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Does a homeopathic medicine reduce hot flushes induced by adjuvant endocrine therapy in localized breast cancer patients? A multicenter randomized placebo-controlled phase III trial

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Purpose Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF). Methods In this multicenter randomized double-blind placebo-controlled phase III study (ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization. Results Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, − 2.9; P, − 2.5 points, p = 0.756) and relative decrease (A, − 17%; P, − 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470). Conclusions The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile.
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ORIGINAL ARTICLE
Does a homeopathic medicine reduce hot flushes induced by adjuvant
endocrine therapy in localized breast cancer patients? A multicenter
randomized placebo-controlled phase III trial
Pierre-Etienne Heudel
1,2
&Isabelle Van Praagh-Doreau
3
&Bernard Duvert
4
&Isabelle Cauvin
5
&
Anne-Claire Hardy-Bessard
6
&Jean-Philippe Jacquin
7
&Laetitia Stefani
8
&Lionel Vincent
9
&Dominique Dramais
10
&
Jean-Paul Guastalla
1
&Ellen Blanc
11
&Aurélie Belleville
11
&Emilie Lavergne
11
&David Pérol
1
Received: 7 September 2017 /Accepted: 30 August 2018 / Published online: 7 September 2018
#Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Purpose Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast
cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy
might allow a better management of hot flushes (HF).
Methods In this multicenter randomized double-blind placebo-controlled phase III study (ClinicalTrials.gov NCT01246427), we
enrolled 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative
Oncology Group-Performance Status (ECOG-PS) 1, treated for at least 1 month with adjuvant ET, and complaining about
moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology
known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS 10 using an
interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm
P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were
calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-)
weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre-
and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed
8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization.
Results Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute
variation (A, 2.9; P, 2.5 points, p= 0.756) and relative decrease (A, 17%; P, 15%, p= 0.629) were not statistically
different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for
respectively 43 (72%) vs 51 (74%) patients (p=0.470).
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00520-018-4449-x) contains supplementary
material, which is available to authorized users.
*Pierre-Etienne Heudel
PierreEtienne.HEUDEL@lyon.unicancer.fr
1
Department of Medical Oncology, Centre Léon Bérard, 28 rue
Laennec, 69373 Lyon Cedex 08, France
2
Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France
3
Centre Jean Perrin, 58, Rue Montalembert,
63011 Clermont-Ferrand, France
4
Centre Hospitalier, 3 Rue Adhémar, 26200 Montélimar, France
5
Centre Hospitalier, BP1125, 73011 Chambéry, France
6
Clinique Armoricaine de Radiologie, 21 rue du Vieux Séminaire,
22000 Saint Brieuc, France
7
Institut de Cancérologie Lucien Neuwirth, 108, avenue
Albert-Raimond, 42270 Saint-Priest-en-Jarez, France
8
Centre hospitalier de la région dAnnecy, 1 avenue de lhôpital,
BP90074, 74374 Annecy, France
9
Centre hospitalier de Roanne, 28, Rue de Charlieu,
42300 Roanne, France
10
Centre hospitalier, 179, Boulevard Maréchal Juin,
26000 Valence, France
11
Department of Clinical Research and Innovation, Centre Léon
Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, France
Supportive Care in Cancer (2019) 27:18791889
https://doi.org/10.1007/s00520-018-4449-x
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Finally, 18 publications were considered relevant due to the inclusion criteria of this present work and were included in this SR. We included 11 studies for endpoints: 0 SRs, 9 randomized controlled trials (RCTs) (Balzarini et al. 2000;Frass et al. 2015;Frass et al. 2020a, b;Heudel et al. 2019;Jacobs et al. 2005;Lotan et al. 2020;Luca Sorrentino 2017;Pérol et al. 2012;Thompson et al. 2005) and 2 controlled trials (CTs) (Karp et al. 2016;Steinmann et al. 2012) which investigated the efficacy of homeopathic treatment in cancer therapy. These studies were heterogeneous in terms of the assessed homeopathic intervention and cancer type. ...
... In another study, 138 randomised patients took the homeopathic remedy BRN-01 (Actheane ® ) or a placebo twice a day for at least 8 weeks in addition to their adjuvant endocrine therapy (aromatase inhibitor or tamoxifen with/without ovarian suppression). There were no significant differences in the HF-score after 4 or 8 weeks (p = 0.756; p = 0.775), compliance (p = 0.606) or satisfaction (Heudel et al. 2019). ...
... Further studies observing QoL did not find significant differences: neither in a controlled trial with 20 non-blinded and non-randomized patients with head and neck tumours (Steinmann et al. 2012), no p values reported) receiving Traumeel S or sage tea for mouth rinses against radiotherapy-or radiochemotherapy-induced oral mucositis, nor in a RCT with 138 patients who took, additionally to their adjuvant endocrine therapy, the homeopathic remedy BRN-01 (Actheane ® ) or a placebo (Heudel et al. 2019). In the latter study no statistical analysis was made between the groups and the result presentation was incomprehensible. ...
