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Annals of Oncology 9: 377 383, 1998.

1
1998 Kluwer Academic Publishers. Primed in the Netherlands.

Review on evidence-based cancer medicine

Searching the medical literature for the best evidence to solve


clinical questions

D. L. Hunt, R. B. Haynes & G. P. Browman


Health Information Research Unit. Department of Clinical Epidemiology and Biostatistics, Me Master University Faculty of Health Sciences,
Hamilton, Ontario, Canada

Key words: continuing education, evidence-based medicine, information retrieval, information technology, Internet, keeping
up-to-date

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Introduction you. She recalls from a recent lecture that chemotherapy
can be effective at improving survival for patients with
Questions about the best care for our patients' problems squamous cell head and neck cancers and asks you
arise frequently in clinical practice. The pace of devel- about offering this patient a short course of chemo-
opment of new evidence from research is too quick therapy before surgery. You are quite certain that neo-
for standard textbooks to be of dependable help. Most adjuvant chemotherapy is not beneficial for patients
often, these questions relate to the best means of con- with locally advanced oral cancer but as you are about
firming a diagnosis or the optimal therapeutic approach to explain this, you realize that you do not know whether
for a given condition. At other times, risk factors, screen- this has been properly evaluated. You quickly turn the
ing, or prognosis may be the principal concerns. Or the tables on the student and suggest that she provide a
questions may relate to the co-morbid conditions of the reference from the literature for your next meeting. To
patient, such as the interactions of their medications for avoid being upstaged (again!), you set off on your own
heart disease or diabetes with the treatments that they search.
might receive for their cancer. When these questions Before you have had a chance to begin finding an
arise, it is unlikely that they will be answered accurately answer, a colleague who coordinates the breast cancer
(or at all) unless we are able to find the answers quickly screening program at your hospital approaches you with
and accurately. As the current best evidence on a given another question. She is concerned about one of her
topic changes at unpredictable times, even the most recent cases. After having a mammogram that was
experienced clinician cannot assume that she knows interpreted as being suspicious for malignancy, the
the answer without looking. Fortunately, the advent of woman went on to have a breast biopsy. This showed no
better research, better information resources, and better evidence of cancer. The patient was naturally elated with
information technology makes it possible and worth- the good news. On reviewing her mammogram with a
while for all clinicians to respond to these challenges by second radiologist, it was suggested that the biopsy was
learning some basic literature search skills and acquir- not needed in the first place: the mammogram was
ing access to key evidence resources in the hospital and negative. Your colleague wonders whether any changes
clinic or at home. In this article, we will describe and could be made to the mammography screening program
illustrate some of the skills and resources for answering to decrease the number of unnecessary breast biopsies,
questions of relevance to the care of patients with cancer. without missing additional cases of breast cancer. She is
considering proposing a policy at the next medical staff
meeting that would require all mammograms to be read
Clinical scenarios by two radiologists before being reported, but is inter-
ested in your thoughts.
Consider the following situations. You have just finished How would you go about trying to address these
seeing a 62-year-old man who was recently diagnosed questions? The first step is to carefully define the ques-
with locally advanced squamous cell carcinoma of the tions. The second step is to retrieve the best current
oral cavity. The patient is a smoker and drinks alcohol evidence that pertains to the question, a task that
moderately; he has no other significant medical condi- includes choosing an appropriate evidence resource;
tions and the tumour appears to be amenable to surgery. developing and executing an effective search strategy;
A visiting medical student is doing an elective with critically appraising the results; and refining the search
378

strategy or moving on to a different database if neces- Knight-Ridder Information, Inc., and HealthGate pro-
sary. Finally, the findings must be applied in a way that vide both online access and access over the Internet.
fits the clinical circumstances of the patient and respects Ovid also provides access to a growing number of full
their wishes. text journal articles. A more complete listing of infor-
mation about CANCERLIT distributors is available at
http://www.graylab.ac.uk/cancernet/400006.html.
Defining the question The majority of these vendors also provide MED-
LINE access. Recently, however, MEDLINE access
The first step for any evidence search is to formulate became available free of charge, for anyone who has
a 'well-built clinical question' [1]. This entails identifying access to the Internet, through PubMed (http://
a question that is important to the patient's well-being, www.ncbi.nlm.nih.gov/PubMed) and Internet Grateful
is interesting to you, and that you are likely to encounter Med (http://igm.nlm.nih.gov). Both services provide
on a regular basis in your practice. (For practical pur- access to all MEDLINE citations as well as the Pre-
poses, it is more efficient and usually better for your MEDLINE database, which includes citations and their
patient if you seek consultants for questions that you abstracts before they have been indexed by the US Na-
seldom address in your practice.) tional Library of Medicine. PubMed also provides links
To be answerable, the question must be specified to a small but growing number of fulltext articles via the
internet home pages of journals. Internet Grateful Med

