Application of Meta-Analysis in Evidence-Based Oncology
=======================================================

* Xiaoping Lin
* Qingsheng Wang

## Abstract

The Cochrane Collaboration is an international not-for-profit and independent organization, dedicated to providing up-to-date evidence-based information about the effects of healthcare in the form of systematic reviews. Meta-analysis is a statistical tool to prepare the systematic reviews. This paper briefly introduces the above terms and how to apply evidence-based oncology. Recent findings by using meta-analysis for cancers of the breast, lung, colon, liver, stomach and cervix uteri were reviewed in three cancer fields, viz., etiologic research, screening and therapy.

KEYWORDS:
*   evidence-based medicine
*   cancer
*   systematic reviews
*   meta-analysis

Evidence-based medicine is a useful research method and brand new theory in medical science, which has developed since the 1970’s. At the present time, cancer is one of most harmful diseases impacting our health and life, so evidence-based oncology should be widely practiced by medical professionals who work on cancer prevention or in clinical settings. Research on evidence-based medicine will produce specific systematic reviews and guidelines to provide the best medical practice. In research involving evidence-based medicine, meta-analysis is frequently used as a basic statistical tool.

## Evidence-Based Medicine

### Definition of evidence-based medicine

Evidence-based medicine has been defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research[1].” More recently it has been described as the “integration of best research evidence with clinical expertise and patient values[2].” The 3 key phrases in this definition are, “best research evidence”, “clinical expertise” and “patient values”.

### Evidence-based medicine and Cochrane Collaboration[3,4]

The Cochrane Collaboration is an international not-for-profit and independent organization, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide. It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. The Cochrane Collaboration was founded in 1993. The major product of the Cochrane Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of the Cochrane Library. The Cochrane Library consists of a regularly updated collection of evidence-based medicine databases, including The Cochrane Database of Systematic Reviews. The Cochrane Library interface is provided by Wiley InterScience. The Cochrane Library collected 5,053 systematic reviews and 522,340 randomized controlled clinical trials. Among those, 373 systematic reviews and 28,743 trials in the field of oncology were collected up to November 2007[4].

### Evidence-based medicine and meta-analysis

Meta-analysis is the quantitative assessment of the pooled results of multiple clinical trials. It is ideally suited for use in assessing results of trials which, in oncology in particular, are often under-powered to detect small differences in primary endpoints, let alone subgroup analyses.

There are 3 levels of evidence when we look at evidence-based medicine. The first level, the highest level, is data from randomized controlled trials, or meta-analyses of randomized controlled trials. The second level is data from case control studies or cohort studies, and the third level of evidence is from case studies or single case reports.

Based on PubMed Medline searching, the publications for researches on evidence-based oncology by using meta-analysis increased from 107 in 1997 to 372 in 2006.

### Basic methods of meta-analysis[5]

Meta-analysis has become a clearly defined technique, with reporting standards for both randomized controlled trials and observational studies.

There is a clear order for proceeding with a meta-analysis beginning with selection of the subject followed by retrieval of primary studies, evaluation of study quality and selection of those studies to be used. Thereafter, an appropriate statistical model must be selected, and the studies evaluated for heterogeneity (qualitative and quantitative). The actual metaanalysis is then performed, and finally the results are evaluated for reproducibility (sensitivity testing) to ensure that bias does not influence the result.

There are a number of freeware programs for meta-analysis. RevMan (Review Manager) developed by the Cochrane Collaboration can be downloaded from [http://www.cc-ims.net/RevMan](http://www.cc-ims.net/RevMan). Another freeware, EPIMETA developed by CDC/USA can be downloaded from [http://ftp.cdc.gov/pub/Software/epimeta](http://ftp.cdc.gov/pub/Software/epimeta).

## Evidence-Based Oncology for Breast Cancer

Recent findings by using meta-analysis for cancers of the breast, lung, colon, liver, stomach and cervix uteri were reviewed in three fields, viz., cancer etiologic research, screening and therapy. The selection categories of publications in this review were based on up-to-date, new problems and inconsistent results obtained from different studies.

