Phase 2 Study of Acupuncture-Like Transcutaneous Nerve Stimulation for Chemotherapy-Induced Peripheral Neuropathy.

A prospective phase 2 study was conducted to evaluate the clinical utility of acupuncture-like transcutaneous nerve stimulation (ALTENS) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Eligible cancer patients had a < 2 ECOG performance score, received neurotoxic chemotherapy, and developed CIPN symptoms for > two months. Randomization was used to eliminate bias in patient selection for ALTENS and was not to compare the effectiveness between the two treatments.ALTENS treatments were delivered using Codetron units. Bilateral acupuncture points included LI4 and LIV3, plus LI11 or ST36 were stimulated. Acupuncture treatments were administered to CV6, SP6, ST6, LI11, Bafeng, Baxie and selective Jing points bilaterally. Twelve treatments were delivered twice weekly over 6 to 8 weeks. The Modified Total Neuropathy Score (mTNS), Numbness Score, and Edmonton Symptom Assessment Score (ESAS) were assessed at baseline, treatment completion, plus at 3 and 6 months follow-up. The primary study endpoint was mTNS score at 6 months. We planned to recruit 23 patients into each group. After 30 patients were recruited, 2 were lost to follow-up at 3 months in the ALTENS group and 3 in the acupuncture group. The research team decided to recruit all remaining consecutive patients only to the ALTENS group to ensure an adequate evaluation of ALTENS, the primary object of evaluation. There were 27 patients in the ALTENS group, with an average symptom duration of 10 months after chemotherapy. Twenty four and 23 patients completed the 3 and 6 month follow-up respectively. The median mTNS scores were 7.1, 4.0, 3.6 and 3.1 at baseline, treatment completion, 3 and 6 months follow-up, respectively. One-way ANOVA analysis showed a significant improvement in mTNS scores (p<0.001) at 6 months. Numbness scores were also significantly improved at 6 months. ESAS pain scores and perception of well-being scores analyses were inconclusive. There were no significant reported side effects of ALTENS. There were only 13 patients in the acupuncture group and the number was insufficient for either an independent or a comparative analysis. The results of this study suggests that ALTENS significantly reduces the mTNS scores and numbness in patients suffering from CIPN symptoms.

Xerostomia health-related quality of life: NRG oncology RTOG 0537.

PURPOSE: The purpose of this secondary analysis was to determine change in overall health-related quality of life (HRQOL) based on patient data obtained from NRG Oncology RTOG 0537 as measured by the RTOG-modified University of Washington Head and Neck Symptom Score (RM-UWHNSS). METHODS: A multi-site prospective randomized clinical trial design stratified 137 patients with post-radiation therapy xerostomia according to prior pilocarpine (PC) treatment and time after radiation therapy and/or chemotherapy and randomized patients into two groups. Patients were assigned to acupuncture or PC. Twenty-four sessions of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) were administered over 12 weeks, or oral PC (5 mg) three times daily over the same 12 weeks. The RM-UWHNSS was administered at baseline and at 4, 6, 9, and 15 months after the date of randomization. RESULTS: There were no between-arm differences in change scores on the RM-UWHNSS in the individual items, total score, or factor scores. For statistical modeling, race and time were significant for all outcomes (total and factor scores), while treatment arm was not significant. The ALTENS arm showed greater yet nonsignificant improvement in outcomes compared to the PC arm. CONCLUSION: Although no significant treatment differences were seen in this trial, patients receiving ALTENS consistently had lower scores, indicating better function, as compared to those receiving PC. Radiation-induced xerostomia improved over time for all patients.

Acupuncture-Like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Radiation-Induced Xerostomia: Results of RTOG 0537 Phase 3 Study.