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clearly so that it includes a specific patient group, the
diagnostic test or treatment or other clinical issue that also includes several additional databases such as AIDS-
you are addressing, and the outcome that you are inter- LINE and SDILine (which permits storing your own
ested in. For example, asking whether chemotherapy search strategies for periodic updates on specific topics).
helps patients with breast cancer is a very broad ques- MEDLINE and CANCERLIT both contain an enor-
tion that would be difficult to answer. Asking whether mous number of citations, describing research from
post-menopausal women with Stage 1 breast cancer that 'bench to bedside'. This comprehensive approach has its
has been treated with lumpectomy and local radiation price. Searching for high quality, clinically relevant stud-
therapy have prolonged survival if treated with tamox- ies requires thought and preparation and even then may
ifen is an example of a focussed question that is more miss important studies (low sensitivity) while retrieving
amenable to answering. For the two scenarios above, the many studies that are not relevant to the searcher's
questions could be: For patients with locally advanced purpose (low precision). PubMed provides direct access
and surgically resectable squamous cell cancer of the to special search strategies that filter the literature
head and neck, what is the effect of neoadjuvant chemo- for studies that are most likely to be applicable to clin-
therapy on survival? For women undergoing screening ical practice (http://www.ncbi.nlm.nih.gov/PubMed/
mammography, what are the effects of duplicate inde- clinical.html). Nevertheless, a basic understanding of
pendent interpretation on the diagnostic accuracy and how articles are indexed in MEDLINE is highly desir-
costs of screening? able for clinical users.
Luckily, some libraries offer training courses in MED-
LJNE searching, and the approach to using CANCER-
Finding best evidence LIT is identical. Librarians have a wealth of experience
in using these services and are valuable consultants for
MEDLINE and CANCER LIT clinicians. Clinicians in the United Kingdom, United
States, and Canada can call the Health Care Informa-
MEDLINE is one of the most readily available resour- tion Service (0171 412 7477), the National Library of
ces for locating important studies. This multipurpose Medicine (1-800-272-4787), or the Canada Institute for
database of medical literature citations and abstracts Scientific and Technical Information (1-800-668-1222),
is produced by the US National Library of Medicine respectively, to inquire about regional medical libraries
(NLM). Over 7,000,000 clinical and pre-clinical studies and programs that have been established to provide
are indexed in MEDLINE. CANCERLIT is a special MEDLINE training.
subset of MEDLINE prepared by the National Cancer Returning to the therapeutic question at hand, you are
Institute's International Cancer Information Center. interested in finding studies that have evaluated the role
CANCERLIT includes almost all of the cancer-related of neoadjuvant chemotherapy for patients with squamous
citations in MEDLINE, but also has abstracts from cell head and neck cancer. MEDLINE indexes citations
meeting proceedings, book citations and theses. for content and methodology using a set of over 14,000
Accessing CANCERLIT is generally quite easy. specific terms and over 18,000 synonyms and other terms.
Many hospital and academic libraries have CD-ROM This is known as the Medical Subject Heading (MeSH)
based systems such as OVID, Aries, CD-Plus, or Silver- vocabulary. During the indexing process, an article is
Platter. Online access using a modem or internet line assigned a number of MeSH terms. Topics that are the
is available through a number of vendors, including major focus of the article are specially coded to indicate
MEDLARS, DIALOG, and HealthGate. Some ven- this. Some MEDLINE systems do this by referring to
dors, such as MEDLARS, Ovid, CDP Technologies, these topics as major subject headings, while other sys-
379

