Report to the NHS Central Research & Development Committee
Annex 9 - Justifications of Priorities

JUSTIFICATION L
Comparison of the value of MRI with current breast cancer screening methods in high risk women

Background

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.

Objectives

To evaluate MRI applied to the breast as a method for screening for breast cancer.

Justification

To improve screening techniques and results and reduce radiation exposure.

JUSTIFICATION M
Appropriate ways of screening for preventing and diagnosing colorectal cancer, including "once only" flexible sigmoidoscopy and molecular screening

Background

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 further research.

Objectives

To evaluate appropriate ways to screen for colorectal cancer and compare their value and cost effectiveness.

Justification

Effective screening for colorectal cancer offers a possible large reduction in deaths from this common cancer.

References

JUSTIFICATION N
The natural history of cervical neoplasia and the potential role of HPV sub-typing in screening

Background

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:

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.

JUSTIFICATION O
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

Background

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 pathological findings.

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 malignancies.

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 phenotype.

Objectives

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 their adoption.

Justification

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.

JUSTIFICATION P
Imaging techniques for the definition of tumour spread, in the detection of metastases and in the evaluation of response to treatment

Background

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.

Objectives

Justification

Accurate staging with the correct number of investigations should result in better patient management and may reduce costs.

JUSTIFICATION Q
The most cost effective way to provide information to meet the needs of cancer patients, their families, health care professionals and the public

Background

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.

Objectives

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.

Justification

Choice of treatment depends on patient information, attitudes and preferences in many phases of cancer care. More effective ways are needed to inform patients.

References

JUSTIFICATION R
The psychosocial consequences for patients who have increased participation in clinical decision making

Background

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 burden (3).

Objectives

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.

Justification

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.

References

JUSTIFICATION S
Methods for managing the introduction of innovative therapies and the development of cancer services in a cost effective way

Background

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

Objectives

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.

Justification

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.

JUSTIFICATION T
Optimal imaging methods for determining residual tumour mass and for the follow up of patients given primary treatment for common solid cancers

Background

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.

Objectives

Studies of the use of available techniques and the introduction of new techniques to evaluate residual tumour masses are needed.

Justification

Clearer understanding of appropriate evaluation for residual masses will result in improved information for patients, better choice of treatment and appropriate follow up regimens.

JUSTIFICATION U
The roles of adjuvant, neo-adjuvant and combined modality treatments for primary common solid cancers

Background

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 related toxicity.

Objectives

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 up.

Justification

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.

References

JUSTIFICATION V
Cancer treatment of the elderly including clinical outcomes and cost effectiveness

Background

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.

Objectives

To evaluate appropriate treatment policies in the elderly and develop appropriate new approaches where existing ones are found to be inadequate.

Justification

Demographic changes will lead to increasing numbers of elderly and very elderly patients with cancer resulting in a major clinical challenge and service requirement.

References

JUSTIFICATION W
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

Background

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.

Objectives

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.

Justification

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 service developments.

References

JUSTIFICATION X
Comparison of the cost effectiveness of different psychosocial interventions

Background

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.

Objectives

To develop and evaluate:

Justification

Effective interventions should reduce the psychosocial morbidity of cancer

References

JUSTIFICATION Y
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?

Background

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.

Objectives

To clarify why patients who wish to die at home may be prevented from doing so and to investigate ways of overcoming the problems.

Justification

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.

References

CRDC Report: Contents Page