PURPOSE AND OBJECTIVES: This report presents the analysis of the RTOG 0537 multicenter randomized study that compared acupuncture-like transcutaneous stimulation (ALTENS) with pilocarpine (PC) for relieving radiation-induced xerostomia. METHODS AND MATERIALS: Eligible patients were randomized to twice-weekly 20-minute ALTENS sessions for 24 sessions during 12 weeks or PC (5 mg 3 times daily for 12 weeks). The primary endpoint was the change in the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) scores from baseline to 9 months from randomization (MFR). Secondary endpoints included basal and citric acid primed whole salivary production (WSP), ratios of positive responders (defined as patients with ≥20% reduction in overall radiation-induced xerostomia symptom burden), and the presence of adverse events based on the Common Terminology Criteria for Adverse Events version 3. An intention-to-treat analysis was conducted. RESULTS: One hundred forty-eight patients were randomized. Only 96 patients completed the required XeQOLS and were evaluable at 9 MFR (representing merely 68.6% statistical power). Seventy-six patients were evaluable at 15 MFR. The median change in the overall XeQOLS in ALTENS and PC groups at 9 and 15 MFR were -0.53 and -0.27 (P=.45) and -0.6 and -0.47 (P=.21). The corresponding percentages of positive responders were 81% and 72% (P=.34) and 83% and 63% (P=.04). Changes in WSP were not significantly different between the groups. Grade 3 or less adverse events, mostly consisting of grade 1, developed in 20.8% of patients in the ALTENS group and in 61.6% of the PC group. CONCLUSIONS: The observed effect size was smaller than hypothesized, and statistical power was limited because only 96 of the recruited 148 patients were evaluable. The primary endpoint-the change in radiation-induced xerostomia symptom burden at 9 MFR-was not significantly different between the ALTENS and PC groups. There was significantly less toxicity in patients receiving ALTENS.

Patient-centered care in cancer treatment programs: the future of integrative oncology through psychoeducation.

The reciprocal relationship between the mind and body has been a neglected process for improving the psychosocial care of cancer patients. Emotions form an important link between the mind and body. They play a fundamental role in the cognitive functions of decision-making and symptom control. Recognizing this relationship is important for integrative oncology. We define psychoeducation as the teaching of self-evaluation and self-regulation of the mind-body process. A gap exists between research evidence and implementation into clinical practice. The patients' search for self-empowerment through the pursuit of complementary therapies may be a surrogate for inadequate psychoeducation. Integrative oncology programs should implement psychoeducation that helps patients to improve both emotional and cognitive intelligence, enabling them to better negotiate cancer treatment systems.

Black cohosh and breast cancer: a systematic review.

BACKGROUND: Many women use black cohosh as a natural treatment for menopausal symptoms. However, controversy exists around safety in breast cancer, because of its purported estrogenic activity. We conducted a systematic review of black cohosh use in women with or at risk of breast cancer. METHODS: We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to July 2012 and October 2012 for human interventional or observational data pertaining to the safety and efficacy of black cohosh in patients with or at risk of breast cancer, including an assessment of the effect of black cohosh on estrogen responsive tissues. RESULTS: Of 450 records, we included 26 articles: 14 randomized controlled trials, 7 uncontrolled trials, and 5 observational studies.The evidence on efficacy for ho t flashes is divided, with some benefits seen when compared with baseline, but not when compared with placebo. Two observational studies found no association between black cohosh and risk of breast cancer, whereas 2 studies reported significant reductions in risk of primary breast cancer among postmenopausal women (adjusted odds ratio = 0.47, 95% confidence interval = 0.27-0.82), and risk of recurrence (adjusted hazard ratio = 0.75, 95% confidence interval = 0.63-0.89). Seventeen trials showed no significant impact on circulating hormone levels or proliferation in estrogen responsive tissues. CONCLUSIONS: Current evidence does not support an association between black cohosh and increased risk of breast cancer. There is a lack of evidence supporting the efficacy of black cohosh for reduction of hot flashes in breast cancer patients. Given conflicting but promising results, and apparent safety, further research is warranted.

Flax and Breast Cancer: A Systematic Review.