terns place an asterisk (*) in front of the medical subject all occurrences of a certain series of letters, regardless of
heading. what letters come afterwards. For example, a textword
It is important to note that when the appropriate search using the term 'neoplas:' (the symbols'for " " a r e
subject heading for an article is being chosen, the most used by many, but not all, CANCERLITand MEDLINE
specific index terms available are used. For example, if systems to denote this concept) would retrieve citations
an article is about apples and oranges (and assuming with a variety of terms including 'neoplasm','neoplasms'
that the MeSH vocabulary actually included such edible and 'neoplastic'. Searching using the textwords 'mortality
products), it would be indexed using these terms. Doing or survival' and then combining the results with the
a search using the MeSH term 'fruits' would not retrieve previous search using 'AND' produces a list of about 27
the article because only articles that deal with fruits in citations in the 1994-1997 MEDLINE database. You now
general would be indexed using the term 'fruits'. To find have a manageable list of citations to review.
the article on apples and oranges, the MeSH term 'apple' As an alternative to the textword search, you could
or 'orange' would need to be used, or a special feature of limit the search to meta-analyses, that is, review studies
MEDLINE called 'exploding' could be used. Asking that summarize the evidence across relevant trials. IGM
MEDLINE to 'explode' a term indicates that you want provides a point-and-click feature for 'publication types',
all articles that include that term to be retrieved, along including reports that use meta-analysis. Combining
with all articles that have been indexed using more this term with the first two search terms above retrieves
specific topics. To continue with the food theme, a search eight articles. Three of these reports include meta-anal-

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using the term 'explode fruits' would retrieve all citations yses of studies of adjuvant chemotherapy for head and
that discussed fruits in general, as well as articles on neck cancer. Retrieving the first relevant article that
apples and oranges (and pomegranates and so on). your search has identified [2], you find that the paper is
Using Internet Grateful Med (IGM) for your search, a meta-analysis of previous studies that have evaluated
you could begin by using the MeSH term 'head and neck the role of chemotherapy in the management of squa-
neoplasms'. IGM automatically explodes this term to mous cell carcinoma of the head and neck region. Un-
include all head and neck neoplasms. This retrieves over fortunately, the meta-analysis publication type is not
16,000 citations in the 1994 to September 1997 version of consistently applied in MEDLINE as yet, as is the case
MEDLINE. To whittle this down, you could do a second for several related terms for review articles.
search using the MeSH term 'chemotherapy, adjuvant'.
This second search retrieves over 3000 citations. How- The temptation, naturally, will be to scan the abstract
ever, you are only interested in articles that deal with and then jump to the conclusions. This approach, how-
both chemotherapy and head and neck cancer. To limit ever, can contribute to drawing inappropriate conclu-
the list of citations to these articles, you will want to sions from studies. Rather, it is important to begin by at
combine them. MEDLINE allows citations from differ- least quickly assessing how a study was conducted, and
ent searches to be combined in various ways. For exam- then to proceed to evaluate the findings if the study
ple, if only articles that appear in both sets are desired, methodology is acceptable. Several publications [3-9]
you can instruct MEDLINE to combine the sets using have presented systematic approaches to assessing ar-
the term 'AND'. On the other hand, if you want to pool ticles about many different types of studies, including
all of the citations that appear in either of the sets of therapeutic interventions, diagnostic tests, prognosis
retrieved articles, you can combine the sets using the studies, and systematic reviews. A simplified approach
term 'OR'. For the head and neck cancer search, you to critical appraisal appears in Table 1. In this case, the
should combine the search results using the term 'AND'. article 'passes muster' as a systematic review. Its evi-
This produces a much smaller list of articles, but there dence-based conclusion is that chemotherapy signifi-
are still over 400, too many to read through in a limited cantly increases treatment toxicity and only improves
amount of time! survival when used concurrently with local definitive
As you are most interested in finding information therapy, but not when used as induction treatment.
about how neoadjuvant chemotherapy affects survival While in this case it is not crucial to limit the set yet
in patients with head and neck malignancies, narrowing further, at times you will find it very helpful to combine
your search to include only articles that deal with mor- a content search, such as the one just completed, with a
tality would be appropriate. One approach could be to methodological quality search, intended to limit the
use the MeSH term 'mortality'. Alternatively, a textword number of studies retrieved to those that are most likely
search could be used. Textword searching involves ask- to be methodologically sound. This can be accomplished
ing MEDLINE or CANCERLIT to search all of the by adding methodological terms into search strategies
titles and abstracts in its database for any occurrence of [10, 11]. Different terms are helpful for identifying studies
a term. This approach is especially useful when search- pertaining to questions of therapy, diagnosis, prognosis,
ing for information about a relatively new topic, such as and etiology (see Table 2). PubMed has these methodo-
a new drug or procedure, before it has its own MeSH logical filters built in so that you do not need to keep a
term. Also, it is the only way to search for citations in copy of them in your lab coat. Most MEDLINE systems
the PreMEDLINE database because these references will allow users to store such filters, to be evoked when
have not been assigned MeSH terms. An important desired.
feature of textword searching is the ability to search for Using the most sensitive strategy in Table 1 for identi-
380