### Etiology

Breast cancer, as one of the known hormone related cancers, is a common malignant female disease. In recent decades, the associations between genes and breast cancer have been studied. Chen, S. and G. Parmigiani[6] analyzed 10 studies with a meta-analysis method, and reported that the cumulative breast cancer risks at age 70 years were 57% (95% confidence interval [CI]=47%~66%) for BRCA1 and 49% 95% CI=40%~57%) for BRCA2 mutation carriers. Another BRCA gene related disease, ovary cancer risk of 40% (95% CI=35%~46%) for BRCA1 and 18% (95% CI=13%~23%) for BRCA2 mutation carriers. The authors concluded that the risk estimates for BRCA1 and BRCA2 mutation carriers can be used by counselors and clinicians.

The association between diabetes mellitus and risk of breast cancer has been summarized by Larsson, et al.[7] by using a random-effects model of metaanalysis including 20 studies (5 case-control and 15 cohort studies). All 20 studies showed that women with (versus without) diabetes had a statistically significant 20% increased risk of breast cancer (relative risk [RR], 1.20; 95% CI=1.12~1.28). The summary estimates were similar for case-control studies (RR, 1.18; 95% CI=1.05~1.32) and cohort studies (RR, 1.20; 95% CI=1.11~1.30). This meta-analysis indicates that diabetes is associated with an increased risk of breast cancer.

It has being asked for decades whether oral contraceptives (OC) increase breast cancer risk. Kahlenborn et al.[8] performed a meta-analysis of case-control studies published after 1980, and examined the association between prior OC use and premenopausal breast cancer. Thirty-four studies were identified. Use of OCs was associated with an increased risk of premenopausal breast cancer in general (odds ratio [OR], 1.19; 95% CI=1.09~1.29) and across various patterns of OC use. OC use was associated with breast cancer risk in both parous (OR, 1.29; 95% CI=1.20~1.40) and nulliparous (OR, 1.24; 95% CI=0.92~1.67) women. Use of OCs is associated with an increased risk of premenopausal breast cancer, especially with use before first full-term pregnancy in parous women.

Green tea is another topic of great interest for the public as well as for medical professionals. Sun et al.[9] concluded that meta-analysis indicated a lower risk for breast cancer with green tea consumption, highest versus non/lowest intake (OR=0.78, 95% CI=0.61~0.98).

Postmenopausal hormone therapy is widely used in developed countries and has become acceptable in China[10]. Shah et al.[10] reported results of a meta-analysis of 13 studies including 700,000 patients. Postmenopausal estrogen therapy showed an increased OR of 1.16 (95% CI=1.06~1.28), with estimates for less than 5 years use, 1.16 (95% CI=1.02~1.32) and more than 5 years use, 1.20 (95% CI=1.06~1.37). Postmenopausal combined (estrogen-progestogen) hormone therapy resulted in an OR of 1.39 (95% CI=1.12~1.72), with estimates for less than 5 years use of 1.35 (95% CI=1.16, 1.57) and more than 5 years use, 1.63 (95% CI=1.22, 2.18).

Megdal et al.[11] summarized that night work showed an increased breast cancer risk among women (RR, 1.51; 95% CI=1.36~1.68).

### Screening

Hay et al.[12] conducted a meta-analysis of 12 prospective studies that measured concern about breast cancer at a baseline and subsequent breast self-examination (BSE) or mammography utilization among 3,342 high-risk and general-population women. The metaanalysis supports the contention that breast cancer concern may motivate screening behavior, and that high levels of breast cancer concern are uncommon. Its finding is very important for behavior intervention research as well as to conduct breast cancer screening.

Benefits of screening mammography used for breast cancer have been analyzed by Hendrick, et al.[13] Meta-analysis including the most recent follow-up data from eight RCTs involving women aged 40~49 at entry demonstrates for the first time a statistically significant 18% mortality reduction due to regular screening mammography in women of this age group.

