The early natural history of cancers that may particularly lend themselves
to screening to reduce mortality (e.g. prostate, oral and skin cancers)
Screening for pre-malignant and early malignant lesions in some epithelial
cancers (e.g. breast and cervical cancer) has an established place in
cancer control. However, other cancers have not yet proved amenable to
this approach. The need to understand the early natural history of these
to design screening and control programmes is apparent. This can be
illustrated for three cancers, those of prostate, oral cavity and skin.
There has been a burgeoning of diagnostic techniques for the non-invasive
detection of prostatic cancer e.g. ultrasound, PSA testing. A full
evaluation of their effectiveness requires a better understanding of the
natural history of this disease. Early, localised, well developed tumours
may have low malignant potential and may not progress during the man's
lifetime. There is some evidence that radical treatment may be
unnecessary. It is vital that we understand which tumours are likely to
progress and therefore which require treatment. The rising incidence of
this cancer coupled with the demographic shift in the male population has
a potential to result in spiraling NHS costs secondary to screening and
management. Therefore, it is essential that we understand the natural
history of this disease more fully.
There is pressure from a number of quarters to introduce screening
programmes for oral cancer despite its rarity and limited existing
knowledge of the significance of pre-malignant lesions. In order to
prevent wastage of NHS resources in futile screening and to rationalise
the management of pre-malignant lesions it is vital that the natural
history of oral cancer is elucidated. Knowledge of those risk factors
associated with progression or oral lesions would enable the
identification of high risk groups who may benefit from screening, early
treatment and/or preventive strategies.
The incidence of skin cancers is increasing. Therefore the treatment of
malignant melanoma, non-malignant skin cancers and pre-malignant lesions
is an increasing burden on the Health Service. A decrease in the
year-on-year increase of skin cancers is a Health of the Nation target.
Local and national strategies have tended to focus on raising public
awareness of how to prevent sunburn through reducing exposure and using
sunscreens (as well as the early detection of melanomas). However, advice
given to the public on their risk of sunburning is based on crude
identification of vulnerable skin types while the evidence of the
effectiveness of sunscreens in preventing melanomas is poor. A more
profound understanding of the role of DNA damage, its relationship with
sunburning and DNA repair mechanisms would enable more precise
identification of vulnerable skin types, the development of protective
agents or procedures and the development of treatments for early skin
Studies which elucidate the early natural history and biology of cancers,
particularly but not exclusively those used here as illustrations, are
need to allow the proper planning and population selection for screening.
The natural history of common cancers, such as prostate cancer, remains
inadequately understood. The potential for avoiding morbidity and death by
early diagnosis and treatment is great but the potential burden on the NHS
of inappropriate screening is also great.
Comparison of the value of MRI with current breast cancer screening
methods in high risk women
Screening for early breast cancer by mammography is accepted as an
important means of reducing breast cancer deaths. However, despite the
significant recent advances in mammography, there are still several grey
areas. For example, mammography may be impossible to interpret in the
younger patient because of the dense mammary tissue at this age. In those
with a positive family history, mammographic review may be started earlier
and at more frequent intervals - with the concerns about radiation
exposure and repeated compression. Furthermore, an equivocal mammogram is
a cause of concern to patients and carers. In this situation, a reliable
test which could direct the need for biopsy would be invaluable.
Magnetic resonance imaging (MRI) with dedicated breast coils and
gadolinium enhancement, is now showing promising results for breast
carcinoma. Its apparent safety makes it suitable for repeated use. The
technology will only improve and become more widely disseminated over the
coming months/years. Accordingly a coordinated assessment of its value in
comparison with mammography in high risk women is now appropriate.
To evaluate MRI applied to the breast as a method for screening for breast
To improve screening techniques and results and reduce radiation exposure.
