbidities (Charlson index) [18]. We defined hospital volume as the mean number of procedures that each hospital carried out on NHI during each of the 5 years. First, we identified all patients who underwent a resection for cancer (stomach, colon, rectum, pancreas, lung, or breast) from 2001 through 2005. Then, we ranked hospitals by year according to the number of each of the procedures carried out on our cohort in order of increasing estimated total volume and defined tertiles of hospital volume (low, medium, and high) by selecting number cut-off points of each the procedures [2, 19, 20]. In sensitivity analysis, we recategorized hospital volume as a binary variable according to the criteria established by the Leapfrog Group for pancreatic resection (11 cases per year [21]) and the potential candidates of volumebased referral for breast (100 [3], 201 [2] per year), lung (25 [6], 67 [19], 84 [5] per year), colon (93 [19], 126 [5], 166 [4] per year), rectal (35 [5] per year), and stomach resection (17 [5, 6] per year). We defined treatment delay as the time between the date of cancer diagnosis and the date of the initiation of definitive treatment [22]. We based the 31-day standard for treatment delay on the UK’s National Health Service cancer waiting time target in the year 2000 [23].
statistical analysis We used the χ2 test to compare the characteristics of patients who underwent resection in a low-volume hospital with those who underwent resection in a high-volume hospital and of patients who waited > 1 month for treatment with those who waited ≤ 1 month. For multivariate multiple logistic regression, we used categorical indicator factors that showed significant association in univariate analysis. We carried out multivariable Cox proportional hazards modeling to assess the effects of waiting time and hospital volume for each procedure in each treatment year on overall survival, adjusting for age, sex, Charlson score, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institution, year of diagnosis, and waiting time. Five-year survival data are based on cases diagnosed in 2001 only. We used SAS software version 9.1 (SAS Institute
Figure 1. Flow of study population.
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by year, with > 180 hospitals currently participating in KCCR. It covers at least 95% of the newly diagnosed malignancies in Korea [15]. The KCCR has patient information including age, sex, region of residence, type of cancer, and date of diagnosis. Details of the history, objectives, and activities of the KCCR have been documented elsewhere [16]. We classified the conditions according to the International Classification of Diseases for Oncology, 3rd edition, and then converted them to the International Classification of Diseases 10th edition (ICD-10) [17]. We obtained the NHI database from the Health Insurance Review and Assessment Service and merged both sets of data using a unique patient identifier. We used the database to select patients aged ≥20 years who had been diagnosed with cancer of the stomach (ICD-10 code: C16), colon (C18), rectum (C19, C20), pancreas (C25), lung (C33 and C34), or breast (C50). Those sites were selected as major sites of interest in Korea at a focus meeting of health professionals that included medical oncologists and surgeons. We excluded patients with multiple cancers and patients who did not undergo cancer surgery as their first definitive treatment. We obtained patient characteristics (age, sex, region of residence, type of cancer, and date of diagnosis) from the KCCR, the date and cause of death from the Korea National Statistical Office database, and information about primary cancer, date of first treatment, insurance, type of hospital, type of treatment, and comorbidities from the Health Insurance Review and Assessment Service database, which covers almost all Koreans. We excluded from this merged database date-error cases and paper-claim cases. To simplify the presentation of our results, we present here the analyses for cancer surgery (± radiotherapy or chemotherapy); we excluded patients who had only radiotherapy, only chemotherapy, or radio and chemotherapy without cancer surgery. We identified 147 682 patients eligible for the study (Figure 1). We first categorized age group using the cut-off of 65 years as the criteria for the elderly. We then categorized according to the age distribution of the patients: under 50, from 50 to 64, and over 65 years of age. We grouped patients by sex, year of diagnosis, type of cancer, type of medical care institution ( private versus public hospital), hospital type (general, university), hospital volume (number of resections per year),
Annals of Oncology
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Annals of Oncology Inc, Cary, NC) and SPSS 12.0 software (SPSS Inc., Chicago, IL) for statistical analysis and calculated P values for statistical significance.
results The mean patient age was 60.0 years (range, 20.0–98.0) for men and 54.4 years (range, 20.0–100.0) for women. The proportion of cancer patients who received surgery in a highvolume hospital changed slightly from 2001 (87.9%) to 2005 (88.7%).
