Acupuncture Prevents Chemobrain in Breast Cancer Patients
Condition: Chemo-brain; Drug-Related Side Effects and Adverse Reactions; Mild Cognitive Impairment; Breast Cancer
MeSH terms: Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Chemotherapy-Related Cognitive Impairment; Cognitive Dysfunction
Study type: Interventional

Summary: 
      Chemobrain is an expression used to describe a cluster of chemotherapy-induced cognitive
      impairment symptoms, including problems with visual and verbal memory, forgetfulness,
      difficulty in learning, attention, concentration and coordination of multitasking and
      organization. Over 75% cancer patients experienced acute cognitive symptoms during
      chemotherapy and 17%-34% of them have long-term post-treatment cognitive deficits which can
      persist up to 10 years. Breast cancer survivors even display as high as 50%-75% prevalence of
      post-treatment cognitive impairment. Chemobrain has become an apparent quality-of-life issue
      for cancer survivors and will be encountered more frequently with the rise of the number of
      cancer survivors. There are no effective interventions available for preventing and treating
      chemobrain.

      Acupuncture is beneficial in reducing various side effects of anti-cancer treatment. It also
      shows the efficacy in improving mild cognitive impairment and other dementia disorders;
      facilitates the recovery of pathological microstructural changes of the brain. These results
      have led to the hypothesis that acupuncture is effective in preventing chemobrain and this
      preventive effect may be associated with the protection against cytokine production,
      epigenetic modification and microstructural changes of the brain.

      To test this hypothesis, an assessor-blinded, randomised controlled trial will be conducted
      to determine if a combination of DCEAS and body acupuncture could reduce the incidence and
      symptoms of chemobrain in breast cancer patients under chemotherapy compared to least
      acupuncture stimulation (LAS) as controls.

      A total of 168 breast cancer patients who are ready for chemotherapy will be randomly
      assigned to comprehensive acupuncture intervention (combined DCEAS and body acupuncture
      regimen + chemotherapy) (CAI) (n = 84) for 2 sessions per week for 8 weeks or least
      acupuncture stimulation (LAS) (minimal acupuncture + chemotherapy) (n = 84). All patients
      receive the standard chemotherapy of breast cancer. Treatment outcomes on cognitive
      performance, fatigue and the depression will be assessed.
    

Detailed description: 
      Although the development of various chemotherapeutic drugs has greatly improved clinical
      outcomes and survival rate of cancer patients, it also causes various adverse side effects.
      Chemotherapy-induced cognitive impairment, often referred to as chemobrain, has drawn
      increasing attention due to the rise in the number of cancer survivors over the past decade.
      Numerous studies have shown that chemotherapy can cause acute and long-term post-treatment
      cognitive impairment, including problems with visual and verbal memory, forgetfulness,
      difficulty in learning, attention, concentration and coordination of multitasking and
      organization. Over 75% cancer patients reported to experience acute cognitive symptoms during
      chemotherapy and 17%-34% of them have long-term post-treatment cognitive deficits which can
      persist up to 10 years. Breast cancer survivors may display higher prevalence of
      post-treatment cognitive impairment. The severity of reported chemobrain symptoms is
      variable, from subtle to more severe. Chemobrain has become an apparent quality-of-life issue
      for survivors and will be encountered more frequency in the future. However, there are no
      effective interventions available to prevent and treat chemobrain, although some
      pharmacological, antioxidant and various cognitive approaches have been tested.

      It is believed that chemobrain is a consequence of brain neuronal injury induced by
      systemically administered chemotherapeutic agents via direct and indirect mechanisms,
      resulting in the suppression of neuronal cell proliferation, epigenetic modification and
      microstructural changes of the brain. These pathological circumstances are largely developed
      from alternations in cytokine milieu. While physical and psychological stressors that cancer
      patients experienced after diagnosis, chemotherapy and long-term follow-up have been shown to
      increase circulating cytokine levels and increased cytokine levels are associated with
      cognitive decline in cancer patients, the administration of chemotherapy also results in
      cytokine production at peripheral and central levels as the medications induce tumor cell
      death and collateral tissue injury. Patients undergoing chemotherapy have been found to
      display significant increases in multiple cytokines.

