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20-April-2012, Vol 125 No 1353
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Great expectations: use of molecular tests and
computerised prognostic tools in New Zealand cancer care
Deborah M Wright, Rob McNeill, Arend E H Merrie, Cristin G
Print
There is an international drive to improve outcomes for
patients with cancer by individualising cancer treatment using technologies
including molecular tests (MT) and computerised prognostic tools
(CPT).1,2 MT utilise molecular information, for
example variations in DNA sequence or RNA expression levels, to diagnose disease
or to predict susceptibility or treatment outcome. CPT use computerised
statistical models to combine large datasets with individuals’ clinical
details to infer individualised prognoses.
MT and CPT designed to aid clinical decision making for
patients with a range of malignancies have been
described.3 Molecular tests available in New
Zealand (NZ) include: MammaPrint4 and
Oncotype DX,5 which use gene
expression analysis to derive a recurrence risk score for patients with early
breast cancer; FLT3, NPM1 and CEBPA mutation analysis
which provide prognostic information for patients with cytogenetically normal
acute myeloid leukaemia (CN-AML) and are recommended in World Health
Organization (WHO) guidelines;6,7 KRAS
mutation analysis, which predicts response to cetuximab, an unfunded
treatment for metastatic colorectal cancer;8
UGT1A1 mutation analysis to predict irinotecan
toxicity;9 EGFR mutation analysis to
predict response to gefinitib and erlotinib for patients with non-small cell
lung cancer.10
In NZ we also have free online access to a number of CPT
including Adjuvant!, which estimates recurrence risk and treatment benefit for
patients with breast, colon or lung cancer.11
Further details of these examples of MT and CPT are given in Table 1.
Table 1 Examples of molecular tests and
computerised prognostic tools currently available in New Zealand for the care of
patients with cancer
CN-AML=cytogenetically normal acute myeloid leukaemia;
CRC=colorectal cancer; ER=(o)estrogen receptor; qRT-PCR=quantitative reverse
transcription polymerase chain reaction.
The utilisation of MT and CPT during the management of
patients with solid organ and haematological malignancy is likely to have a
significant impact on clinical practice and health economics in NZ, however it
has not been evaluated to date. The intent of this study is to determine the
awareness and specific utilisation of MT and CPT amongst NZ cancer clinicians
treating solid organ and haematological malignancy, and to ascertain their
predictions for the impact of these technologies over the next 10 years.
MethodsAn anonymous online questionnaire was used to survey
clinicians who treat patients with cancer in NZ.
The questionnaire was implemented using LimeSurvey
software (Carsten Schmitz, Germany), a free open source survey application. It
comprised 185 questions in three sections. Most questions in sections one and
two had fixed ‘click button’ answer options and a free text
‘other’ option; where a numeric answer was required a free text box
or slide rule was provided.
In section 3, participants were shown clinical
scenarios relating to their area of specialty. The scenarios presented
situations in which molecular tests are purported to assist with clinical
decision-making: stage II breast cancer, stage II colon cancer and CN-AML in
remission after chemotherapy. Participants were invited to leave free text
comments at the end of each section of the survey.
The questions presented to each participant were
determined by their previous responses such that each participant saw only those
questions relevant to their clinical practice. The questionnaire took
approximately 15 minutes to complete.
Please visit
http://www.bioinformatics.auckland.ac.nz/doc/project_data/Supplemetary_figure_and_tables_FINAL.docx
to view the questionnaire in full and all supplementary figures and tables. The
University of Auckland Human Participants Ethics Committee granted ethical
approval for this study.
Medical and radiation oncologists, haematologists,
pathologists and general surgeons practicing in NZ at specialist and trainee
level were invited to participate by email via their professional societies and
colleges. All trainees were enrolled in college-approved training programmes.
Reminder emails were sent out 2 and 4 weeks after the initial invitation.
Participation was incentivised with an iPad (Apple Inc., California, USA), won
by a participant selected using a random number generator.
The survey was conducted over 11 weeks, from
17th May to
1st August 2010. Responses from clinicians
practicing outside NZ were excluded from analysis, as were incomplete responses
that did not include details of the participant’s specialty and seniority.
