The paper from McNally et al in this issue is interesting in that it raises many issues
well beyond what the authors probably conceived when they started out on the project.
Guidelines are written for a number of reasons: firstly, to help health-care providers
plan their treatments and the delivery of the service. Secondly, it is increasingly
recognised that patients should be treated using standardised protocols or schedules
that allow consistency of approach and they are important when involving clinical
governance. There may be financial or budgetary advantages to standardised treatments
and finally audit is facilitated. The paper ostensibly looks at the application of
guidelines into clinical practice and populations. These include the applicability
of transferring clinical research and trials into practice, the issues of applicability
to whole populations especially when this may involve rurality on the one hand and
high levels of social deprivation on the other hand. When looking at whole populations,
one realises that a population-based survey should encompass the whole gamut of clinical
indications and clinical situations. Furthermore, there will be huge differences nationally
and internationally between the composition of the population as determined by their
social deprivation status, accessibility to transport and other compounding factors.
The translation of clinical research into clinical practice is rarely a straightforward
issue. Patients entering into clinical trials are required to fit into selection criteria
that are generally far more strict than those that are used to select patients for
routine treatments. These criteria usually require patients to be of good performance
status and to have normal or near-normal biochemistry and haematology, which fit the
parameters consistent with drug toxicity, and for there to be any lack of significant
ill health or other contraindicating factor to permit clinical trial entry.
However, there are also other issues that are commonly not considered when patients
are selected for clinical trial entry, which may not be apparent to all clinicians.
Scotland is an interesting and diverse country for clinical trial recruitment and
one would think that with a population of 5 000 000 and only five designated cancer
centres, it would be possible to incorporate the majority of suitable or eligible
patients into clinical trials or to offer the optimal and best designed treatments.
The paper by McNally et al illustrates some of the problems when a community is examined
for the ability of its patients to receive optimal recommended treatments. Issues
such as rurality and the distance between the patient's home and the cancer centre
can often be limiting factors in choosing the patient's appropriateness and suitability
for treatment. The Grampian region in the North East of Scotland covers a large geographical
area with a majority of population located in the urban area of Aberdeen, but provides
a cancer referral practice for patients living up to 100 miles (160 km) away on the
mainland and also provides cover for patients living on the Shetland Islands which
are some 10–12 h by ferry or an hour by aeroplane. This is in complete contrast to
an urban population such as Glasgow where 3 000 000 people live within 35 miles (55 km)
from the city centre that houses some of the worse social deprivation in Europe. Thus,
patients can live within five miles of the second largest cancer centre in the UK
and yet not be suitable candidates for optimal treatment.
So, what is optimal treatment, how do we define it and who defines it? NICE in England
and Wales (with Scottish equivalents in CSBS (Clinical Standards Board Scotland),
HTBS (Health Technology Board Scotland) and its successor NHSQIS National Health Service
Quality Improvement Scotland, and the Scottish Medicines Consortium) have tried to
make recommendations for treatment. Prior to the publication of the results of the
ICON-3 paper on ovarian cancer, it looked as though the combination of a platinum
and a taxane such as carboplatin and taxol was the optimal treatment for first-line
chemotherapy in advanced ovarian cancer. This certainly would be the viewpoint held
in both the United States and much of mainland Europe. However, the apparent equivalence
of carboplatin (or CAP) to carboplatin and taxol in the ICON-3 study has thrown open
to question–what is the optimal treatment for ovarian cancer? Opinion is strongly
divided as to whether carboplatin given at optimal dosage is an adequate treatment
for these patients. This viewpoint would be difficult to substantiate in the USA,
but what this paper reviews is what actually happens in clinical practice, that is,
how many patients are actually fit enough and well enough to receive the combination?
The paper examined patients in the Grampian region over a 3-year period who were referred
in for treatment of ovarian cancer. Virtually, all the patients were treated surgically
in the regional cancer centre at Aberdeen. A proportion of patients had stage 1 disease
of low risk for whom adjuvant treatment was not indicated, but there remained 117
out of 133 patients who were identified as requiring chemotherapy. For a variety of
reasons, a number of other patients were deemed unsuitable for treatment so that only
106 were left, and of these only 68 were deemed fit enough for a Platinum/ Taxane
combination either with paclitaxel/carboplatin or docetaxel/carboplatin (some of these
patients were participating in the Scottish Gynaecological Cancer Group trial evaluating
the latter carboplatin and docetaxel combination).
It initially seems very disappointing that so few patients (not a great deal more
than 50%) actually received the platinum/taxane combination, and yet there were very
good reasons why many of the patients were treated with carboplatin alone. Of the
patients receiving carboplatin only, 38 had a median age of 76 years. This has important
consequences for health service planners when trying to determine budgets and services
and also when trying to determine the number of patients likely to enter into clinical
trials. Incidentally, one must compliment them on achieving 29% participation in clinical
trials, which is substantially above the national averages. Our population is ageing
and therefore we are likely to see more patients who will be deemed unsuitable for
intensive treatment regimens. Currently, we are being encouraged to improve clinical
trial entry, but despite huge efforts to do this, a large cohort of patients are not
suitable for recruitment. With this in mind, the Scottish Gynaecological Cancer Group
has been considering ideas for carboplatin-based protocols to evaluate fixed dosing
vs flexible dosing in the management of these trials. Recent informal discussions
about the applicability of this trial to clinical practice have raised enormous variations
in approach throughout Europe with some specialists indicating that virtually all
their patients can be treated with platinum/taxane and yet here we have substantial
and significant evidence to question that approach.
It is often not appreciated by those who do not work with patients from areas of high
levels of social deprivation that there are special problems. Ignorance, fear and
lack of understanding are only some of the issues. Lack of transport and support are
often equally problematic. It is in major contrast to areas where the articulate,
educated and affluent arrive in the clinic with sheaves of pages downloaded from the
Internet. There is a strange paradox that the more socially deprived patients anticipate
that the doctor knows best and should be able to advise or recommend the best treatment.
The apparent uncertainty in the specialist may undermine patient's confidence and
inhibit clinical trial entry. While for those with excessive knowledge (and remember
a little learning can be a dangerous thing), too much knowledge can bring its own
problems in trying to encourage recruitment into clinical trials.
We must commend the Aberdeen Group for entering nearly 30% of their patients into
clinical trials, which is well above the National average. It also clearly supports
the concept of a unified service where all the patients are treated in a single centre.
This concept should be embraced by planners in defining future cancer trial organisations.
There is a movement towards decentralisation at present, but the proof of the pudding
will lie in the eating in that the major centres are much more likely to enter a higher
proportion of patients into clinical trials, although they must have the appropriate
infrastructure to support this.