Unlike screening with mammography, breast self-examination (BSE) for early detection of breast cancer has produced significant results. Hackshaw and Paul[14] presented a meta-analysis of the effect of regular BSE on breast cancer mortality. There was no difference in the death rate in studies on women who detected their cancer during an examination (pooled RR 0.90, 95% CI=0.72~1.12). None of the trials of BSE training showed lower mortality, but showed more women seeking medical advice and having biopsies.

### Therapy

Human epidermal growth factor receptor-2 (HER-2) expression and breast cancer has been widely investigated. De Laurentiis, et al.[15] reported a meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. The authors concluded that HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.

Earlier detection of a breast cancer recurrence and metastases is important for patients with breast cancer. Isasi, et al.[16] summarized the diagnostic performance of 18F-2-deoxy-2-fluoro-D-glucose-positron emission tomography (FDG-PET) in the evaluation of breast cancer recurrence and metastases. The pooled sensitivity was 90% (95% CI=86.8~93.2), and the pooled false positive rate was 11% (95% CI =7.8~14.6), after the exclusion of outliers. The maximum combined sensitivity and specificity, was 88% (95% CI=86.0~90.6). FDG-PET is a valuable tool for detecting breast cancer recurrence and metastases.

Mauri et al.[17] reported results of a meta-analysis and concluded that patients with breast cancer treated preoperatively with systemic therapy was apparently equivalent to those treated postoperatively with the same regimen in terms of survival and overall disease progression.

Whelan et al.[18] conducted a meta-analysis including 18 trials (6,367 patients). Locoregional radiation after surgery in patients treated with systemic therapy was shown to reduce the risk of any recurrence (OR, 0.69; 95% CI=0.58~0.83), local recurrence (OR, 0.25; 95% CI=0.19~0.34), and mortality (OR, 0.83; 95% CI= 0.74~0.94).

## Evidence-Based Oncology for Lung Cancer

### Etiology

Except cigarette smoking, some other risk factors were analyzed recently by using meta-analysis. Based on 12 studies during 1990~2006, which detailed the relationship between lung cancer and the type of exposure, Mahjub and Sadri[19] reported that the OR of asbestos, cooking fuel, cooking fumes, motor and diesel exhaust related to lung cancer were 1.67, 1.99, 2.52 and 1.42 (*P*<0.001), respectively. The OR of metal fumes related to lung cancer was 1.28 (*P*<0.01). The combined OR for the environmental and occupational exposure related to lung cancer was 1.67 (*P*<0.001).

Residential radon exposure is of serious public concern due to the fact that people stay in their rooms most of the time. Darby et al.[20] concluded that residential radon is a cause of lung cancer in the general population. The estimated risks at 0, 100, and 400 Bq/m3, relative to life-long nonsmokers, with no radon exposure, were 1.0, 1.2, and 1.6 for life-long nonsmokers, and 25.8, 29.9, and 42.3 for continuing smokers of 15~24 cigarettes/day.

Taylor et al.[21] analyzed 43 primary studies from 1981 to the end of 1999. The abundance of evidence clearly indicated that non-smokers exposed to environmental tobacco smoke (ETS) are at increased risk for lung cancer. The pooled RR for never-smoking women exposed to ETS from spouses, compared with unexposed never-smoking women was 1.29 (95% CI=1.17~1.43).

### Screening

Many studies have examined different screening strategies for lung cancer. Through meta-analysis, Manser et al.[22]concluded that the current evidence does not support screening for lung cancer with chest radiography or sputum cytological examination. They suggested that frequent chest radiography might be harmful.

Diederich et al.[23] reported that preliminary studies of low-dose CT in heavy smokers had demonstrated a high proportion of asymptomatic, early, resectable cancers with good survival, but some bias existed and there were no evidence of mortality reduction. General recommendations to screen individuals at risk for lung cancer with low-dose CT should be made.