Data analysis was carried out using PASW Statistics 18.0 (IBM Corp., NY, USA),
Excel 2008 version 12.2.9 (Microsoft Corp., Washington, USA) and VassarStats
(faculty.vassar.edu/lowry/VassarStats.html). Relationships between independent
categorical variables were analysed using the chi-square test for independence
of association, relationships between non-independent variables were analysed
using McNemar’s test. Where multiple tests were performed the Bonferroni
correction was used. A P value of <0.05 was held to be significant
and P<0.01 as highly significant.
ResultsSurvey participants - 739 clinicians were
invited to participate in the survey. 186 clinicians accessed the online
questionnaire; 137 completed it (Figure 1). Participants represented all invited
specialties and included both specialists and trainees (Table 2). Specialists
were significantly under represented relative to trainees (P<0.01);
pathologists were significantly under represented relative to other specialties
(P<0.05 for both pathology specialists and trainees). Participants
worked in secondary, tertiary, academic and private practice settings.
Figure 1. Participation in a survey
investigating utilisation of molecular tests and computerised prognostic
tools
 Table 2. Seniority and specialty of survey
participants
Current practice—A greater proportion
of participants were aware of MT than CPT (92% vs. 69%,
P<0.01) (Table 3). Awareness of MT by specialists vs.
registrars showed no statistically significant difference (6% and 10%,
respectively), however specialists were significantly less likely to be aware of
CPT than registrars (60% vs. 81%, P <0.05). Fewer participants had ever used
MT than CPT (43 vs. 78, P<0.01). Of participants aware of MT, 59/126
(47%) reported that they had never used MT relevant to their clinical practice.
Of participants aware of CPT, 12/94 (13%) reported that they had never used CPT
relevant to their clinical practice.
Table 3. Awareness and utilisation of molecular
tests and computerised prognostic tools amongst New Zealand cancer
clinicians
Table 4 presents data on factors that limited the use of
those MT and CPT most commonly used in NZ. Supplementary Tables 1 and 2 present
this data for all of the MT and CPT included in the survey.
Factors reported to limit the use of MT and CPT varied. For
example, awareness of both the CPT Adjuvant! and the MT Oncotype DX was
high (78% and 86%) amongst participants who managed breast cancer (n=94) but
while the use of Oncotype DX was most commonly limited by cost, use of
Adjuvant! was most commonly limited by lack of clinical time (Table 4).
For participants who prescribed chemotherapy, both the cost
of mutation analysis and, in some instances, the cost of unfunded medications
(e.g. cetuximab) limited their uptake of MT.
Table 4. Factors that limited the use† of
molecular tests and computerised prognostic models for the management of
patients with cancer in New Zealand
At the time of the survey 80% of participants managing
breast cancer (75/94) were aware of the prognostic MT Oncotype DX and
MammaPrint; Oncotype DX was currently being used by six, MammaPrint by
two. Of the 26 participants managing CN-AML, 92% had heard of
FLT3, NPM1 or CEBPA
mutation analysis; FLT3, NPM1 and CEBPA mutation
analysis were currently being used by 22 (85%), 15 (41%) and two (8%) of these
clinicians, respectively. Thirty-four participants prescribed chemotherapeutic
agents of whom 29 (85%) had heard of KRAS, UGT1A1, or
EGFR testing. Twelve (35%), one (3%) and four (12%) of these clinicians
currently used KRAS, UGT1A1 and EGFR mutation
analysis, respectively.
Table 5. Impact of molecular tests and
computerised prognostic tools on the management of patients with cancer in New
Zealand
Participants were asked to comment on the influence these
tools had on their practice (Table 5). For 19 participants FLT3
mutation analysis affected their clinical decisions; 16 were more likely to
offer allogeneic stem cell transplantation, two were more likely to suggest
deferring treatment and one was more likely to offer chemotherapy. For 10
participants KRAS mutation analysis, which predicts response to
cetuximab, affected their clinical decisions; six reported that it resulted in
offering fewer patients treatment with this drug and two that they offered more
patients treatment with cetuximab.
Twenty-eight participants reported that Adjuvant! for breast
cancer affected their clinical decisions; 18 considered adjuvant therapy for
fewer patients and 10 for more.
Overall, MT were more likely than CPT (P<0.01)
to affect the clinical decisions of participants currently using them. However,
because fewer participants used MT than CPT, the global effect of MT and CPT on
clinical decisions was similar; 33/137 participants reported that MT affected
their clinical decisions, 35/137 participants reported that CPT did so.