BACKGROUND: Flax is a food and dietary supplement commonly used for menopausal symptoms. Flax is known for its lignan, α-linolenic acid, and fiber content, components that may possess phytogestrogenic, anti-inflammatory, and hormone modulating effects, respectively. We conducted a systematic review of flax for efficacy in improving menopausal symptoms in women living with breast cancer and for potential impact on risk of breast cancer incidence or recurrence. METHODS: We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to January 2013 for human interventional or observational data pertaining to flax and breast cancer. RESULTS: Of 1892 records, we included a total of 10 studies: 2 randomized controlled trials, 2 uncontrolled trials, 1 biomarker study, and 5 observational studies. Nonsignificant (NS) decreases in hot flash symptomatology were seen with flax ingestion (7.5 g/d). Flax (25 g/d) increased tumor apoptotic index (P< .05) and decreased HER2 expression (P< .05) and cell proliferation (Ki-67 index; NS) among newly diagnosed breast cancer patients when compared with placebo. Uncontrolled and biomarker studies suggest beneficial effects on hot flashes, cell proliferation, atypical cytomorphology, and mammographic density, as well as possible anti-angiogenic activity at doses of 25 g ground flax or 50 mg secoisolariciresinol diglycoside daily. Observational data suggests associations between flax and decreased risk of primary breast cancer (adjusted odds ratio [AOR] = 0.82; 95% confidence interval [CI] = 0.69-0.97), better mental health (AOR = 1.76; 95% CI = 1.05-2.94), and lower mortality (multivariate hazard ratio = 0.69; 95% CI = 0.50-0.95) among breast cancer patients. CONCLUSIONS: Current evidence suggests that flax may be associated with decreased risk of breast cancer. Flax demonstrates antiproliferative effects in breast tissue of women at risk of breast cancer and may protect against primary breast cancer. Mortality risk may also be reduced among those living with breast cancer.

Soy, red clover, and isoflavones and breast cancer: a systematic review.

BACKGROUND: Soy and red clover isoflavones are controversial due to purported estrogenic activity and possible effects on breast cancer. We conducted a systematic review of soy and red clover for efficacy in improving menopausal symptoms in women with breast cancer, and for potential impact on risk of breast cancer incidence or recurrence. METHODS: We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to March 2013 for human interventional or observational data pertaining to the safety and efficacy of soy and red clover isoflavones in patients with or at risk of breast cancer. RESULTS: Of 4179 records, we included a total of 131 articles: 40 RCTs, 11 uncontrolled trials, and 80 observational studies. Five RCTs reported on the efficacy of soy for hot flashes, showing no significant reductions in hot flashes compared to placebo. There is lack of evidence showing harm from use of soy with respect to risk of breast cancer or recurrence, based on long term observational data. Soy intake consistent with that of a traditional Japanese diet (2-3 servings daily, containing 25-50mg isoflavones) may be protective against breast cancer and recurrence. Human trials show that soy does not increase circulating estradiol or affect estrogen-responsive target tissues. Prospective data of soy use in women taking tamoxifen does not indicate increased risk of recurrence. Evidence on red clover is limited, however existing studies suggest that it may not possess breast cancer-promoting effects. CONCLUSION: Soy consumption may be associated with reduced risk of breast cancer incidence, recurrence, and mortality. Soy does not have estrogenic effects in humans. Soy intake consistent with a traditional Japanese diet appears safe for breast cancer survivors. While there is no clear evidence of harm, better evidence confirming safety is required before use of high dose (≥ 100 mg) isoflavones can be recommended for breast cancer patients.