### Therapy

Based on 19 trials employing meta-analysis, Baggstrom et al.[24] concluded that third-generation chemotherapy agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan) have achieved a significant advance in the treatment of non-small cell lung cancer (NSCLC) (12% survival difference versus second-generation (2G) platinum-based regimens).

Pijls-Johannesma et al.[25] conducted a systematic review, and meta-analysis of randomized controlled trials on the timing of chest radiotherapy in patients with limited stage small cell lung cancer (LS-SCLC). When platinum-based chemotherapy concurrently with chest radiotherapy is used, the 2- and 5-year survival rates of patients with LS-SCLC may be in favor of early chest radiotherapy, with a significant difference if the overall treatment time of chest radiation is less than 30 days.

Burdett et al.[26] investigated 12 eligible randomized controlled trials to look at outcome of chemotherapy and surgery versus surgery alone in NSCLC. This analysis showed a significant benefit of preoperative chemotherapy and is currently the best estimate of the effectiveness of this therapy. Whether particular types of patients may benefit more or less from preoperative chemotherapy is unknown.

A meta-analysis of phase III randomized trials as to whether chemotherapeutic combinations for advanced non-small cell lung cancer should use a platinum-based protocol, was made by Pujol et al.[27] A platinum-based doublet induced a statically significant reduction in the risk of death when compared with non-platinum chemotherapy without inducing an unacceptable increase in toxicity.

## Evidence-Based Oncology for Colon Cancer

### Etiology

The association between dietary fruits/vegetables and cancer have been investigated in many studies. In a pooled analysis of 14 cohort studies, Koushik et al.[28] concluded that dietary fruit and vegetables were not strongly associated with colon-cancer risk overall, but may be associated with a lower risk of distal colon cancer (RR= 0.74, 95% CI=0.57~0.95, *P*=0.02).

Gorham et al.[29] reported that the evidence to date suggests that daily intake of 1,000~2,000 IU/day of vitamin D could reduce the incidence of colorectal cancer with minimal risk (OR=0.49, *P*<0.0001, 95% CI=0.35~0.68).

Larsson and Wolk[30] analyzed the pooled risk of meat consumption for colon cancer and identified 15 prospective studies on red meat (involving 7,367 cases) and 14 prospective studies on processed meat consumption (7,903 cases). The summary RRs of colorectal cancer for the highest vs. the lowest intake categories were 1.28 (95% CI=1.15~1.42) for red meat and 1.20 (95% CI=1.11~1.31) for processed meat. The meta-analysis supported the hypothesis that high consumption of red meat and of processed meat is associated with an increased risk of colorectal cancer.

Larsson et al.[31] conducted a meta-analysis including 6 case-control and 9 cohort studies. The results support a relationship between diabetes and increased risk of colon and rectal cancer in both women and men (summary RR=1.26, 95% CI=1.05~1.50).

Samad et al.[32] reported a meta-analysis including 19 cohort studies that showed considerable evidence that physical activity is associated with reduced risk of colon cancer in both males and females.

### Screening

Heresbach et al.[33] reported that biennial fecal occult blood testing decreased colorectal cancer mortality by 14% (RR= 0.86; 95% CI=0.79~0.94) when performed over 10 years.

Rosman and Korsten[34] analyzed thirty studies in which meta-analysis of CT colonography was used. The results showed that CT colonography has a reasonable sensitivity and specificity for detecting large polyps, but was less accurate than endoscopic colonoscopy for smaller polyps. Thus, CT colonography may not be a reasonable alternative in situations in which a small polyp may be clinically relevant.

### Therapy

The benefits of early chemotherapy in asymptomatic metastatic colorectal cancer were analyzed by Ackland et al.[35] There was no difference in overall quality of life or its individual domains between the two treatment strategies (immediate or delayed treatment at onset of predefined symptoms) at baseline, or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved quality of life compared to withholding treatment until symptoms occurred.

Bonjer et al.[36] performed a meta-analysis of trials randomizing patients with colon cancer to laparoscopically assisted or open colectomy. They confirmed that laparoscopically assisted colectomy for cancer is safe.