Estimated value of molecular
tests—The median estimated value of hypothetical tests that
provided reliable patient-specific recurrence and response data was $1000 (Table
6). The majority of participants concluded that such a test could save the
health service money, with no significant difference between the scenarios
offered.
Table 6. Participants estimated the value of
hypothetical molecular tests in response to clinical scenarios, and whether such
tests could reduce health costs
Estimates of test worth are median value in NZ$
(interquartile range). All other data are number of participants (percentage).
AML=acute myeloid anaemia.
Predictions for the future – All
participants (n=137) were asked to predict the change in impact of MT and CPT on
the care of patients with cancer over the next decade. Over 85% of participants,
whether or not they currently used these tests and tools, predicted that they
would have a greater influence and a stronger evidence base within the next 10
years (Table 7).
Table 7. Predicted change in the influence and
impact of molecular tests and computerised prognostic tools on the management of
patients with cancer over the next 10 years
DiscussionThis study has elucidated the use of molecular tests (MT)
and computerised prognostic tools (CPT) by 137 clinicians treating patients with
solid organ and haematological malignancy in NZ, the factors that limit their
uptake and their predicted impact over the coming decade. For each point below
we will first draw conclusions from our data and then discuss the potential role
of MT and CPT in NZ cancer care.
Survey response rate—The ‘click
through’ response rate to our survey was 25% (186/739); most clinicians
who visited the survey completed it (137/186, 72%). However the figure of 186
responders to 739 invitations may significantly underestimate response due to
difficulties in accurately determining the number of eligible participants. Some
members of the relevant colleges and professional societies are members of more
than one organisation (e.g. haematologists may be members of both RACP and
RCPA), others are currently practicing overseas and are likely to have
determined that they were ineligible to participate prior to accessing the
survey’s website. Participation was unevenly distributed amongst the
invited specialities; a significantly smaller proportion of invited pathologists
participated than clinicians invited other specialties.
In order to maximise participation we utilised strategies
that have been found effective including reminder notices and
incentivisation;15 participation was modest
nonetheless. Studies have found that clinicians have the lowest survey response
rate of all health care providers,16 with
Australasian physicians less likely to participate than their international
colleagues.17 It has also been shown that
response rates to electronic surveys vary widely, from
0.1%18 to
83%,19,16 but tend to be lower than to postal
surveys.18 Reviews of survey-based research
have commented that surveys with low response rates can provide useful and
representative data.16 We are therefore
confident that our data is a helpful contribution to this field.
Current use—We found that MT and CPT
currently influence the treatment offered to a significant number of patients
with cancer in NZ; our data suggests that the care of up to 80% of patients with
CN-AML is impacted by the use of FLT3 mutation analysis and that the
care of up to 40% of women with early breast cancer is impacted by the use of
the CPT Adjuvant!. 67-73% of participants who used these technologies believed
that they positively impact patient outcomes. Overall a greater number of
participants were aware of MT than were aware of CPT, but CPT were more commonly
used.
It is interesting to speculate on the factors that may
explain this difference. We propose that awareness of MT may be enhanced by the
larger number of publications about them than about CPT (8,600 versus 159
PubMed-referenced publications in 2010) and by the effort of manufacturers to
raise the profile of some expensive MT within Australasia.
The MT discussed in this paper range in cost from around
$300 per patient for FLT3 mutation analysis testing (Canterbury Health
Laboratories, http://www.labnet.co.nz/testmanager/)
to around $4500 per patient for MammaPrint (personal communication with Ronald
van Klaveren, Agendia, March 2011). In contrast we suggest that the greater
uptake of CPT may be because they are often available free of charge and can be
accessed using computer hardware and software commonly available in clinical
settings.
Use of MT and CPT may also be influenced by their inclusion
in current clinical guidelines. For example FLT3 testing for patients
with CN-AML is recommended in the current WHO
guidelines6 and was used by 85% of participants
who treat this malignancy. In contrast, MammaPrint, which was used by only 2% of
participants who manage breast cancer, is not mentioned in NZ’s Early
Breast Cancer Guidelines.20
64 to 78% of participants estimated that the use of
hypothetical MT might reduce healthcare costs even at prices that would
significantly increase the cost of pathological
assessment.21 In the USA, industry-associated
studies have previously calculated that use of
MammaPrint22 and Oncotype
DX23 may indeed reduce healthcare costs.