Table I. Guidelines for critical screening of journal articles on clinical research topics."

Therapy Diagnosis Prognosis Causation Reviews

Random allocation of Clearly identified com- Inception cohort, early in Clearly identified com- Comprehensive search for
patients to comparison parison groups, one being the course of the disorder parison group for those relevant articles
groups free of the disorder and initially free of the at risk of, or having, the
outcome of interest outcome of interest

Outcome measure of Objective or reproducible Objective or reproducible Blinding of observers of Explicit criteria for rating
known or probable clinical diagnostic standard, assessment of clinically outcome to exposure; relevance and merit
importance applied to all participants important outcomes blinding of observers of
exposure to outcome

Hollow-up of at least 80% Blinded assessment of test Follow-up of at least 80% Follow-up of at least 80% Inclusion of all relevant
and diagnostic standard studies

" Based on references 3-9.

fying all therapy trials, more than 200,000 citations are

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Table 2. Search strategies for identifying studies relating to treatment,
diagnosis, prognosis, or etiology using MEDLINE. a retrieved from 1994-September 1997 in MEDLINE.
Combining ('ANDing') these with the results of the
Treatment
Combination of terms with placebo.tw. ('tw' indicates textword)
previous content search reduces the number of citations
best specificity: OR double.tw. AND blind:.tw. to 19. Reviewing these, 16 have to do with esophageal
carcinoma, one is about nasopharyngeal cancer, and
Combination of terms with Randomized controlled trial.pt.
best sensitivity: OR random:.tw. two are about the treatment of head and neck cancer.
OR drug therapy (as a subheading One of the two papers on head and neck cancer treat-
of the subject) ment is a non-randomized study assessing the role of
OR therapeutic use (as a subheading chemotherapy and radiotherapy in organ preservation.
of the subject)
This leaves but one potentially relevant study, the same
Diagnosis one that was retrieved by the search using meta-analysis
Combination of terms with Explode 'sensitivity and specificity' as a publication type [2].
best specificity: OR predictive.tw. AND value:.tw. An alternative search strategy is to determine whether
Combination of terms with Explode 'sensitivity and specificity' someone has already done all the work for you, looking
best sensitivity: OR explode diagnosis for evidence-based practice guidelines based on a cur-
OR sensitivity.tw. rent systematic literature review. MEDLINE has a pub-
OR specificity.tw.
OR diagnostic use (as a subheading
lication type, 'practice guidelines', but a search for 'head
of the subject) and neck neoplasms' did not yield any citations for
locally advanced head and neck cancer in this instance.
Prognosis MEDLINE indexing for practice guidelines is improv-
Combination of terms with Prognosis ing but is not yet perfect, and some ingenuity and luck in
best specificity: OR survival analysis
searching are required.
Combination of terms with Incidence
best sensitivity: OR explode mortality
OR follow-up studies EMBASE
OR prognos:.tw.
OR predict:.tw. Excerpta Medica produces a comparable database to
OR course:.tw. MEDLINE that may be more accessible in Europe.
OR mortality (as a subheading of the EMBASE and MEDLINE overlap in coverage but are
subject)
not coincident, so that some valuable information may
Etiology or cause be in EMBASE that is not included in MEDLINE,
Combination of terms with Cohort studies particularly for pharmaceutical trials. EMBASE is con-
best specificity: OR case-control studies siderably more expensive to use than MEDLINE (the
Combination of terms with Explode cohort studies production of which is supported by US taxpayers and
best sensitivity: OR explode risk subsidised by foreign end-users). Clinical trials are not
OR odds.tw. AND ratio:.tw.
as consistently indexed in EMBASE.
OR relative.tw. AND risk.tw.
OR case.tw. AND control.tw.
The Cochrane Library
" Based on references 10 and 11.
While the MEDLINE searches were successful in locat-
ing a relevant article, you may be wondering what other
electronic resources are available to facilitate locating
381