## Evidence-Based Oncology for Liver Cancer

### Etiology

Overweight and obesity have shown a weak association with liver cancer risk. Larsson and Wolk[37] used meta-analysis to analyze 11 cohort studies and found that if normal weight is employed as a reference group, the summary RRs of liver cancer were 1.17 (95% CI=1.02~1.34) for those who were overweight, and 1.89 (95% CI=1.51~2.36) for those who were obese. Excess body weight is associated with an increased risk of liver cancer.

Based on a meta-analysis conducted by Larsson and Wolk[38] on 4 cohort and 5 case-control studies, involving 2,260 cases and 239,146 controls, the results suggested that an increased consumption of coffee may reduce the risk of liver cancer. The summary RRs of liver cancer for an increase in consumption of 2 cups of coffee per day were 0.56 (95% CI= 0.35~0.91) and 0.69 (95% CI=0.55~0.87) respectively for persons with or without a history of liver disease.

Boffetta et al.[39] analyzed the association between occupational exposure to vinyl chloride and cancer mortality in a meta-analysis. The meta-standardized mortality ratio for liver cancers other than angiosarcoma was 1.35 (95% CI=1.04~1.77).

Shi et al.[40] analyzed 32 case-control studies involving 3,201 patients with liver cancer and 4,005 controls, identified from a computer-based literature search from 1966 to 2004 in China. The pooled OR for HBsAg (hepatitis B surface antigen) positivity was 14.1 (95% CI=10.6~18.8); for anti-HCV (HCV=hepatitis C virus)/HCV RNA positivity was 4.6 (95% CI=3.6~5.9) and positivity for both HB-sAg and anti-HCV/HCV RNA was 35.7 (95% CI= 26.2~48.5). Hepatitis B virus and Hepatitis C virus infections are main independent risk factors and in China act as synergists for hepatocellular carcinoma (HCC) if both are positive.

### Screening

De Masi et al.[41] evaluated the benefits of screening for hepatocellular carcinoma. The available screening tests to detect hepatocellular carcinoma are alphafetoprotein and ultrasound with reported sensitivity and specificity of 50~85% and 70~90%, respectively. Although screening for the early detection of hepatocellular carcinoma has become quite common in clinical practice, its effectiveness remains controversial due to possible lead-time bias.

### Therapy

There is no standard treatment for patients with unresectable HCC. Llovet and Bruix[42] analyzed 14 randomized controlled trials assessing arterial embolization (7 trials, 545 patients) or tamoxifen (7 trials, 898 patients). Arterial embolization improved 2-year survival compared with the controls (OR=0.53; 95% CI=0.32~0.89; *P*=0.017). Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin (OR, 0.42; 95% CI=0.20~0.88), but none with embolization alone (OR, 0.59; 95% CI=0.29~1.20). Tamoxifen showed no antitumoral effect and no survival benefits (OR, 0.64; 95% CI=0.36~1.13; *P*=0.13). The authors conclude that chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment.

Laparoscopic surgery for hepatic neoplasms aims to provide curative resection while minimizing complications. In a meta-analysis, Simillis et al.[43] reported that laparoscopic resection results in reduced operative blood loss and earlier recovery with oncologic clearance comparable with open surgery. When performed by experienced surgeons in selected patients, it may be a safe and feasible option.

Although transarterial chemoembolization improves survival in patients with HCC, it is not known if transarterial chemoembolization combined with other treatments is beneficial. Marelli et al.[44] used the meta-analysis method and concluded that a combined approach involving transarterial chemoembolization and percutaneous ablation improves survival. Adjuvant transarterial injection of chemotherapeutic drugs mixed with lipiodol improves outcome after hepatectomy. Transarterial chemoembolization is useful to control a tumor burden while the patient is on a waiting list for orthotopic liver transplantation. Multimodal treatment seems to be the best way to optimize transarterial chemoembolization outcomes in HCC.