Appropriate ways of screening for preventing and diagnosing colorectal
cancer, including "once only" flexible sigmoidoscopy and
Bowel cancer is the second commonest cancer in the UK affecting 4% of the
population and causing 20,000 deaths per year. The main determinant of
survival remains the stage at which the disease is diagnosed and 5 year
relative survival is only 39% although there is hope of limited further
improvement from the use of adjuvant chemotherapy. Screening the general
population for early asymptomatic localised cancers or pre-malignant
adenomas is considered to be a possible means for reducing the burden of
bowel cancer in the population. Two methods are currently available;
faecal occult blood testing (FOBT) and flexible sigmoidoscopy. Randomised
controlled trials of FOBT are currently ongoing in the UK, the US, Denmark
and Sweden and their results will show by how much colorectal cancer
mortality can be reduced by this method.
Flexible sigmoidoscopy has two distinct advantages over FOBT. Firstly, it
has the potential to prevent bowel cancer because of its high sensitivity
for pre-cancerous adenomatous polyps as small as 5 mm. Secondly, polyps
can be removed endoscopically during screening in most cases, so that the
screening procedure can be both diagnostic and therapeutic. This reduces
the number of people requiring follow up since those with hyperplastic
polyps or low risk adenomas can be discharged.
It has been estimated that a 'once only' flexible sigmoidoscopy screen at
around age 60 with selective colonoscopic surveillance for the 3% - 5%
found to have high risk adenomas (1 cm or villous histology) could
potentially prevent 45% of bowel cancers up to age 80 or 5,500 cases in
the UK each year. The cost of this screening regimen would be only
slightly more than is currently spent on treating the disease (£5,500 per
cancer prevented vs £4,500 to treat the disease).
The understanding of the genetics of colorectal cancers is rapidly
advancing. Familial colorectal cancer is associated with a gene mapped to
chromosome 2 and accounts for up to 15% of colorectal cancer. The APC gene
responsible for familial adenomatosis polyposis which accounts for about
1% of colorectal cancer maps to chromosome 5. APC is a tumour suppressor
gene as are DCC, on chromosome 18, and p53 on chromosome 17. The study of
blood genomic DNA to identify inherited susceptibility and the genetic
testing of stools to detect neoplasia merits serious consideration for
To evaluate appropriate ways to screen for colorectal cancer and compare
their value and cost effectiveness.
Effective screening for colorectal cancer offers a possible large
reduction in deaths from this common cancer.
||Atkin S et al. Prevention of colorectal cancer by
once only sigmoidoscopy. Lancet 341; 736-40 (1993)
||Winawer SJ et al. Colorectal cancer screening. J
Natl Cancer Inst 83; 243-53 (1991)
The natural history of cervical neoplasia and the potential role of HPV
sub-typing in screening
There is now substantial evidence that cervical cancer is caused by
certain types of the human papillomavirus (HPV). Well organised
population-based cytology screening programmes can reduce mortality from
cervical cancer. But the specificity of cytology is low, especially in
identifying women with minor abnormalities only a small proportion of
which progress to severe disease. It now appears that the presence of HPV
DNA in cervical smears may identify those minor cytological abnormalities
that are likely to progress. There is thus potential for HPV testing to be
used in conjunction with cervical cytology to identify those women with
minor abnormalities (about 5% of those screened) who are at high risk of
progression (about 5% - 10% over three years). These women could be
offered further investigations, while HPV negative women would not have to
undergo unnecessary investigations, or surveillance.
Whether this is an acceptable adjunct to cytology screening depends on the
sensitivity and specificity of HPV testing in identifying those minor
cervical abnormalities that will progress and also on the costs involved.
This information needs to be obtained and can only be done satisfactorily
in a randomised trial.
Objectives and justification
A randomised controlled trial is proposed, where women with minor
cytological abnormalities would be tested for HPV and before disclosure of
the result would be randomly allocated to a study group or a control
group. The HPV test result would be disclosed for the study group but not
for the controls. HPV +ve women in the study group would be biopsied,
those who were HPV -ve and all women in the control group would be managed
in the standard way without colposcopy.