Sweet bee venom pharmacopuncture for chemotherapy-induced peripheral neuropathy.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is sensory and motor nerve damage to the peripheral nervous system caused by chemotherapeutic agents. It often causes pain and other varying degrees of neuropathic symptoms accompanied by functional limitations and reduced quality of life. Currently, there is no standard treatment protocol for the treatment of CIPN. OBJECTIVE: In need of more research to develop new therapeutic options focusing on their safety, efficacy, and long-term sustained clinical effects, a pilot study of sweet bee venom pharmacopuncture (SBVP) for CIPN was conducted to build up preliminary efficacy data in the process of preparing for a future larger scale randomized controlled SBVP trial for CIPN. METHODS: We conducted a prospective case series by analyzing the clinical observations made of CIPN patients treated with SBVP. A total of 11 eligible consecutive CIPN patients who visited East-West Cancer Center from June 1, 2010, to February 28, 2011, were treated with total of six SBVP treatments given within the 3-week period. The outcomes were measured using World Health Organization Common Toxicity Criteria for Peripheral neuropathy (WHO grading system), Patient Neurotoxicity Questionnaire (PNQ), Visual Analogue System (VAS), and Health-Related Quality of Life (HRQOL) collected at the baseline, post-second, fourth, and the final treatment. Patients were followed 3 weeks into no intervention to determine the sustained effects of pharmacopuncture. RESULTS: Both of the WHO CIPN grade and PNQ scores have shown a decrease in the level of neuropathy. VAS pain level has also shown a great decrease and improvement in patients' quality of life have also been detected though modest. Changes in WHO grade, VAS and Total HRQOL scores between the baseline and after the last treatment session were significant. Changes in WHO grade, Total PNQ, PNQ-sensory, VAS, Total HRQOL, and HRQOL-functional scores between the baseline and the 3-week follow-up were significant. CONCLUSION: The positive result of the study supports the potential value of conducting a fully powered trial to explore further efficacy of SBVP for CIPN. However a single positive result within this pilot study must be interpreted with caution.

Phase 2 results from Radiation Therapy Oncology Group Study 0537: a phase 2/3 study comparing acupuncture-like transcutaneous electrical nerve stimulation versus pilocarpine in treating early radiation-induced xerostomia.

BACKGROUND: In this phase 2 component of a multi-institutional, phase 2/3, randomized trial, the authors assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. METHODS: Patients with cancer of the head and neck who were 3 to 24 months from completing radiotherapy with or without chemotherapy (RT ± C) and who were experiencing xerostomia symptoms with basal whole saliva production ≥0.1 mL per minute and were without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 sessions over 12 weeks) using a proprietary electrical stimulation unit. The primary study objective was to assess the feasibility of ALTENS treatment. Patients were considered compliant if 19 of 24 ALTENS sessions were delivered, and the targeted compliance rate was 85%. Secondary objectives measured treatment-related toxicities and the effect of ALTENS on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). RESULTS: Of 48 accrued patients, 47 were evaluable. The median age was 60 years, 84% of patients were men, 70% completed RT ± C for >12 months, and 21% had previously received pilocarpine. Thirty-four patients completed all 24 ALTENS sessions, 9 patients completed 20 to 23 sessions, and 1 patient completed 19 sessions, representing a 94% total compliance rate. Six-month XeQOLS scores were available for 35 patients and indicated that 30 patients (86%) achieved a positive treatment response with a mean ± standard deviation reduction of 35.9% ± 36.1%. Five patients developed grade 1 or 2 gastrointestinal toxicity, and 1 had a grade 1 pain event. CONCLUSIONS: The current results indicated that ALTENS treatment for radiation-induced xerostomia can be delivered uniformly in a cooperative, multicenter setting and produces possible beneficial treatment response. Given these results, the phase 3 component of this study was initiated.

Effects of sweet bee venom pharmacopuncture treatment for chemotherapy-induced peripheral neuropathy: a case series.