## Evidence-Based Oncology for Stomach Cancer

### Etiology

Larsson et al.[45] analyzed the association between processed meat consumption and stomach cancer risk in a meta-analysis. Increased consumption of processed meat is associated with an increased risk of stomach cancer, but the possibility that the association may be confounded or modified by other factors cannot be ruled out.

It has been suggested that consumption of soy foods may be associated with a reduction in risk of various cancers. Wu et al.[46] conducted a pooled analysis of 14 studies with data on eating fermented soy foods. They showed an OR/RR of 1.26 (95% CI=1.11~1.43) for stomach cancer in association with high intake of such foods. In contrast, the pooled analysis of 10 studies with data on non-fermented soy foods found an OR/RR of 0.72 (95% CI=0.63~0.82) in association with a high intake of these foods. However, the authors reminded the readers that the results were not adjusted for salt, fruit and vegetable intake. Based on a meta-analysis conducted by Lunet et al.[47] fruit or vegetable intake was associated with a decreased risk of gastric cancer regardless of the anatomical location and the histological type, although dietary intake had a more clear-cut protective effect on intestinal-type cancers.

Wang et al.[48] conducted a meta-analysis on the association between *Helicobacter pylori* infection and early gastric cancer (EGC). This study indicated that *H. pylori* infection is strongly associated with EGC when compared with non-neoplasm controls or advanced gastric cancer. To determine more accurately the extent of *H. pylori* in EGC, age-matched normal controls or adjustment for age in the analysis should be considered in *H. pylori*-related gastric cancer casecontrol studies.

### Screening

For the purpose assessing the validity of the measurement of pepsinogen I and II as a screening test for gastric cancer and pre-malignant lesions, namely low-grade dysplasia, both in the general population and in selected groups of patients, Dinis-Ribeiro et al.[49] pooled 42 data sets including 27 (64%) population-based screening studies (n=296,553) and 15 (36%) sets of selected individuals (n=4,385). A pepsinogen test definition should include the pepsinogen I/II ratio due to its consistent result. Further studies of this test in the management of high-risk patients seem to be worthwhile.

### Therapy

Hosono et al.[50] analyzed short-term outcomes of 1,611 procedures from 4 randomized controlled trials and 12 retrospective studies after laparoscopy-assisted distal gastrectomy. Laparoscopy-assisted distal gastrectomy for early gastric cancer is associated with a lower morbidity, less pain, faster bowel function recovery, and shorter hospital stay.

Assessment of the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer was studied in a systematic review by using metaanalysis by Wagner et al.[51] Best survival results are achieved with 3-drug regimens containing fluorouracil (FU), an anthracycline, and cisplatin. Among these, regimens including FU as a bolus exhibited a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin, cisplatin, and continuous-infusion FU.

Casaretto et al.[52] conducted a meta-analysis to compare the efficacy of chemotherapy and support treatment in patients with advanced non-resectable gastric cancer. Five studies fulfilled the inclusion criteria, for a total of 390 participants, 208 (53%) receiving chemotherapy, 182 (47%) receiving support care treatment and 6 losses (1.6%). Chemotherapy increased the 1-year survival rate of the patients and provided a longer symptom-free period of 6 months and an improvement in quality of life.

## Evidence-Based Oncology for Cancer of the Cervix

### Etiology

Castellsague, et al.[53] pooled data from 8 case-control studies of cervical cancer. A total of 167 cases with invasive cervical adenocarcinoma (112 with adenocarcinoma and 55 with adenosquamous carcinoma) and 1,881 hospital-based control subjects were included. The adjusted overall OR for cervical adenocarcinoma in human papillomavirus (HPV)-positive women compared with HPV-negative women was 81.3 (95% CI=42.0~157.1). HPV16 and HPV18 were present in 82% of the patients. HPV appears to be the key risk factor for cervical adenocarcinoma. HPV testing in primary screening using current mixtures of HPV types and HPV vaccination against main HPV types should reduce the incidence of this cancer worldwide.