high quality studies. The Cochrane Library is one such one citation is in the 'Abstracts of quality assessed sys-
resource, produced by the Cochrane Collaboration, an tematic reviews', one citation is in the 'Other assessed
international organization that prepares, maintains, and reviews' section, while two citations appear under 'Other
disseminates systematic reviews of randomized trials of reviews'. The first of these is the El-Sayed paper [2].
many health care interventions. The Cochrane Library, Moreover, this version includes an independently pre-
available on CD-ROM from UpDate Software in Ox- pared structured abstract that summarises the method-
ford, is updated quarterly and contains four biblio- ology and results of the review and indicates that the
graphic sections: the Cochrane Database of Systematic meta-analysis has some weaknesses. Nevertheless, the
Reviews (CDSR), the Database of Reviews of Effective- commentary accepts the authors' conclusions that che-
ness (DARE), the Cochrane Controlled Trials Registry motherapy has significantly increased treatment toxicity
(CCTR), and the Cochrane Review Methodology Data- and only improved survival when used concurrently
base (CRMD). CDSR consists of complete reports of with local definitive therapy, but not when used as induc-
Cochrane Collaboration systematic reviews. This section tion treatment.
also lists the protocols for Cochrane systematic reviews
under development. DARE comprises systematic reviews Best evidence
that have been published outside of the Collaboration.
Certain methodological quality criteria have to be met for Another valuable resource for locating high quality
a systematic review to be included in DARE. Unfortu-

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studies quickly is Best Evidence, available from the
nately, some of the citations in DARE lack abstracts. American College of Physicians and BMJ Publishing
The third section of the Library, the CCTR, contains a Group. This is the electronic version of two paper-based
growing list of over 160,000 references to therapeutic abstract journals: ACP Journal Club and Evidence-Based
intervention trials. Once again, though, many of these do Medicine. Best Evidence only includes studies that are
not have abstracts available within the Library. CDSR is methodologically-sound [12] and summarizes the ma-
also available via the Internet (http://www.medlib.com; jority of them using a structured abstract. In addition,
http://www.hcn.net.au/healthbase/cochrane/intro.htm). each abstract is followed by a commentary, written by
The Cochrane Collaboration also assists the US National a clinical expert, that is designed to place the study
Library of Medicine to improve the consistency of index- findings into clinical perspective. Updated annually,
ing randomised controlled trials and controlled clinical Best Evidence has articles relating to general internal
trials that are not randomised. medicine dating back to 1991. Since 1995, a broader
Searching The Cochrane Library is easy. A simple range of articles encompassing other fields of medical
search mechanism permits words and terms to be en- care, such as obstetrics and gynecology, family medi-
tered for full text searching across all databases. For cine, pediatrics, psychiatry and surgery, have been
example, entering 'head and neck cancer' retrieves no added. Some articles specifically addressing oncology-
citations in CDSR, four in DARE, and 232 in CCTR. related issues are also included. Best Evidence, however,
The first of the citations in DARE is the El-Sayed meta- will generally be more useful for answering those patient
analysis article [2]. The Cochrane Library also includes care questions that are not oncology-specific.
an advanced search engine that allows both textwords Turning to the clinical question on mammography, a
and MeSH terms to be used, and sets of citations can be search using Best Evidence is straightforward. Best
combined using the terms AND and OR. To answer the Evidence supports both textword searching (using the
question of the role of neoadjuvant chemotherapy in 'Search' option) and MeSH term searching (using the
patients with head and neck cancers, one can begin by index' function). After clicking on the 'Search' button
clicking on the 'MeSH' button on the advanced search and entering the textword 'mammography', Best Evi-
screen. Enter the term 'neoplasms'and then select 'Head dence provides a listing of 23 citations that include this
and neck neoplasms' from the listing by double-clicking term. Reviewing the list reveals an article specifically
on it. Asking the program to 'Explode and search' using dealing with double reading of mammograms. Double-
this term retrieves 578 citations (using Issue 3 of the clicking the reference title reveals the full structured
1997 Cochrane Library). A search for the MeSH term abstract and commentary. This indicates that consensus
'chemotherapy, adjuvant' yields no citations, so a text- double reading of mammograms resulted in fewer false
word search using the term 'chemotherapy' is appro- positives and false negatives than single reading and,
priate. This retrieves 4421 citations. Combining the two because of the reductions in errors, was ultimately less
sets using the AND function produces a smaller collec- costly. Non-consensus double reading, on the other
tion of 178 citations. Double-clicking on this line allows hand, led to detection of more tumours than single
you to see the citations. The Cochrane Library always reading (but not than consensus double reading), but
indicates how many 'hits' there were in each of the four also had more false positives and higher costs.
different sections in the top panel of the screen. In this The Cochrane Library also has numerous citations
case, it found no citations in the CDSR, four citations concerning breast cancer screening. Searching using the
in DARE, and 174 citations in the CCTR. To see the term 'mammography' retrieves 126 references, including
citations in the DARE, double-click on the appropriate two that are directly pertinent to the question of improv-
line. A further subclassification appears indicating that ing the yield of screening [13, 14],
382