At the end of the study period (3 years) all women would
be referred for biopsy. The outcome measures would be:
||CIN III detected at final biopsy in each group.
||The HPV status in women who developed CIN III in
each group and those who did not.
||Women's satisfaction and psychological well-being in
||The cost of management for each group.
Randomisation should be the responsibility of the
cytology laboratory. About 2,000 women with mildly atypical smears would
need to be recruited and these could be identified in a few centres.
The study could be completed in four years and the costs would be largely
for a study coordinator in each centre and the extra laboratory tests.
Application of new technologies, including imaging and molecular pathology
(e.g. PCR, fish, cytogenetics), for improving tumour diagnosis, and for
the prediction of tumour behaviour and response to therapy
Successful treatment of cancer depends on localising cancers or
pre-malignant lesions in the patient, often by imaging techniques, and
establishing the nature of the disease process by pathological techniques.
Current imaging methods need to be improved and correlated with
The morphological classification of tumours can now be augmented by the
recognition of molecular defects - ranging from tumour specific
translocations in some childhood tumours and in sarcomas to the
identification of point mutations in specific oncogenes. The involvement
of different oncogenes in subsets of tumours with similar morphology is
important in relation to new therapeutic approaches and to determine
whether differential responses to existing treatment correlate with
different oncogene mutations. The identification of tumour specific
translocations offers the possibility of greatly improved diagnostic
accuracy in the particularly difficult group of connective tissue
The polymerase chain reaction (PCR) allows the identification of mutations
in fresh or fixed tumours and the detection of very small quantities of
normal and abnormal nucleic acid. It can be used to study not only
tumours, as discussed, but also to identify mutations in non-neoplastic
tissue, and determine whether the patient has an inherited predisposition
to malignancy. Fluorescence In-Situ Hybridisation (FISH) can be used to
identify translocations and non-radioactive in-situ hybridisation can be
applied to tissue sections to identify specific gene products and also
translocations. Treatment of cancer must be based on accurate diagnosis
and an understanding of cancer biology, the applications of these new
technologies holds great promise for improving that accuracy and
increasing our understanding of processes involved in the malignant
New diagnostic technologies for cancer - both imaging and molecular
pathology - must be thoroughly evaluated before introduction. The extent
of new information gained, its comparison to information available by
existing methods, the benefits in terms of selection or treatment and the
cost effectiveness of the new technologies must be understood prior to
New technologies may substantially improve knowledge of diagnosis,
prognosis and selection for treatment. However, they can generate
additional costs, do not necessarily result in patient benefits and
require rigorous evaluation.
Imaging techniques for the definition of tumour spread, in the detection
of metastases and in the evaluation of response to treatment
Accurate radiological assessment of the extent of a tumour is at the
corner-stone of treatment. The initial therapeutic approach is heavily
dependent on radiological staging - even though this is currently
imprecise. In those patients undergoing therapy, imaging can provide a
rapid indication of whether that particular therapy, which may be very
expensive and have unpleasant side-effects, is proving successful.
There is wide geographical variation in the extent and type of
radiological evaluation, even for the common forms of cancer. Of course
this may depend on local availability and expertise, but even in centres
with comprehensive facilities, different authorities champion different
radiological techniques. It is certainly not in the best interests of the
patient or the community if an extensive range of radiological techniques
is performed, each providing slightly different answers. The optimal
imaging tests (or sequence of tests) need to be identified and
standardised. The development of new techniques, designed to improve the
detection of tumour spread, should be encouraged. These new imaging
techniques should be measured against agreed standards.
||The evaluation of the best and most cost effective
of the existing investigations that attribute stage and response to
treatment for tumours.
||The evaluation of any new approaches to tumour
Accurate staging with the correct number of investigations should result
in better patient management and may reduce costs.
The most cost effective way to provide information to meet the needs of
cancer patients, their families, health care professionals and the public
Increasing complexity in cancer treatment and acknowledgement of resource
limitation increases patients' and carers' needs for information. The
recent Audit Commission report identified a number of barriers to
effective delivery of information, including inadequate organisation of
key interviews, poor communication skills on the part of key staff, poorly
conceived and presented written information and inadequate identification
and use of available resources; for example national self-help group
literature, local and national telephone helplines (1, 2).