OBJECTIVE: This is a case series reporting safety and degree of response to 1 dose level of sweet bee venom pharmacopuncture (SBVP) or melittin as a symptom-control therapy for chemotherapy-induced peripheral neuropathy (CIPN). SETTING: All treatments were conducted at the East West Cancer Center (EWCC), Dunsan Oriental Hospital, Daejeon University, Republic of Korea, an institution that uses complementary therapies for cancer patients. METHODS: Five consecutive patients with CIPN were referred to the EWCC from March 20, 2010, to April 10, 2010. Patients with World Health Organization Chemotherapy-Induced Peripheral Neuropathy (WHO CIPN) grade 2 or more were treated with SBVP for 3 treatment sessions over a 1-week period. Measures of efficacy and safety. Validated Visual Analog System (VAS) pain scale, WHO CIPN grade, and Functional Assessment of Cancer Therapy-General (FACT-G) were compared before and after the 1-week course of treatment. To ensure the safety of SBVP, pretreatment skin response tests were given to patients to avoid any potential anaphylactic adverse effects. All patients were closely examined for any allergenic responses following each treatment session. RESULTS: One patient discontinued treatment after the first session, and 4 patients completed all treatment sessions. Using each patient as their own comparator, marked improvements of VAS, WHO CIPN grade, and physical section scores of FACT-G were seen in 3 patients. Most important, there were no related adverse side effects found. CONCLUSION: This safety results of the SBVP therapy merits further investigations in a larger size trial for it to develop into a potential intervention for managing CIPN symptoms. This study will be extended to a dose-response evaluation to further establish safety and response, prior to a randomized trial.

Systems modeling in integrative oncology.

Systems modeling provides an integrated framework to capture and analyze diverse and multidisciplinary data in a standardized manner. The authors present the Integrative Oncology Systems Model (IOSM) to help assess the impact of behavior modification and various therapeutic interventions on cancer development and progression and the resultant effect on survival and quality of life outcomes.

Selenium and lung cancer: a systematic review and meta analysis.

BACKGROUND: Selenium is a natural health product widely used in the treatment and prevention of lung cancers, but large chemoprevention trials have yielded conflicting results. We conducted a systematic review of selenium for lung cancers, and assessed potential interactions with conventional therapies. METHODS AND FINDINGS: Two independent reviewers searched six databases from inception to March 2009 for evidence pertaining to the safety and efficacy of selenium for lung cancers. Pubmed and EMBASE were searched to October 2009 for evidence on interactions with chemo- or radiation-therapy. In the efficacy analysis there were nine reports of five RCTs and two biomarker-based studies, 29 reports of 26 observational studies, and 41 preclinical studies. Fifteen human studies, one case report, and 36 preclinical studies were included in the interactions analysis. Based on available evidence, there appears to be a different chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status (serum<106 ng/mL), but increase risk of lung cancers in those with higher selenium (≥ 121.6 ng/mL). Pooling data from two trials yielded no impact to odds of lung cancer, OR 0.93 (95% confidence interval 0.61-1.43); other cancers that were the primary endpoints of these trials, OR 1.51 (95%CI 0.70-3.24); and all-cause-death, OR 0.93 (95%CI 0.79-1.10). In the treatment of lung cancers, selenium may reduce cisplatin-induced nephrotoxicity and side effects associated with radiation therapy. CONCLUSIONS: Selenium may be effective for lung cancer prevention among individuals with lower selenium status, but at present should not be used as a general strategy for lung cancer prevention. Although promising, more evidence on the ability of selenium to reduce cisplatin and radiation therapy toxicity is required to ensure that therapeutic efficacy is maintained before any broad clinical recommendations can be made in this context.

Phase II Randomized Trial of Acupuncture-Like Transcutaneous Electrical Nerve Stimulation to Prevent Radiation-Induced Xerostomia in Head and Neck Cancer Patients.

Current evidence indicates that acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) can provide sustained benefit for established radiation-induced xerostomia (RIX) symptoms. This is further being evaluated by comparing it with standard treatment (pilocarpine) in a randomized controlled trial. This report studies the potential effectiveness of xerostomia prevention using ALTENS delivered concomitantly with radiotherapy administered to head and neck cancer patients. Sixty patients were randomized to either the treatment group (n = 30) that received ALTENS daily with radiotherapy or the control group (n = 26) that had standard mouth care only. Stimulated and basal unstimulated whole saliva production (WSP) plus RIX symptoms visual analogue score (RIXVAS) were assessed at specific time points. Generalized linear models and generalized estimating equations were used for analysis. RIXVAS at 3 months follow-up after therapy completion was used as the primary study endpoint. The mean RIXVAS for the ALTENS intervention at 3 months was 39.8, which was not significantly different from the control arm value of 40.5. There were no statistically significant differences between the two groups for their mean RIXVAS and WSP at all assessment time points. In conclusion, there was no significant difference in mean WSP and RIXVAS between the two groups, so ALTENS is not recommended as a prophylactic intervention.