Textbooks mammograms should be used. Unfortunately, despite


the win-win evidence for consensus duplicate mammo-
Finally, we come to textbooks. These can be very useful gram reading, it is unlikely to be widely implemented
for reviewing the pathophysiology of a condition, or the unless payors and managers can be induced to shift
mechanism of action of a medication. Texts may also resources to permit it.
help to broaden the differential diagnosis in more com-
plex cases. Unfortunately, texts are less useful when it
comes to topics for which the evidence can change Conclusion
rapidly, such as the optimal treatment for a given con-
dition. This is because the most recent editions of many With an ever increasing number of trials evaluating
textbooks are often two to three years out-of-date, and different aspects of medical care, being able to quickly
many important new studies may have been published in locate valid, up-to-date information is becoming more
the interim. Also, textbooks are seldom explicit about and more important. Textbooks simply cannot keep up
the evidence or the quality of the evidence used for their with such advances. General purpose evidence databases
recommendations. such as MEDLINE, CANCERLIT and EMBASE pro-
These limitations suggest that textbooks, by and vide access to almost all relevant studies in medicine,
large, should not be relied upon for therapeutic decision but their size makes searches for clinically pertinent and

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making. If you find yourself managing a condition that sound studies clumsy at best. New resources like The
you have not dealt with recently, however, you may Cochrane Library and Best Evidence that only include
wish to refer to a textbook. For general medical con- high quality clinical studies and summarize the findings
ditions, an electronic textbook that is updated regularly, are beginning to improve this process for the fields and
such as Scientific American Medicine, is an option. For types of studies that they cover. But being familiar with
oncology-specific topics, a good choice would be PDQ. how to use larger bibliographic databases, such as CAN-
This is the US National Cancer Institute's cancer infor- CERLIT, is still essential for finding the current best
mation database. It is available on-line and over the evidence about many clinical questions.
Internet (e.g., http://wwwicic.nci.nih.gov/health.htm),
as well as on CD-ROM. Regularly updated, this database
includes information on cancer treatment and screen- Acknowledgements
ing, new investigational drugs, and ongoing clinical
trials, as well as a listing of physicians and organizations This work was supported by the Health Evidence Appli-
involved in cancer care. Information for patients is also cation and Linkage Network (HEALNet, a Canadian
available. Network of Centres of Excellence Program). Dr. Hunt is
Finding information about a malignancy in PDQ is supported by a HEALNet fellowship. Dr. Haynes is
primitive but efficient. A table lists the types of cancers supported in part by a National Health Scientist award
that are discussed, and by selecting the appropriate line, from the National Health Research and Development
a complete description is available. Recalling the first Program, Health Canada. Dr. Browman is supported by
clinical scenario, selecting 'oropharyngeal cancer' leads the Cancer Care Ontario Program in Evidence-Based
to several documents about oral cavity tumours includ- Care.
ing diagnostic work-up, cellular classification, staging,
and treatment options. Note, however, that the sys-
tematic review that we found using CANCERLIT and References
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ANNU Symp Comp Appl Med Care 1994; 17: 601-5. E-mail: bhaynes(nsfhs.mcmaster.ca

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