hospital volume and surgical treatment delay
In sensitivity analysis of the concurrent effects of hospital volume and treatment delay according to recommended volume, overall survival changed only for breast cancer, showing that treatment delay was not associated with worse survival in high-volume hospitals (Table 2).
discussion In this study of the survival of patients with any of six types of cancer who were treated surgically in Korean hospitals from Table 1. Five-year survival of surgical cancer patients according to hospital volume and surgical treatment delay Variable
Hospital volumea HR (95% CI)
Surgical treatment delayb HR (95% CI)
70.5 1.66 (1.61–1.71) 1.38 (1.33–1.43)
1.10 (1.07–1.14) 1.10 (1.07–1.14)
68.9 1.63 (1.55–1.70) 1.36 (1.29–1.44)
0.94 (0.90–0.98) 1.03 (0.99–1.08)
66.0 1.47 (1.37–1.57) 1.41 (1.29–1.52)
1.08 (0.98–1.19) 1.10 (1.00–1.21)
66.3 1.52 (1.41–1.63) 1.39 (1.27–1.52)
1.29 (1.18–1.41) 1.28 (1.17–1.40)
16.2 1.49 (1.34–1.66) 1.26 (1.11–1.43)
1.33 (1.16–1.53) 1.23 (1.07–1.41)
50.1 1.69 (1.56–1.84) 1.60 (1.47–1.74)
1.12 (1.02–1.23) 1.16 (1.06–1.27)
90.5 2.12 (1.89–2.39) 1.86 (1.62–2.15)
1.57 (1.35–1.81) 1.59 (1.37–1.84)
survival by hospital volume and surgical treatment delay
Overall 5-year survival (%) Unadjusted HR Adjustedc Type of cancer Stomach (C16) 5-year survival (%) Unadjusted HR Adjustedc Colon (C18) 5-year survival (%) Unadjusted HR Adjustedc Rectal (C19, C20) 5-year survival (%) Unadjusted HR Adjustedc Pancreatic (C25) 5-year survival (%) Unadjusted HR Adjustedc Lung (C33, C34) 5-year survival (%) Unadjusted HR Adjustedc Breast (C50) 5-year survival (%) Unadjusted HR Adjustedc
Among cancer patients who received surgery in high-volume hospitals, treatment delays > 1 month were associated with worse survival for patients with rectal or breast cancer but not for those with stomach, colon, pancreatic, or lung cancer (Figure 2). All cancer patients who received surgery in low- to mediumvolume hospitals, regardless of the length of treatment delays, showed worse survival than patients who had treatment delays < 1 month in a high-volume hospital. Patients who had treatment delays > 1 month in low- to medium-volume hospital had the worst survival regardless of cancer site (Figure 2).
Derived from Cox proportional hazards models for crude (unadjusted) and adjusted analyses. a Low to medium (versus high). We recategorized hospital volume defined by number of operations/yr with cut-off points (tertiles) of low, medium, and high. The cut-off points are for high-volumes of stomach resection (≥56 per year), colon (≥24 per year), rectal (≥23 per year), pancreatic (≥5 per year), lung (≥15 per year), and breast (≥31 per year). b Surgical treatment delay > 31 days (versus ≤ 31 days). c Adjusted for age, sex, Charlson scale, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institution, year of diagnosis, and treatment delay or hospital volume. CI, confidence interval; HR, hazard ratio.
five-year survival according to hospital volume and surgical treatment delay The overall 5-year survival rate based on cases diagnosed in 2001 was 70.5%. Risk-adjusted long-term survival based on Cox proportional hazards modeling showed worse survival for patients who underwent surgery at low- to medium-volume hospitals than at high-volume hospitals (Table 1). Among surgery patients, treatment delays > 1 month were associated with worse survival for patients with rectal [adjusted hazard ratio (aHR) = 1.28], pancreatic (aHR = 1.23), lung (aHR = 1.16), or breast (aHR = 1.59) cancer than treatment delays <1 month (Table 1).