Can the therapeutic gain of radiotherapy be increased by concurrent administration of Asian botanicals?

Therapeutic gain by radiotherapy can be achieved through improved targeting, selectively sensitizing malignant cells, or protecting normal tissue. The majority of synthetic chemical radiation sensitizers and normal tissue protectors have proved to be too toxic at effective clinical doses. However, Asian botanicals (from both Chinese and Ayurvedic medicine) are being evaluated for their ability to improve therapeutic gain through the modulation of reactive oxygen species. An increase in the efficacy of radiotherapy on tumor tissue allows a reduction in the dose applied to normal tissues. In addition, some botanicals may selectively protect normal tissue or increase its repair following radiation therapy. The results are promising enough to consider clinical trials.

The role of integrative oncology in a tertiary prevention survivorship program.

OBJECTIVE: Since 64% of cancer patients survive more than 5 years beyond diagnosis, oncologists are challenged to expand their focus from acute care to managing the long-term health consequences of cancer treatment and ensuring the integration of cancer prevention into their practices. This review defines the cancer prevention role of integrative oncology as a key component in survivorship programs. METHODS: A narrative review consisting of the results of preclinical studies, randomized controlled trials and systematic reviews that may contribute to cancer prevention. RESULTS: Integrative oncology focuses on the complexities of health and proposes a multitude of approaches. Its categories are mind-body techniques, physical therapies, nutrition plus supplements, and botanicals or natural health products. Behavioral modification, through selected integrative oncology interventions may enhance cancer prevention. CONCLUSION: Opportunities exist for oncologists to promote lifestyle changes that improve patients' length and quality of life. Integrative oncology utilizes techniques for self-empowerment, individual responsibility, and lifestyle changes that could potentially reduce both cancer recurrence and second primary tumors. Education in the principles of integrative oncology and evidence-based complementary therapies is lacking. There is a need for studies on cost-utility and effectiveness of whole systems programs of integrative oncology for the tertiary prevention of cancer.

Acupuncture as an evidence-based option for symptom control in cancer patients.

OPINION STATEMENT: Current technology suggests that acupuncture modulates neurological processes within the central nervous system, especially the spinal cord gating mechanisms, cerebral subcortical nuclei, and the hypothalamic-endocrine axis. Many single arm clinical studies report the effectiveness of acupuncture for controlling symptoms in cancer patients. However, the challenge has been to separate the nonspecific effects of the practitioner, as well as regression to the mean, from the neurophysiological effects of needle penetration. Recently, randomized controlled trials have attempted to answer this question, with mixed results. For example, needle penetration (or equivalent stimulation) is effective for nausea and vomiting, whereas it does not appear to be a major factor in reducing hot flashes. Safety and quality are priorities, so regulation of the practice of acupuncture is important, as well as excellent communication between practitioners. In addition, continuing research is mandatory, using validated methodology and reporting principles as outlined in the CONSORT and STRICTA recommendations.

Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?

Despite nearly two decades of research investigating the use of dietary antioxidant supplementation during conventional chemotherapy and radiation therapy, controversy remains about the efficacy and safety of this complementary treatment. Several randomized clinical trials have demonstrated that the concurrent administration of antioxidants with chemotherapy or radiation therapy reduces treatment-related side effects. Some data indicate that antioxidants may protect tumor cells as well as healthy cells from oxidative damage generated by radiation therapy and some chemotherapeutic agents. However, other data suggest that antioxidants can protect normal tissues from chemotherapy- or radiation-induced damage without decreasing tumor control. We review some of the data regarding the putative benefits and potential risks of antioxidant supplementation concurrent with cytotoxic therapy. On the basis of our review of the published randomized clinical trials, we conclude that the use of supplemental antioxidants during chemotherapy and radiation therapy should be discouraged because of the possibility of tumor protection and reduced survival.