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... Hot flushes may be treated with serotonin reuptake inhibitors (i.e., venlafaxine LoE1a/A/AGO+). Homeopathy and phytotherapy had no effect on hot flushes in large randomized trials compared with placebo in breast cancer survivors (LoE1b/B/AGO−) [97]. Sleep disturbances might be treated with melatonin (LoE2b/C/ AGO+). ...
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... A recent study found that 2.5 or 5.0 mg oxybutynin twice a day for 6 weeks was an effective treatment option for women with hot flushes [74] (LoE 1b/A/AGO+/-). Homeopathy and phytotherapy had no effect on hot flushes in large randomized trials compared with placebo in breast cancer survivors (LoE 1b/B/AGO-) [75]; interestingly, in these studies a substantial effect was observed also in the control arm ("placebo effect"). Sleep disturbances might be treated with melatonin (LoE 2b/C/AGO+). ...
... Iatrogenic hot flashes are an important side effect of some cancer treatments, notably hormonal treatment in breast cancer. Data indicates that homeopathy may be effective in reducing menopausal hot flashes, and studies in patients with breast cancer suggest that it may also be beneficial in reducing (i.e., improving) hot flashes scores with a positive impact on quality of life [27,28]. Management of nausea and vomiting was also considered relevant; again, this matches our own experience, especially when persistent despite taking conventional antiemetics. ...
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... However, the experimental preparation Actheane had a positive effect on the perceived quality of life for the patients. Thus, Actheane was not completely unnecessary, as better quality of life is certainly important for a cancer patient [3]. ...
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Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer (NSCLC). Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life. A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, -3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful. Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.
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Women who have been treated for breast cancer identify vasomotor symptoms, such as hot flushes and night sweats, as a serious problem. These symptoms can be unpleasant, with a significant impact on daily life and sleep quality: It’s as though somebody has built a furnace inside of you and it’s your whole body. It starts almost at your feet and works up and you just feel as though you are literally on fire inside and it’s trying to escape and you just want to escape but you can’t escape, there’s nowhere to go and nothing to do [1]. The social consequences of this embarrassing experience can affect employment, personal relationships and quality of life: Umm, when they were at their worst I would be yeah pretty much dripping in, in err, various places umm err from really from the nose downwards; the lips; the neck; umm chest and back; crooks of my arms. And I could, you know, often if I was sitting down I would get up and my trousers would be really wet and it would go right down to my toes [1]. Oestrogen replacement remains the most effective treatment for hot flushes. However, this is contraindicated in the majority of women with oestrogen-dependent breast cancer. An estimated 550 000 people live in the UK today with a diagnosis of breast cancer and up to 70% experience hot flushes [2e5], which are exacerbated by a lack of safe and effective management strategies [4]. Although hot flushes may occur for a number of reasons, including natural or chemotherapy-induced menopause, they may also be side-effects of adjuvant hormonal therapies, such as tamoxifen and the aromatase inhibitors. Two recent clinical trials (aTTom [6] and ATLAS [7]) showed that 10 years of tamoxifen significantly reduces the risk of recurrence and breast cancer mortality. However, an increasing number of studies report that over 50% of women do not adhere to 5 years of endocrine treatment with an associated increase in mortality [8]. The lack of effective management of vasomotor symptoms may be an important contributory factor to this lack of adherence [9]. The pathophysiology of hot flushes is poorly understood. Proposed mechanisms include altered peripheral vascular reactivity and a narrowed thermoneutral zone [10], although how this relates to oestrogen deprivation is not understood. Without a fuller understanding of the physiology, mechanisms and triggers it will be difficult to develop new targeted therapies. Adrienne Morgan says ‘I was diagnosed with breast cancer eight years ago and continue to take anti-oestrogen drugs because my cancer has returned. I have had a hot flush every 45 minutes for the last eight years. It is difficult to convey to anyone who has never had a hot flush how awful they are; exhausting, embarrassing, agitating.. I am fatigued, unable to work, sleep is only possible with medication and every morning my bed is soaked. I have tried everything. Only the SSRIs have some effect by reducing the severity of the hot flushes (venlafaxine made me feel horrible so I take Citalopram)but they make me anorgasmic. It surprises me that there is not more basic research being done into the causes of hot flushes. After all, most women will have them at some stage in their lives - not just breast cancer patients - and now men with prostate cancer are getting them too’.
Article
To assess the psychometric properties of the Hot Flash Related Daily Interference Scale (HFRDIS), a sample of breast cancer survivors and an age-matched comparison group completed a questionnaire packet and 2-day prospective hot flash diary at an initial time point and again 6 months later. There were 71 breast cancer survivors and 63 comparators at Time 1, and 54 survivors and 46 comparators at Time 2. The HFRDIS was internally consistent, with alphas of 0.96 at times 1 and 2. Validity was supported through 1) correlations with other hot flash variables, 2) correlations with measures of affect and mood, 3) significant differences between women with hot flashes and those without, and 4) demonstrated sensitivity to change over time. The HFRDIS is a psychometrically sound measure for assessing the impact of hot flashes on daily activities and overall quality of life in clinical practice or research protocols.