In 2018, the number of new cases of breast invasive cancer in France was estimated to be
over 58 500, with a median age at diagnosis of 63 years.
The 5-year survival rate (as measured by age) has improved over time thanks to various
treatments . Hormonotherapy is one of the disease's treatment options, and it includes a
variety of molecules, including aromatase inhibitors. Despite their effectiveness,
aromatase inhibitors cause a variety of side effects, including arthralgia in 35 percent
to 50% of patients. The physiopathological mechanisms underlying these arthralgies would
include articular inflammation, increased intra-articular fluid, and the appearance of a
tenosynovitis. These side effects are frequently responsible for the premature
discontinuation of hormone therapy and, as a result, the therapeutic effect of molecules.
In order to improve the management of arthralgias caused by aromatase inhibitors, and
because current recommendations are unclear, the effects of whole-body cryotherapy in
patients who are taking an aromatase inhibitor for a hormono-dependent cancer in an
adjuvant setting will be investigated. In fact, cryotherapy has already demonstrated its
efficacy in the treatment of arthritic pain in a variety of diseases (rheumatoid
arthritis,..).
This is a category 1, comparative, randomized, prospective, multicenter study. The
patient and investigator will be blinded to the treatment. Only the cryotherapist will
have knowledge of the treatment group.
Randomization will be performed after information and signature of informed consent on
the day of the inclusion visit.
Patients will be randomized to either
either in the Whole Body Cryotherapy group (Arm A),
or in the placebo Cryotherapy group (Arm B). Randomization will be stratified by
center, initial BPI score of most severe pain (greater than or equal to 7 vs. less
than 7) and duration of initial pain exposure (greater than or equal to 6 months vs.
less than 6 months). It will be centralized, accessible online (on the Internet) and
programmed by minimization using the Ennov Clinical software (CSRandomization
module) by the Clinical Research Unit of the Medical Information Department (DIM) of
the Montpellier University Hospital. Patients will be recruited from the
gynecological consultation service of the Arnaud de Villeneuve Hospital in
Montpellier and the Caremeau Hospital in Nîmes. Patients consulting for the
follow-up of a breast cancer and presenting arthralgias under anti-aromatase will be
included in the study after verification of the inclusion and non-inclusion criteria
and collection of consent.
Oral and written information will be given at the inclusion visit. Written consent will
be collected at the end of the same visit after a reflection period.
Prior to the cryotherapy sessions, the patient will be asked not to exercise, take a
shower or take any stimulant (tea or coffee) before a cryotherapy session. Before the
first cryotherapy session, after a new verification of the absence of contraindication to
cryotherapy, a blood pressure and temperature measurement will be taken (questionnaire
before/after cryotherapy). The patient will receive information on the course of a
cryotherapy session and will then be prepared: protection of recent skin wounds, wearing
of a bathing suit and a surgeon's mask, protection of the extremities by gloves, slippers
and a polar cap provided by the CryoMed.
Before each of the following sessions, a blood pressure reading and a skin temperature
reading between the Achilles heel and the triceps will be taken. The occurrence of
undesirable events since the last session will be investigated (questionnaire
before/after cryotherapy).
After the patient enters the cryotherapy chamber (CryoAir, MecoTec), a permanent visual
contact is kept on the patient throughout the session, thanks to a glass window. It is
also possible to hear and communicate with the patient throughout the session.
The sessions will be performed according to the randomization arm as follows
Whole body cryotherapy group: 10 sessions will be performed daily, over a period of
12 to 21 days. For each session, the patient enters a chamber at -85°C for 4 minutes
30 seconds.
Placebo cryotherapy group: 10 sessions will be performed daily, over a period of 12
to 21 days. For each session, the patient enters a chamber at -85°C for 1 minute.
Patients can stop the cryotherapy session at any time. The duration of each session will
be noted on the Before-After Cryotherapy questionnaire.
Finally, after the cyrotherapy sessions:
Whole body cryotherapy group: In order to better understand the thermal shock and to
adjust the following sessions, the patient's temperature will be recorded between
her Achilles tendon and her triceps, as soon as she leaves the cryotherapy chamber:
If > 12°C, the duration of exposure to -85°C will be increased by 20 seconds during
the following sessions.
If < 5°C, the duration of exposure to -85°C will be decreased by 20 seconds during
the following sessions.
This process will be repeated with each new cryotherapy session.
• Placebo Cryotherapy Group: In order to promote blindness, the patient's temperature
will be recorded between her Achilles tendon and her triceps, as soon as she leaves the
cryotherapy chamber, but no change will be made to the duration of the following
sessions.
Adverse events will be investigated at the end of each session (before/after cryotherapy
questionnaire).
Each patient will complete the BPI-SF and HAQ questionnaires 15 days +/- 7 days prior to
the start of cryotherapy, at the 6 week, 3 and 6 month post-cryotherapy visit.
Each patient will indicate the number of days of anti-aromatase therapy in the 6 months
prior to inclusion and at 6 weeks, 3 and 6 months after cryotherapy. For this purpose,
each patient will indicate the number of hormone therapy tablets taken in the 15 days
prior to the inclusion visit, the 6 week, 3 and 6 month visit. A calendar will be given
to each patient: the patient will indicate the use of hormone therapy and analgesics
during the 15 days preceding the visits.
Each patient will indicate the analgesic treatments used, classified in three categories:
levels 1, 2 and 3 at the inclusion consultation and at 6 weeks, 3 and 6 months after
cryotherapy (analgesics taken during the 15 days preceding the visit).
The evaluation of the tolerance with the collection of the undesirable effects will be
made before and at the end of each session by the professionals of the CryoMed. It will
also be evaluated in the week following the end of cryotherapy during a telephone call.
A difference of 2 points or more in the BPI-SF score is considered as clinically
significant. Under this assumption and that of a standard deviation of 2.3 points in both
groups, the number of subjects to be analyzed to demonstrate a difference between the
groups, with a two-sided alpha risk of 5% and a power of 80%, is 42 subjects, i.e. 21
subjects per group. In this study, there is a risk of attrition during or after the
sessions, evaluated at 20%, and a risk of attrition of 20% between inclusion and the
first session, due to organizational constraints and the possible appearance of
contraindications to cryotherapy. In case of attrition between the inclusion and the
first session, for a provisional reason, the patients could be re-included. A total of 70
inclusions are finally possible. As soon as 56 patients (28 per group) have completed at
least one session, recruitment can be stopped.
The threshold of significance is set at 0.05 bilaterally for all analyses. Qualitative
variables will be described by their number and percentage. Quantitative variables will
be described by their mean, standard deviation, extrema, median and quartiles, in the
randomized population, in the ITT population, in the PP population, in the safety
population, and in each of the two groups within each of these populations. In addition,
all baseline variables will be described in the included population. A flow-chart will be
performed.
The main analysis will be performed in the ITT population by comparing the mean of the
primary endpoint (most severe pain at 6 weeks) between the two groups by a test
appropriate to the distribution of the data. Missing data will not be imputed.
The primary analysis will be supplemented by a secondary analysis of the YAC in which
missing data will be imputed by multiple imputation, in the randomized population, and by
an analysis in the PP population.
Secondary endpoints will be compared between the two groups, in the ITT population and in
the PP population, without imputation for missing data:
Adverse events will be compared between the two groups in the safety population.