Authors
- Mathews, Megan BA, MBBS, BSc Med
Abstract
Review objective: The aim of this review is to identify the effects of coenzyme Q10 on women with breast cancer.
More specifically, the objective is to identify the effects of coenzyme Q10 on:
* Death/survival rate
* Standard blood, immune and tumor parameters
* Primary and secondary tumors
* Recurrence of cancer
* Adverse events
* Adherence to conventional treatment
* Impact on conventional treatment
* Measures of quality of life.
Background: Excluding basal and squamous cell skin cancers, breast cancer was the most common cancer amongst Australian women in 2009.1 Breast cancer comprised 27.4% of all new cancer cases in Australian women and it has been estimated that one in eight Australian women will be diagnosed with breast cancer before they reach 85 years of age. Breast cancer is the leading cause of disease burden amongst Australian women.2 At the end of 2008, there were 159,325 Australian women alive who had been diagnosed with breast cancer in the preceding 27 years.2
Over the last four decades, the incidence of breast cancer has increased globally3, with the highest incidence in developed countries such as Australia1,2, New Zealand4, North America5, England6 and Western Europe.7 Australian data show that between 1982 and 1995, the age-standardized incidence rate rose from 81.1/100,000 to 115.9/100,000 and thereafter stabilized at 113.5/100,000.1 Global population growth will further increase the number of women diagnosed with breast cancer. In Australia: 13,668 women were newly diagnosed with breast cancer in 2009; it is estimated that 15,000 women will be diagnosed during 20131 and that this number will rise to around 17,210 women by 2020.2 In the USA, new breast cancer cases rose from 182,800 in 2000 to 226,870 in 2012.8 The number of women with breast cancer in the USA is expected to double by the year 2050.3
Survival rates for women with breast cancer
In 2010, breast cancer was responsible for 6.7% of all Australian cancer-related deaths and 15.3% of Australian cancer-related deaths in women, equating in 2013 to approximately 3000 deaths.1,2 On the positive side, relative survival rates after diagnosis have significantly improved worldwide.1-3,5-8 Australian data shows that between 1994 and 2010 the age-standardized mortality rate for breast cancer decreased by 30%, from 30.8/100,000 to 21.6/100,000. During the period 1982-1987, five-year survival was 72%, while during 2006-2010 it rose to 89.4%.1,2
Diagnosis and conventional treatment for breast cancer
This significant improvement in five-year survival rates is partly due to mass screening programs, early cancer detection and better conventional treatment regimens (surgery, radiotherapy and chemotherapy).9 For example, it is clear that size of a tumor at diagnosis strongly predicts prognosis. Australian data for 1997-2006 show that five year relative survival for women with breast cancer was 98.2% for 0-10mm tumors, compared to 73% for women with 30mm tumors.2
Breast cancer is classified according to its histo-pathological type, the tumor grade and stage and the expression of tumor proteins and genes.10, 11 Classification indicates the presence, extent and aggressiveness of a cancer as well as the most appropriate treatment options. Prognosis, or the effectiveness of a cancer treatment regime, is reflected in the patient's history, physical examination, ongoing test results, and both positive and negative responses to treatment.11-1 Tests commonly used to measure the presence of cancer and the effectiveness of treatment include biochemical markers, biopsies and imaging scans These tests assess the patient's general health, inflammation levels (erythrocyte sedimentation rate, c-reactive proten)14, whether the cancer has spread to organs (liver, bone, bone marrow), as well as levels of predictive biomarkers (Ca15.3, CA125, CEA ) that are associated with tumor type and activity.15
Treatment depends on the type, grade and staging of the breast cancer, as well as the health of the patient.12,13,16 The three standard broad treatment options recommended by conventional medicine oncologists are surgery, radiotherapy and chemotherapy, including hormonal therapy. The appropriate treatment regime for a patient might be any combination of these options.