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Supplemental Table S1 (available at Annals of Oncology online) shows the results of χ2 analysis of the association of treatment delay and hospital volume with patient characteristics. Patients within low- to medium-volume hospitals were significantly older, had medical aid, had fewer comorbidities, received radiotherapy or chemotherapy, and were admitted to a private hospital. Patients within low- to medium-volume hospitals were more likely to have rectal, lung, or pancreatic cancer and less likely to have stomach or breast cancer. Patients with treatment delays of over 1 month were significantly older, male, received medical aid, had fewer comorbidities, did not receive chemotherapy, and were admitted to a public highvolume hospital. Patients with treatment delays were more likely to have rectal, breast, pancreatic, lung, and stomach cancer than colon cancer. Delays of > 1 month were experienced by 13.6% of the subjects over the study period.
sensitivity analysis of overall survival by hospital volume and surgical treatment delay
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2001 through 2005, we showed that the effects of hospital volume and treatment delay varied. Table 2. Sensitivity analysis of hazard ratios for overall survival in patients who had resection for each type of cancer according to surgical treatment delaya and hospital volumeb as a binary variable according to previously established criteria aHRc (95% CI)
Type of cancer Stomach (C16) High and 31 day High and > 31 day Low and ≤ 31 day Low and > 31 day Colon (C18) High and ≤ 31 day High and > 31 day Low and ≤ 31 day Low and > 31 day Rectal (C19, C20) High and ≤ 31 day High and > 31 day Low and 31 day Low and > 31 day Pancreatic (C25) High and 31 day High and > 31 day Low and 31 day Low and > 31 day Lung (C33, C34) High and 31 day High and > 31 day Low and 31 day Low and > 31 day Breast (C50) High and 31 day High and > 31 day Low and 31 day Low and > 31 day
≤ 17 1 1.01 (0.96–1.05) 1.54 (1.41–1.68) 2.42 (2.05–2.84) ≤ 93 1 1.04 (0.89–1.22) 1.27 (1.18–1.36) 1.48 (1.30–1.67) ≤ 35 1 1.20 (1.08–1.34) 1.21 (1.11–1.32) 1.84 (1.57–2.16) ≤ 11 1 1.07 (0.84–1.36) 1.21 (1.08–1.36) 1.60 (1.33–1.92) ≤ 25 1 1.00 (0.89–1.13) 1.30 (1.20–1.41) 1.94 (1.69–2.23) ≤ 100 1 1.21 (0.97–1.51) 1.28 (1.13–1.44) 2.66 (2.18–3.24)
aHRc (95% CI)
aHRc (95% CI)
≤ 126 1 1.04 (0.88–1.24) 1.32 (1.22–1.41) 1.53 (1.35–1.73)
≤ 166 1 1.08 (0.87–1.33) 1.37 (1.26–1.48) 1.55 (1.36–1.76)
≤ 67 1 1.04 (0.90–1.20) 1.43 (1.31–1.55) 1.83 (1.62–2.08) ≤ 201 1 1.03 (0.77–1.36) 1.17 (1.03–1.33) 2.37 (1.96–2.87)
≤ 84 1 1.07 (0.90–1.26) 1.45 (1.33–1.58) 1.82 (1.61–2.07)
a
Delay of cancer surgery > 31 day versus 31 day. The bold values mean the criteria for hospital volume category. In sensitivity analyses, we recategorized hospital volume as a binary variable according to the criteria established by the Leapfrog Group for pancreatic resection (≥11 per year [21]) and the potential candidates of volume-based referral for stomach resection (≥17 per year), lung (25 [6], 67 [19], and 84 [5] per year), and breast (100 [3] and 201 [2] > per year). c Adjusted for age, sex, Charlson scale, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institution and year of diagnosis. aHR, adjusted hazard ratio; CI, confidence interval. b
Figure 2. Survival of patients who had resection of each cancers according to hospital volumea and surgical treatment delayb (adjusted HR, 95% CI). aHR, adjusted hazard ratio; CI, confidence interval. All types of P < 0.01. aWe recategorized hospital volume defined by number of operations per year with cut-off points (tertiles) of low, medium, and high as a binary variable (low–medium versus high). The cut-off points are for high volumes of stomach resection (≥56 per year), colon (≥24 per year), rectal (≥23 per year), pancreatic (≥56 per year), lung (≥15 per year), and breast [≥31 per year]. bSurgical treatment delay > 31 days (versus ≤ 31 days). Adjusted age, sec, Charlson scale, hospital type, insurance, radiotherapy, chemotherapy, type of medical care institutions, year of diagnosis.