Several studies have confirmed cancer patients' and carers'
dissatisfaction with information provided and have investigated different
ways to improve this, including access to specialist staff, audio taping
of key interviews (3, 4) and provision of written information.
Evaluation of the most cost effective way to provide information to meet
the needs of cancer patients, their families, health care professionals
and the public.
Choice of treatment depends on patient information, attitudes and
preferences in many phases of cancer care. More effective ways are needed
to inform patients.
||Audit Commission. What seems to be the matter:
communication between hospitals and patients HMSO (1993)
||Bradburn J, Maher EJ, Young J, Young T. Community
based cancer support groups: an undervalued resource? Clin Oncol
||Hobgin B, Fallowfield L Getting it taped: the 'bad
news' consultation with cancer patients. Br J Hosp Med
||McHugh P, Lewis SW, Ford S et al. The efficacy of
audiotapes in promoting psychological well being in cancer patients.
A randomised, controlled trial. Br J Cancer. In press.
The psychosocial consequences for patients who have increased
participation in clinical decision making
Recent studies have highlighted disparities in the aims and expectations
of cancer treatment between different health care professionals and
between them and their patients (1, 2). These together with the rise of
consumer-based culture have led to demands for greater patient involvement
in clinical decision making. However, for some this is an unacceptable
To clarify patient preferences (4); distinguish between the needs for
information and control over decisions (5, 6) and to measure the short and
long term psychological consequences of different approaches.
Improved clinical decision making with appropriate degrees of patient and
family information and involvement improves the service provided, and was
highlighted as important by the Expert Advisory Group on Cancer's advice
to the Chief Medical Officer.
||Slevin ML, Plant H, Lynch D, Drinkwater J, Gregory
WM Who should measure quality of life, doctor or patient? Br J
||Maher EJ, Jefferis AF. Decision making in advanced
cancer of the head and neck; variation in the views of medical
specialists. J R Soc Med 1990;83:356-359
||Gray ER, Doan BD, Church K. Empowerment issues in
cancer. Health Values 1991;15:22-28
||Degner LF, Sloan JA. Decision making during serious
illness; what role do patients really want to play? J Clin Epidemiol
||Cassileth BR, Zupkis RV, Sutton-Smith K, March VJ.
Information and participation preferences among cancer patients. Ann
Intern Med 1980;92:832-836
||Sutherland HJ, Llewellen Thomas HA, Lockwood GA,
Trichler DL, Till JE. Cancer patients: their desire for information
and participation in treatment decisions. J R Soc Med
Methods for managing the introduction of innovative therapies and the
development of cancer services in a cost effective way
The NHS faces new challenges in cancer services. Service organisation is
being extensively re-evaluated. New treatments are constantly being
introduced and choice in methods of treatment is becoming wider. Patient
expectations both for the availability of new treatments and their full
explanation are increasing.
Among key issues are likely to be those of
||Developing new links between primary and secondary
||Defining viable size and organisation for cancer
units and centres
||Defining strategies for choice in drug therapy and
the introduction of new treatments
||Developing integration between the acute treatment
of cancer patients and their palliative care.
Research can clarify key questions for purchasers and providers faced with
the introduction of new services and new treatments. For instance, the
relationship between outcomes and service volumes is understood for many
cancers in terms of patient survival but quality of life has rarely been
studied. Although approaches to evaluating new treatments for clinical
benefits are established, the most cost effective way of introducing
beneficial new treatment is much less clear.
Cancer care is a large part of NHS activity which has to be integrated
with other agencies and across the service and to respond to constant new
approaches and demands. Further studies of service organisation and
innovation are needed.