Rise in the use of complementary and alternative medicine (CAM) by women with breast cancer
The last four decades have witnessed a global increase in the use of complementary and alternative (CAM) therapies.17-24 This period has also seen an increase in women's use of CAM therapies for treating breast cancer.25-29 For example, a Canadian study comparing survey data from 1998 and 2005 reported that CAM use amongst women with breast cancer rose from 66.7% in 1998 to 81.9% in 2005.25 In addition, a 2005 Australian survey found that women with breast cancer are more likely to use CAM therapies than other women with or without cancer.26 They used CAM therapies soon after diagnosis, during treatment, as well as years later. A 2004 USA study showed that 66% of women diagnosed with breast cancer were using CAM therapies on average 3.5 years after diagnosis.27 The main reasons reported by women with breast cancer for using CAM therapies included reducing side effects of conventional treatment, enhancing recovery and improving general health, boosting the immune system, taking control and curing the cancer.29
CAM consists of a group of diverse healthcare systems that share common beliefs.30-32 The aim of treatment is to address the underlying cause(s) of a disease rather than its symptoms; the body, mind, spirit and ecology need to be treated as an integrated whole and health is a positive state of wellbeing, not the absence of measurable disease.30-32 The main tools used by CAM practitioners include mind-body interventions, biologically-based treatments, manipulative and body-based methods and energy therapies.30-32 CAM practitioners believe their approach strengthens and utilizes the body's vital force and healing capacity.30-32
Factors that have contributed to the rise in CAM usage included the introduction of traditional healthcare systems from indigenous and foreign cultures33, growth of the wholefood and health products movements33,34, global increase in rates of chronic illness35,36, extension of health insurance coverage to include CAM treatments37, inclusion of CAM modalities in physician university training and hospital treatments38 and the substantial rise in government funding for CAM research and treatment centers.30-32 A 2012 systematic review of surveys of UK conventional medicine physicians revealed that around 20% of physicians were practicing CAM therapies with their patients and 39% were referring patients to CAM practitioners.39
While most patients always told their CAM practitioner about their conventional treatments, less than 50% always told their conventional medicine practitioner they used CAM.25-27 The consequence can be that general practitioners and oncologists are unaware of the CAM therapies patients are using and therefore unable to assess their safety and effects on conventional treatment and prognosis. An additional consequence is that general practitioners and oncologists are unable to advise patients about the evidence-based use of CAM therapies to improve patient tolerance of conventional treatment, as well as treatment outcomes.
Coenzyme Q10
Coenzyme Q10 is a specific CAM treatment for breast cancer. A 2002 survey of licensed North American naturopathic physicians found that 77% had treated breast cancer and their most common specific treatments were coenzyme Q10, vitamin C and the Hoxsey herbal formula.40
Coenzyme Q10 was first isolated in 1957 and its chemical structure was ascertained in 1958.41 Coenzyme Q10 is a fat-soluble, vitamin-like, compound that is found in all mammalian cellular systems and almost every fluid, cell, tissue and organ.42,43 The body synthesizes coenzyme Q10 and also absorbs it from food and supplements.42,43 Highest natural levels are found around age 25 years and decline with ageing, stress, poor diet and illness.41,42
Coenzyme Q10 is found in two main redox states - the fully reduced form, ubiquinol and the fully oxidized form, ubiquinone. Coenzyme Q10 moves between these two states by donating or accepting electrons and this allows it to play crucial roles in the electron transport chain of cellular energy production and as an antioxidant.42-44 Coenzyme Q10 is involved in cell processes that characterize the differences between healthy and cancerous cells.43,45 The three most important areas of coenzyme Q10 function pertaining to cancer are as follows:
Coenzyme Q10 it is an essential component of the electron transport chain in aerobic respiration (oxidative phosphorylation) that mostly occurs in mitochondria.42,43 This very efficient process converts fatty acids and carbohydrates into 30-36 adenosine triphosphate molecules (ATPs)/molecule glucose and provides around 95% of the cell's energy requirements for growth, repair and reproduction. In contrast, cancer cells mostly use anaerobic respiration, a relatively inefficient process with much lower energy yields - 1-2 ATPs/molecule glucose. Energy production is one of the fundamental metabolic differences between healthy and cancer cells.45
