Discussion
Cystic fibrosis landscape is expected to change significantly over the
next years. The place in CF therapy of each CFTRm by indication is still
to be fully understood, especially with regards to expected long term
effects and potential benefits of early intervention, in particular in
very young patients. Physicians opinion will predictably evolve as more
real world data are being collected and with increasing experience. We
undertook this survey to see how clinical use of CFTRm changed over time
with their increasing availability in Italy. Ivacaftor and
lumacaftor/ivacaftor were the only CFTRm available at the time of our
study, the latter available for F508del homozygous patients above
12 years of age at the time of the first survey conducted in 2015, its
indication extended to younger ages at the time of the 2018 survey. No
drug was available for patients with residual function mutations until
2018, however tezacaftor/ivacaftor phase III data on both patients
homozygous for F508del mutation and those carrying a residual
function mutation had already been published in the scientific
literature. Considering that these new indications or extensions
introduced the use of CFTRm in new patient groups, we designed the
questionnaire to explore physicians attitude in F508delhomozygous patients aged 12 years and above as an historical group
compared to younger F508del homozygous patients and those with
residual function mutations. Reaching out to all CF physicians was
facilitated by the centralization of care in CF centers evenly
distributed on the national territory. Response rate of 76% was
satisfactory and similar to that of previous survey14,
showing the willingness of Italian health care professionals to share
their experience and allowing to consider the outcome as representative
of the general opinion in Italy. Of note, most respondents had
significant experience in the field of CF, with at least 5 years of work
in a CF center. A general overview of responses to the different
questions shows that traditional parameters such as lung function and
nutrition status remain key evaluation criteria in relation to
initiation and monitoring of CFTRm in all groups and physicians expect
to observe improvement, consistently with clinical trial results.
Nutritional status is considered a fundamental parameter in relation to
initiation of CFTRm across all the different patient groups and growth
percentiles is considered a useful parameter to monitor in pediatric
patients. This is in line with literature data showing that improvement
of nutritional status is directly linked with increased survival in CF
patients. With regard to pulmonary outcomes, it should be underlined
that more than FEV1, the number of exacerbations is considered
particularly relevant in all groups for both initiation and monitoring
of therapy. This is consistent with the expected deleterious effect of
increasing number of exacerbations on FEV1 decline and survival. We also
observed interest in measuring exercise tolerance and patient related
outcomes such as ability to conduct daily activities as well as in tools
that can help detect early manifestations of disease such as LCI and
imaging. LCI was deemed particularly relevant in the younger age group,
with 36% of physicians who judged this test very useful inF508del homozygous patients under 12 years of age. Imaging can
also be useful in all patient groups to identify early lung damage and
as such, was viewed as useful by clinicians for initiation and
monitoring of CFTRm therapy. For follow up in particular, imaging can
provide objective signs of the effects of CFTRm on lung parenchyma. A
few studies report CT scan parameters combined through a scoring system
as exploratory endpoints. In particular, reduction of mucus plugging,
bronchiectasis15,16 and airway wall
thickness17 were observed after one year of treatment
with ivacaftor, while improvement of bronchiectasis and air trapping
were seen after 6 months of lumacaftor/ivacaftor
treatment18. Limitations related to cumulative
exposure to ionizing radiation might be overcome by tools such as
Magnetic Resonance Imaging that look promising for closer monitoring of
the effect of CFTRm19. Relatively little emphasis was
given to pancreatic function, but this is consistent with the start of
CFTRm (at the time of conduct of the survey) at an age deemed too old to
expect great impact. Encouraging data on modification of biological
markers with younger age of CFTRm start raises some hopes on possibility
of changing pancreas exocrine function status with very early
intervention with this class of drugs20. Sweat
chloride measurement was also mentioned as useful monitoring tool and it
is likely used by physicians to estimate adherence. When asked about
treatment initiation according to clinical presentation and disease
stage, health care professionals provided similar responses in
homozygous F508del patients under or over 12 years of age and
residual function patients as well, showing that severity/instability of
disease prevails on this decision and is not influenced by mutation type
or age range. A relatively small proportion of physicians would treat
systematically asymptomatic patients with less than 20% for youngerF508del homozygous patients or those with residual function
mutations and somewhat more (27%) for F508del homozygous over 12
years of age. Intention to initiate treatment increases considerably
(over 50% in all groups) when patients show light manifestations of
disease. Further explorations of what is meant by light manifestations
would be interesting to understand biomarkers of interest to detect
initial organ damage before symptoms occur. Willingness to initiate
CFTRm treatment reaches 69-78% in case of fully expressed disease and
exceeds 90% in patients with worsening disease. Interestingly, compared
to survey conducted in 201513, intention to initiate
CFTRm treatment in F508del homozygous over 12 years of age
increased by 8-11% in all severity categories and even doubled for
patients in terminal stage, showing increasing confidence of physicians
with increasing experience of CFTRm. Nevertheless, some concern on
initiating CFTRm in asymptomatic pediatric patients actually exists and
this might be related to lack of long term experience of CFTRm in
pediatric CF patients. This is in contrast with general belief in early
intervention which is at the basis of CF care with all efforts made to
intervene as soon as possible once diagnosis of disease is made, in
order to warrant optimal long term outcomes. Continued observation will
help us understand the magnitude of long term impact of early use of
CFTRm. For now, simulation models can be used to predict long term
effects, showing increased survival up to 23.4 years in pediatric CF
patients treated early with lumacaftor/ivacaftor21.
Registry data will allow documentation of effect of CFTRm on hard
outcomes such as mortality and transplant, already shown for
ivacaftor22. Limitations of this study are inherent to
surveys based on voluntary participation, however high response rate
allows to consider the sample as representative of the opinion in the
Italian CF community. Survey can be conducted quickly and can inform how
health care professional opinion is formed as new tools are made
available and this could be of particular value in a rare disease field.
We are not aware of any other published survey similar to ours.
In conclusion, the introduction of CFTRm in the therapeutic
armamentarium is progressively changing treatment protocols in CF. Early
intervention with drugs that act on the causal mechanism of disease have
the potential to change the progression of disease, stimulating some
physicians to start treatment regardless of symptoms. Our survey shows
that CF HCPs have high expectations on CFTRm effectiveness. Pulmonary
exacerbations represent the most important outcome to consider in CF
patient both for start a CFTRm and as a monitoring parameter. This is
consistent with the attitude of physicians to consider CFTRm treatment
according to disease stage, considering more severe disease or non
stable disease as priorities. On the other hand, there is increasing
interest in parameters such as imaging and above all LCI as useful tools
in order to predict disease progression in asymptomatic and/or pediatric
patients. It is arguable that with increased experience with CFTRm and
with new insight into the understanding of disease progression the
attitude towards early intervention could become more prominent.
Treatment scenario is rapidly changing and will call for revision of
current guidelines.