Optimal imaging methods for determining residual tumour mass and for the
follow up of patients given primary treatment for common solid cancers
There are successful forms of treatment for several types of cancer
(lymphoma, testicular tumours etc). However, despite reduction of tumour
bulk with therapy, a sizeable residual mass may remain. This poses special
problems. Should more therapy (with a risk of over treatment) be given?
Should surgery (with attendant morbidity) be performed? Should the
residual abnormality merely be watched, waiting for progression (and the
risk of delay)? Even in those patients whose tumour has been fully
resected, the appropriate level of imaging follow up is unknown. Some
patients undergo numerous computed tomographic (CT) studies, which are
costly and result in additional radiation burden. There is a need for
improved knowledge about imaging in these clinical situation. The
available options currently include plain radiography, ultrasound, CT,
nuclear medicine (gallium, PET, etc), MRI.
Studies of the use of available techniques and the introduction of new
techniques to evaluate residual tumour masses are needed.
Clearer understanding of appropriate evaluation for residual masses will
result in improved information for patients, better choice of treatment
and appropriate follow up regimens.
The roles of adjuvant, neo-adjuvant and combined modality treatments for
primary common solid cancers
It is now standard therapy in certain cancers to give adjuvant
chemotherapy after elimination of macroscopic disease by primary surgery.
Neo-adjuvant chemotherapy as the initial treatment offers advantages, both
real and theoretical, in the management of locally advanced solid tumours.
Radiotherapy is used successfully to improve the durability of local
control achieved with primary treatment where the disease is not far
advanced but is otherwise less successful. This approach does not remove
the risk of distant metastases appearing. Early Phase II trials in
patients with several types of solid tumours have demonstrated the
feasibility of adjuvant chemotherapy followed by local and regional
treatment. In Phase III trials in lung cancer, improved survivals have
been shown using chemotherapy with radiation therapy but local control has
remained a major problem. A Phase III trial in oesophageal cancer has
shown that adding chemotherapy to radiotherapy improved survival with
fewer local and distant recurrences. However, there was more treatment
Further prospective trials of multi-modal combined therapy are required to
be able to define the role of this encouraging approach. Research is also
needed into why combinations known to be effective are not always taken
The appropriate use of these adjuvant approaches has already resulted in
significant advances in some common cancers. Further definition of
benefits and improvements may lead to significant, if small, increases in
cure rates for common cancers.
||Schnall SF, Macdonald JS. Adjuvant therapy in
colorectal carcinoma. Semin Oncol 1991;18:560-70
||Strauss GM et al. Multimodality treatment of stage
IIIA non-small cell lung carcinoma: a critical review of the
literature and strategies for future research. J Clin Oncol
||Rusch VW et al. Surgical resection of stage IIIA
and stage IIIB non-small cell lung cancer after concurrent induction
of chemoradiotherapy. J Thorac Cardiovasc Surg 1993;105:97-106
||Herskovic A et al. Combined chemotherapy and
radiotherapy compared with radiotherapy alone in patients with
cancer of the oesophagus. N Engl J Med 1992;326:1593-8
Cancer treatment of the elderly including clinical outcomes and cost
Cancer is more common in the elderly. Entry criteria of patients into
clinical trials often exclude the elderly. Many physicians consider that
treating elderly people who have cancer does not bring great benefits in
terms of quality of life or additional years or life and, indeed, that
aggressive treatments diminish rather than enhance these aspects. However,
it has been argued that cancer treatment needs should not be so readily
disregarded. The appropriate therapeutic regimens for the elderly patient
may differ from the younger patient who may be better able to tolerate
certain treatments. Clinical and cost effectiveness studies are needed to
address this subject area objectively and systematically.
To evaluate appropriate treatment policies in the elderly and develop
appropriate new approaches where existing ones are found to be inadequate.