Coenzyme Q10 is a ubiquitous and endogenous fat-soluble antioxidant that protects fat-rich molecules and structures from free radical attack. It also helps re-activate spent antioxidants such as tocopherol and ascorbate.43,44 Breast cancer tissue has higher levels of oxidative stress and lipid peroxidation than non-malignant breast tissue.46-48
Coenzyme Q10 has been shown to reduce levels of tumor-associated cytokines (TNF-alpha, IL-2), superoxide anions and DNA damage in peripheral lymphocytes.43,49 It also helps increase IgG levels, T4/T8 ratios and thymus function.50 Coenzyme Q10 plays roles in redox control of cell growth and signaling, membrane channel structure and fluidity, hydrogen peroxide production, apoptosis, gene expression and formation of thiol groups.51-53
Coenzyme Q10 plays an important role in the adjuvant treatment of a wide range of diseases54-60, including cancer.61-63 Some women with breast cancer have lower than normal range plasma and tissue levels of coenzyme Q10 and this is associated with a poorer prognosis.61-66 Supplementation with coenzyme Q10 either in combination with other nutrients67-72, or oral hormonal therapy (Tamoxifen) plus nutrients73-76 is associated with tumor regression and increased years of survival. As these studies often utilize small sample sizes and/or observational study designs, a synthesis of studies in this area will better determine whether coenzyme Q10 is effective and safe for women with breast cancer.
Coenzyme Q10 can be administered orally or intravenously. No serious adverse events have been reported for coenzyme Q10 taken alone, but it can augment warfarin treatment.77,78 The most common minor adverse events include dizziness, headache, reflux, nausea, insomnia, fatigue, irritability, light sensitivity, right upper abdominal pain and raised liver enzymes.77,78
In summary, due to their widespread use, CAM therapies are a significant practice issue for GPs and oncologists managing breast cancer patients. Very little is known about what specific CAM therapies are being used by women with breast cancer and whether they interfere, complement or augment conventional treatment. There is a pressing need to critically review the literature concerning coenzyme Q10 and determine its evidence-based role in the treatment of breast cancer. A preliminary search of the JBI Database of Systematic Reviews, the Cochrane Library, PubMed and CINAHL has shown that to date, no systematic review has addressed this issue.
Article Content
Inclusion criteria
Types of participants
This review will consider studies that include adult women aged 18 years or older who have been managed with conventional treatment (surgery, radiotherapy and/or chemotherapy including hormonal therapy- either alone or in any combination) regardless of type, stage or grade of breast cancer.
Types of intervention(s) and comparators
The intervention of interest is coenzyme Q10 therapy following or in addition to conventional treatment (surgery, radiotherapy and/or chemotherapy, including hormonal therapy), either alone or in addition to other nutrients or antioxidants. This study will consider supplementation with coenzyme Q10 regardless of the route or dosage and for a minimum of one week administration.
The comparison group is adult women with breast cancer who have had conventional treatment (surgery, radiotherapy and/or chemotherapy, including hormonal therapy). In some study designs there may not be a comparator group and coenzyme Q10 will be considered as an exposure.
Types of outcomes
This review will consider the following parameters that indicate increased survival, reduced recurrence and tumor burden, and cancer cure.
* Death/survival rate;
* Blood concentrations of biochemical markers - standard tests (FBC, EUC, LFT); inflammatory markers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)14; tumor markers (CA 15.3, CA 125, CEA)15; and tumor-related markers (such as but not limited to TNF-alpha, IL2, IL6 and IL8);
* Size of primary tumor assessed by ultrasound (US), mammography, computerized axial tomography (CAT scan), magnetic resonance imaging (MRI), positron emission tomography (PET);
* Number and size of secondary tumors assessed by ultrasound, chest X-ray, mammography, computerized axial tomography (CAT scan), magnetic resonance imaging (MRI) or positron emission tomography (PET scan);
* Adverse events resulting from coenzyme Q10;
* Adherence to conventional therapy;
* Impact of coenzyme Q10 on conventional treatment. This may be either to inhibit, augment or ameliorate actions or adverse events resulting from conventional treatment; and
* Effect of coenzyme Q10 on measures of patient quality of life (such as sleep, nausea, vomiting, hair loss, appetite, mobility, lymphedema, pain and patient satisfaction) related to the cancer as well as the cancer treatment-related symptoms.