      A large body of evidence well confirms that acupuncture is effective in reducing anti-cancer
      treatment-caused side effects, including pain, nausea, hot flashes, fatigue, xerostomia,
      anxiety, depression and sleep disturbance. Numerous studies further have shown the
      effectiveness of acupuncture therapy in improving cognitive function of patients with mild
      cognitive impairment (MCI) and various dementia. The reduced severity of cognitive symptoms
      is associated with neuroimaging improvement in brain regions associated with learning and
      memory process. Acupuncture also ameliorates cognitive impairment in various animal models.
      Studies have further revealed that the cognition-improving effects of acupuncture are
      associated with the inhibition of cytokine-mediated neuronal cell apoptosis, inflammatory
      reaction and oxidative cellular injury and the effects in reducing cognitive symptoms are
      related to the protection of neuronal cells, improvement of electrophysiological activities
      of the hippocampus and brain cell proliferation. Moreover, acupuncture also displays a
      significant effect in facilitating the recovery of the brain at microstructural
      histopathological level in patients with cerebral infarction and in rats with transient focal
      cerebral ischemia. The investigators therefore hypothesize that acupuncture may be also
      effective in preventing and reducing chemotherapy caused cognitive impairment.

      Recently, the investigators have developed a novel acupuncture stimulation called dense
      cranial electroacupuncture stimulation (DCEAS) on the basis of neuroanatomical rationale. In
      this mode, electrical stimulation is delivered on dense acupoints located on the forehead
      innervated by the trigeminal nerve. The trigeminal sensory pathway has much intimate fiber
      connections with brain regions associated with sensory, locomotor, visceral function, sleep,
      emotion, learning and memory. Therefore, DCEAS can effectively modulate brain functions. Over
      the past 5 years, the investigators have completed several clinical studies and demonstrated
      the benefits of DCEAS in the treatment of major depression, insomnia, OCD, postpartum
      depression and post-stroke depression. In the proposed study, a combination of DCEAS and body
      acupuncture will be employed to prevent and treat chemobrain in breast cancer patients.
    

Intervention name(s): Dense cranial electroacupuncture stimulation; Body acupuncture; Least acupuncture stimulation; Cytoxan-containing chemotherapy regimens
Intervention type(s): Procedure; Procedure; Procedure; Drug
Intervention description(s): DCEAS is a is a novel stimulation mode in which electrical stimulation is delivered on acupoints located on the forehead.
Six pairs of acupoints are used: Baihui (GV20) and Yintang (EX-HN3), left Sishencong (EX-HN1) and Toulinqi (GB15), right Sishencong (EX-HN1) and Toulinqi (GB15), bilateral Shuaigu (GB8), bilateral Taiyang (EX-HN5), and bilateral Touwei (ST8).
Disposable acupuncture needles (Hwato®, 0.30 mm in diameter and 25-40 mm in length) are inserted at a depth of 10-30 mm perpendicularly or obliquely into acupoints. Manual manipulation is then conducted to evoke needling sensation, followed by electrical stimulation (ITO ES-160, continuous waves at 2 Hz).; Following acupoints are used: Shui-Gou (GV26), Shen-Men (HT7). He-Gu (LI4), Wai-Guan (TE5), Zhong-Wan (CV12), Guan-Yuan (CV4), Zu-San-Li (ST36), Feng-Long (ST40) and San-Yin-Jiao (SP6).
Disposable acupuncture needles (Hwato®, 0.30 mm in diameter and 25-40 mm in length) are inserted at a depth of 10-30 mm perpendicularly or obliquely into acupoints. Manual manipulation is then conducted to evoke needling sensation. No electrical stimulation is delivered.; The acupoints chosen are less related to the treated syndromes based on Traditional Chinese Medicine (TCM) theory; the number of acupoints used and the intensity of electrical stimulation are also lower than the comprehensive acupuncture regimen. The following 6 acupoints will be used in LAS control: bilateral Tong-Tian (GB17), bilateral Shou San-Li (LI10) and bilateral Fu-Yang (BL59). Electrical stimulation will be only performed on bilateral Tong-Tian (GB17) and the intensities are adjusted to a level at which patients just start feeling the stimulation.; Each subject shall receive oral administration or venous injection or both with adjuvant or neoadujuvant chemotherapy regimens, as decided by clinical oncologist.
In clinical practice, the most commonly used Cytoxan-containing regimens include but are not limit to:
AC (x4) [Adriamycin + Cytoxan], TC (x4) [Taxotere + Cytoxan], AC-P (4+4) [Adriamycin + Cytoxan + Paclitaxel], TAC (x6) [Taxotere + Adriamycin + Cytoxan], or AC-PH (4+4) [Adriamycin + Cytoxan + Paclitaxel + Herceptin].
Other intervention name(s): DCEAS; BA; LAS; Chemo
Intervention MeSH terms: Cyclophosphamide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Chemo-brain; Drug-Related Side Effects and Adverse Reactions; Mild Cognitive Impairment; Breast cancer