Appleby et al.[54] combined individual data on 13,541 women with and 23,017 women without cervical carcinoma, from 23 epidemiological studies. Smokers are at an increased risk of squamous cell (RR=1.95, 95% CI=1.43~2.65), but not of adenocarcinoma (RR=1.95, 95% CI =1.43~2.65) of the cervix. The risk of squamous cell carcinoma increases in current smokers with the number of cigarettes smoked per day, and with a younger age at which smoking starts. Plummer et al.[55] reported that smoking increases the risk of cervical cancer among HPV positive women.

### Screening

Koliopoulos et al.[56] identified 25 studies fulfilling the inclusion criteria. The pooled sensitivity of Hybrid Capture 2(HC2), PCR, cytology [ASCUS (atypical cells of undetermined significance) or worse] and cytology [LSIL (low-grade squamous intraepithelial lesion) or worse] was respectively 90%, 80.9%, 72.7% and 61.6%, and the pooled specificity was respectively 86.5%, 94.7%, 91.9% and 96.0%. The combination of HC2 and cytology had the highest sensitivity and lowest specificity, but there was no evidence to conclude reduction of the incidence of or mortality from invasive cervical cancer among HPV-screened subjects compared to cytologically screened subjects.

Cuzick et al.[57] summarized the studies on HPV testing in primary cervical cancer screening. HPV testing was substantially more sensitive in detecting CIN2+(moderate dysplasia) than cytology (96.1% vs. 53.0%), but less specific (90.7% vs. 96.3%). The results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive.

Bernstein et al.[58] pooled 25 studies to investigate a liquid-based cervical cytological smear study and conventional Papanicolaou smears comparing cytological diagnosis and sample adequacy. The ThinPrep test improved sample adequacy, and led to improved diagnosis of low-grade and high-grade squamous intraepithelial lesions. No difference was found in the rate of atypical cells of undetermined significance diagnosis between ThinPrep and conventional smear groups.

### Therapy

Tzioras, et al.[59] analyzed 65 trials with survival data on 11,180 women to access the effects of different chemotherapy regimens on survival for advanced cervical cancer. The summary relative hazard was 1.02, (95% CI=0.84~1.24) for trials using neo-adjuvant chemotherapy and 0.85 (95% CI=0.73~1.00) for trials using concurrent chemotherapy. Evidence on chemotherapy in women with advanced cervical cancer is not encouraging for major survival benefits. However, small benefits have been observed in some trials, especially with short-length cycles of cisplatin-based regimens and concurrent chemotherapy and radiotherapy.

## Current Problems and Future of Evidence-Based Oncology in China

Oncology is the most updatable science in the medical fields, with the application of new theories, new techniques, new medicines and a huge budget. An incredible quantity of information in oncology and related fields in the changing world will be a terrible burden for medical professional oncologists. The Cochrane Collaboration, evidence-based medicine, systematic reviews and meta-analysis serve the needs of oncologists to catch up on those well-organized knowledge in order to provide the best medical service based on recent evidence for cancer prevention and treatment.

Currently in China, there are 3 general problem areas in the development of evidence-based oncology. First, a lack of knowledge, attitude and a belief that evidence-based oncology will fit the situation for most oncologists in China. The second is a lack of national and international collaboration in evidence-based oncology and a lack of a well-organized professional team. The third problem area is the disconnection between research and practice, between the statistician and clinician, and between scientists who conduct research and study the theory of evidence-based oncology and health authorities.

To develop evidence-based medicine, a team of related professionals should be established.

To train oncologists and standardize clinical procedure with the best evidence-based knowledge, the Chinese version of evidence-based guideline for cancer treatment, screening guideline for cancer early detection and oncology nursing guidelines should be developed.

To help people for a healthy and longer life, a healthy life guideline should be developed by medical professionals in different fields including those who work on cancer prevention.

*   Received December 17, 2007.
*   Accepted January 20, 2008.


*   Copyright © 2008 by Tianjin Medical University Cancer Institute & Hospital and Springer

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