Demographic changes will lead to increasing numbers of elderly and very
elderly patients with cancer resulting in a major clinical challenge and
||Fentiman IS. Treatment of cancer in the elderly. Br
J Cancer 1991;64:993-5
The value of integrating quality of life (QL) data and data on costs in
the measurements of outcome in prevention, treatment and care of cancer
patients and their carers
The traditional ways of evaluating cancer care are measurement of patient
survival and the local or general response of a cancer to treatment and
its subsequent control. Increasingly it is recognised that outcome
measures should include evaluation of the quality of life after an
intervention and several scales have been produced for this purpose in
cancer patients. These are now widely used in clinical trials but their
value as measures of outcome in clinical practice needs to be determined.
The integration of quality measures with measures of cost and of survival
is the subject of ongoing research.
There is a need for qualitative research to examine the difference between
the perspective of patients themselves and those of carers and specialists
and research methodology is lacking in this area.
The value of quality of life indices on clinical practice needs to be
determined and research into analysis and implementation of quality of
life end points, survival and costs needs to be carried out.
Patients and carers regard QL as a crucial outcome measure for cancer care
and its appropriate use on a wide scale should result in a more informed
and responsive service and more effective choice of treatment options and
||Selby P The value of quality of life scores in
clinical cancer research. Eur J Cancer 1993;29A:1656-7
||Maher EJ, Hopwood P, Girling DJ, Macbeth FR, Mansi
JL Measurement of outcome in palliative oncology. Journal of Cancer
Care 1994. In press.
Comparison of the cost effectiveness of different psychosocial
There is evidence of substantial psychiatric, social and psychological
morbidity following cancer diagnosis and treatment. Increasing knowledge
of vulnerability factors for such morbidity is needed so that appropriate
preventive measures and psychological treatments can be increasingly
targeted where they are most needed. Research has confirmed the value of
some approaches, such as the role of specialist breast nurses (1) and
adjuvant psychological therapy (2) but others, such as drug treatments for
depression and anxiety, require to be determined. Improved treatment
strategies need to be identified. Interventions, such as the role of nurse
counsellors and complementary therapies, have become widely available but
lack proven efficacy or cost effectiveness (3, 4) in reducing or
preventing psychological distress. Moreover, training in counselling and
specific therapies has been shown to be seriously lacking or inadequate.
To develop and evaluate:
||The relative effectiveness and efficiency of models
of psychological intervention provided by specialist nurses,
Macmillan nurses, nurse counsellors, mental health professionals and
practitioners of complementary therapies
||Methods of preventing psychological morbidity in
patients and families
||Innovative psychosocial interventions for patients
Effective interventions should reduce the psychosocial morbidity of cancer
||Maguire P, Tait A, Brooke M, Thomas C, Sellwood R
Effect of counselling on the psychiatric morbidity associated with
mastectomy. BMJ 1980;281:1454-1456
||Greer S, Moorey S, Baruch J et al Adjuvant
psychological therapy for patients with cancer: a prospective
randomised trial. BMJ 1992;304:675-680
||Booth B. Health alternatives. Nursing Times
||Kingman S Complementary Medicine. BMJ 1993;306:1713
What prevents terminally ill patients from dying at home, if they so wish,
and how can general practitioners and their teams access information to
help them care more effectively for their patients at home?
More patients wish to die at home than actually appear to do so. This may
result from inadequate resources for support in the home but there may be
other factors. The ways to overcome any barriers and the resources
required to enable this to happen require further study. GPs need to be
able to access information easily to help them undertake palliative care
for their patients. Increasing numbers of Gps own computers. Research is
needed to assess the feasibility of providing a central resource of
information, using information technology to assist in this process.
To clarify why patients who wish to die at home may be prevented from
doing so and to investigate ways of overcoming the problems.
Improved quality of care at home and increased good care options for dying
cancer patients will result in better quality of life in the terminal
phase of cancer and reduce the stress on professional and family carers.
||Townsend J et al Terminal cancer care and patients'
preference for place of death: a prospective study. BMJ
||Thorpe G. Enabling more dying people to remain at
home. BMJ 1993;307:915-918
||Preece J. The use of computers in General Practice
2nd Edition. London, Churchill Livingstone: 1990
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