Types of studies
This review will consider both experimental and epidemiological quantitative studies including randomized control trials, non-randomized control trials, quasi-experimental, case control, cohort case series and case reports which examine the effects of coenzyme Q10 on women with breast cancer.
Search strategy
A three-step search strategy will be used in this systematic review to find both published and unpublished studies between 1961 to the present date (April 2014). This deliberately broad time-frame is designed to capture any early clinical studies on coenzyme Q10. First, a limited search of MEDLINE and CINAHL, followed by analysis of the text words contained in the title and abstract, then the index terms used to describe the articles. Then, a second search will be conducted across all appropriate databases using all identified keywords and index terms. Then, a third search of the reference lists of all identified reports and articles will be done.
Studies published in any language will be considered for inclusion in this review.
Databases and repositories to be searched include PubMed, CINAHL, Scopus, BIOSIS, EMBASE, CancerLit, Science Direct, Web of Science, International Congress on Complementary Medicine Research, American Society of Clinical Oncology, MedNar, Cochrane Central Register of Controlled Trials, WHO register of trials, http://www.clinicaltrials.gov and http://www.controlled-trials.com. Australian National University Digital Theses, Open Access Theses and Dissertations and ProQuest Dissertations and Theses.
The following keywords/terms will be used for the initial search:
cancer/tumour/tumor/neoplasm/carcinoma/malignan*/breast/mammary/breast cancer/breast tumour/breast tumor, AND
coenzyme Q10/co-enzyme Q10/coQ10/CoQ 10/vitamin 10/ubiquinol/ubiquinone/ubiquinone Q10/ubiquinone 50/ubidecarenone/2,3-dimethoxy-5-methyl-6-decaprenylbenzoquinone/Q-ter/ubisemiquinone/ ubisemiquinone radical/Bio-Quinone Q10/coenzyme Q10, isomer/coenzyme Q10, ion (1-), (all E)-isomer
Studies identified by the search will be considered against the inclusion criteria. Those that match the criteria will undergo methodological quality assessment. Those that do not match the inclusion criteria will be excluded.
Assessment of methodological quality
Titles and abstracts of studies identified during the search process will be screened by the primary reviewer. Articles selected for retrieval based on title and abstract will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standard critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.
Data collection
Quantitative data will be extracted from papers included in this review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. The information collected will include the following:
* Methods: study design, methods of allocation, allocation concealment, blinding, dropout rates from studies and reasons for dropping out.
* Participants: country of origin, setting, sample size, diagnosis, age, ethnicity.
* Intervention: type, program length, frequency, duration (for experimental and comparator interventions).
* Outcomes: type of outcomes, assessment instruments, assessment time point and follow-up time point.
Data synthesis
Data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratios (for categorical or dichotomous data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
Conflicts of interest
None.
Acknowledgements
As this systematic review forms partial submission for the degree award of Masters of Clinical Science through the University of Adelaide, a secondary reviewer (Ms Dagmara Riitano) will be used for critical appraisal of literature considered for inclusion in the review.
The primary reviewer wishes to thank the University of Adelaide and the Joanna Briggs Institute for this opportunity to extend her skill-base and do such interesting research. She also wishes to thank Associate Professor Edoardo Aromataris for previous supervision.
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Appendix I - Critical Appraisal instruments
MAStARI appraisal instruments[Context Link]
Appendix II: Data extraction instruments[Context Link]
Keywords: Complementary; adjunct; CoQ10; ubiquinone; ubiquinol; mammary carcinoma