However, some may argue that assessing the economic value of MT in NZ may be
premature before more robustly establishing their ability to improve patient
outcomes.24,25
Future use—Nearly all clinicians
forecast that MT and CPT will be used more frequently and will have a greater
influence on clinical decisions within the next decade. Participants predicted
that this increased impact and influence would be supported by a stronger
evidence base and greater ability to improve patient outcomes. Less than 1% of
respondents believed that these tools would become less important over the next
10 years.
Discussion of the role of MT and CPT in NZ cancer
care—This survey showed that clinicians are currently using MT
and CPT to make clinical decisions about patients with cancer in NZ and have
great expectations for their increasing contribution over the next 10 years. It
also suggested that a subset of clinicians saw the relative lack of research
into the effect of MT or CPT on patient outcomes as limiting MT or CPT uptake.
MammaPrint, Oncotype DX and other MT that have not yet completed
prospective trials are currently influencing patient care in this
country.26-28 The NZ Cancer Control Strategy
supports an evidence-based approach to the management of patients with
malignancy.29 Therefore, we would like to
suggest that high quality research evaluating the effects of MT and CPT on
patient outcome should be a priority. This view is backed by overseas studies,
which have found that some MT have worrying variations in their technical
use,30 that others are marketed before a
convincing evidence base has been assembled31
and that the clinical evaluation of some MT and CPT has lagged behind the
technological leaps that have allowed these tests to be
used.32,33
Defining the role of MT and CPT in NZ cancer care requires
input from a wide range of clinical specialists and scientists. Pathologists
were under-represented amongst survey respondents, yet their involvement in a
multidisciplinary effort to integrate traditional histopathology with
developments in the molecular understanding of cancer can not be
overestimated.34 For example, Cummings et
al stress that new MT will only produce maximal clinical benefit for
patients with breast cancer if they are used by pathologists as an adjunct to
their existing armamentarium.35
In conclusion, our survey suggested that MT and CPT already
influence treatment provided to NZ cancer patients and that NZ cancer clinicians
overwhelmingly expect their use and influence to increase. This has important
clinical and health economic implications for NZ. Although these technologies
may represent exciting opportunities to improve cancer care and patient outcomes
it seems important that their use is supported by high quality evidence and that
research is undertaken into their effects on both patient outcome and future
health resource utilisation.
As with any health care intervention, MT and CPT cannot be
considered in isolation, but rather should be considered as elements of a
co-ordinated strategy that includes primary prevention, early referral,
screening, and optimal specialist management to improve the quality of cancer
care in NZ.
Competing interests: None.
Author information: Deborah M Wright, PhD
Student;1,2 Rob McNeill, Senior
Lecturer;3 Arend EH Merrie*, Colorectal
Surgeon, Honorary Clinical Senior Lecturer;2,4
Cristin Print*, Associate Professor of
Pathology.1,5
1Department of Molecular
Medicine and Pathology, University of Auckland, Auckland.
2Department of Surgery,
University of Auckland, Auckland.
3School of Population
Health, University of Auckland, Auckland.
4Colorectal Unit,
Department of Surgery, Auckland City Hospital, Auckland.
5Bioinformatics Institute,
University of Auckland, Auckland.
*Joint Senior Authors.
Acknowledgements: This work is supported by
the Newmarket Rotary Charitable Foundation Oncology Award, the Foundation for
Surgery NZ Research Fellowship, and the Foundation for Research, Science and
Technology.
The authors also thank Professor Peter Browett for his
technical advice; Dr Ben Lawrence for his assistance with survey development;
Gail Le Claire and Helena Cox of the RANZCR, Sue Jansen of the RCPANZ, Heather
Rosser of the RACP, and Bronwen Evans of the NZAGS for distributing invitations
to participate to their members; and all those who completed our
questionnaire.
Correspondence: Dr Deborah Wright,
Department of Molecular Medicine and Pathology, Faculty of Medical and Health
Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New
Zealand. Fax: +64 (0)9 3737492; email: deborah.wright@auckland.ac.nz
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