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Variable
Our finding that risk-adjusted long-term conditional survival was better for patients who underwent surgery at high-volume hospitals than at low- to medium-volume hospitals regardless of cancer site is consistent with several earlier studies [2–7, 19], but not with other studies of patients with lung [24], rectal [25], or gastric cancer [26], wherein hospital volume appeared to have no effect on overall survival. The relationships between hospital volume and long-term survival after cancer surgery could not be fully explained by volume-related differences in the patient characteristics identified in this study (age, sex, hospital type, type of insurance, type of cancer, and Charlson index). Numerous quality-of-care factors may contribute to improved long-term outcomes at high-volume hospitals, including completeness of resection [27], number of lymph nodes harvested [3], utilization of multimodality therapy (such as administration of adjuvant systemic therapy) [7], more intensive surveillance with follow-up treatment of recurrent cancer [5, 6], and better treatment of comorbidities [6], all good prognostic factors. In the present study, however, addition of adjuvant chemotherapy and radiotherapy to Cox proportional hazards modeling as independent variables did not alter the main outcomes. Despite the general recommendation that the waiting time from diagnosis to surgery should not exceed 4 weeks [28] or 31 days, we found that 13.6% of surgery patients in Korea waited > 31 days and that patients at high-volume hospitals waited longer for treatment than those in low- to mediumvolume hospitals, We showed that many factors, both personal and institutional, influenced wait time, which is consistent with the findings of others [10, 13]. Others have also reported that patients at high-volume hospitals wait longer for treatment than those at low- to medium-volume hospitals [13]. This can be attributed to hospital crowding due to centralization and to an increased travel burden [1, 11]. Although earlier studies reported no effect of therapeutic delay on 5-year survival for breast [14], colorectal [13], lung [29], or pancreatic cancer [12] patients, we did find an effect. Our results were in agreement, however, with another study that looked at wait times of 6 and 12 weeks for breast cancer patients [30]. Thus, the effect of therapeutic delay on prognosis is still not clear, but it differs with type of cancer, stage of disease, and delay duration [13]. Study inconsistencies can be due to variations in study populations, cancer stage, and time frames. Furthermore, some studies are inconclusive due to methodological limitations, such as a failure to perform multivariate analyses with risk adjustment. Surprisingly, there are too few population-based studies with sample sizes large enough to lead to definitive conclusions [13]. The kind of large prospective randomized trial needed to conclusively answer this question would be ethically unacceptable. This study also showed that the effect of treatment delay on survival for
original articles
acknowledgements We thank Miriam Bloom (SciWrite Biomedical Writing & Editing Services) for professional editing.
funding National Cancer Center (1010081).
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disclosure The authors have declared no conflicts of interest.
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patients with each type of cancer differs according to hospital volume, but if the stage is right for surgery, a 1-month delay might put patients at risk for micro metastases. Our findings support the recommendations of the Canadian Society of Surgical Oncology, the American College of Chest Physicians (ACCP) [31], and the British Thoracic Society [28]. As part of its National Health Service Cancer Plan published in 2000, the UK government introduced cancer waiting time targets, stipulating that the overall time from referral of a patient with suspected cancer to diagnosis and treatment initiation should not exceed 62 days and that patients with confirmed cancer should be treated within 31 days. Furthermore, noncompliance could lead to financial penalties [12]. As of 2007, excellent progress had been reported toward achievement of the 31-day goal [32]. Together with earlier studies, the present study suggests that policymakers should consider strategies for centralization by volume-based referral without subjecting patients to therapeutic delays or unreasonable travel burdens and indicates a need to monitor wait times closely [1, 4, 11]. To accommodate more patients at high-volume hospitals without increasing wait times, either existing high-volume hospitals must increase their capacity or new high-volume hospitals must be developed [1]. Our study had several limitations. First, nonrandomized studies should be interpreted with caution because of the potential for confounding. Second, despite our adjustment of variables known to affect patient outcomes, we could not differentiate the confounding effect of variables such as cancer stage that may have impacted patient outcomes, at least for some of the less frequently carried out operations, such as pancreatic and lung resection. Third, the reason for treatment delay was unknown in these cases. The patients with greater delay may have been more ill or presented with more advanced disease, which required greater preoperative intervention, but these factors could not be controlled in our analysis. Fourth, we cannot exclude the possibility that the threshold for the impact of therapeutic delay on survival might differ with type of cancer and treatment. Evidence for maximum acceptable wait times is not adequate, and further studies are needed. Finally, our definitions of high-volume and medium- to lowvolume hospitals were arbitrary and did not necessarily reflect thresholds for optimal performance [6, 7]. Sensitivity analysis based on minimal volume standards, however, supports our conclusions. Despite its limitations, our study suggests that the combined effect of hospital volume and therapeutic delay on overall survival should be considered when formulating or revising national health policy on quality cancer care. Continuous monitoring of the impact of centralization and treatment delay is crucial for evaluating policy at the national level.
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Annals of Oncology 23: 2737–2742, 2012 doi:10.1093/annonc/mds212 Published online 16 August 2012
A. Tavani1*, S. Malerba1, C. Pelucchi1, L. Dal Maso2, A. Zucchetto2, D. Serraino2, F. Levi3, M. Montella4, S. Franceschi5, A. Zambon6 & C. La Vecchia1,7 1 Department of Epidemiology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan; 2Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, Aviano (Pordenone), Italy; 3Cancer Epidemiology Unit and Registre Vaudois des Tumeurs, Institut universitaire de médecine sociale et préventive, Lausanne, Switzerland; 4Unit of Epidemiology, Istituto Tumori ‘Fondazione Pascale’, Naples, Italy; 5International Agency for Research on Cancer, Lyon, France; 6Department of Statistics, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Milan; 7Department of Clinical Sciences and Public Health, University of Milan, Milan, Italy
Received 18 May 2012; accepted 24 May 2012
Background: Folate deficiency leads to DNA damage and inadequate repair, caused by a decreased synthesis of thymidylate and purines. We analyzed the relationship between dietary folate intake and the risk of several cancers. Patients and methods: The study is based on a network of case–control studies conducted in Italy and Switzerland in 1991–2009. The odds ratios (ORs) for dietary folate intake were estimated by multiple logistic regression models, adjusted for major identified confounding factors. Results: For a few cancer sites, we found a significant inverse relation, with ORs for an increment of 100 μg/day of dietary folate of 0.65 for oropharyngeal (1467 cases), 0.58 for esophageal (505 cases), 0.83 for colorectal (2390 cases), 0.72 for pancreatic (326 cases), 0.67 for laryngeal (851 cases) and 0.87 for breast (3034 cases) cancers. The risk estimates were below unity, although not significantly, for cancers of the endometrium (OR = 0.87, 454 cases), ovary (OR = 0.86, 1031 cases), prostate (OR = 0.91, 1468 cases) and kidney (OR = 0.88, 767 cases), and was 1.00 for stomach cancer (230 cases). No material heterogeneity was found in strata of sex, age, smoking and alcohol drinking. Conclusions: Our data support a real inverse association of dietary folate intake with the risk of several common cancers. Key words: cancer risk, case–control study, diet, folates
introduction Folates, the water-soluble vitamin B9, play a central role as cofactors in nucleotide synthesis and have been involved in both prevention and promotion of cancer [1]. Many epidemiological studies have shown that dietary folate intake is inversely related with cancer at several sites [2]. A meta-analysis of 18 case–control studies of colorectal cancer *Correspondence to: Dr A. Tavani, Department of Epidemiology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via G. La Masa 19, 20156 Milan, Italy. Tel: +39-02-39014722; Fax: +39-02-3320-0231; E-mail: [email protected]
found an overall odds ratio (OR) for high versus low intake of folates of 0.85 [95% confidence interval (CI) 0.74–0.99] [3], and a pooled analysis of 13 prospective studies found a relative risk (RR) of colon cancer for highest versus lowest intake of folate of 0.92 (95% CI 0.84–1.00) [4]. As for other cancers of the digestive tract, a meta-analysis found overall RRs for the highest versus the lowest intake of dietary folates of 0.66 (95% CI 0.53–0.83) for esophageal squamous cell carcinoma (based on four case–control studies), 0.50 (95% CI 0.39–0.65) for esophageal adenocarcinoma (three case–control studies) and 0.90 (95% CI 0.72–1.13) for gastric cancer (two cohort and
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Dietary folates and cancer risk in a network of case–control studies