Integrative Cancer Therapies

Research Progress of Traditional Chinese Medicine Monomer Inhibiting Metastatic Colonization of Ovarian Cancer Cells Based on Cell Biology

Ovarian cancer, a frequently occurring gynecological malignancy with a poor prognosis and a 5-year survival rate below 45%, often progresses due to metastatic colonization. This review highlights the potential of traditional Chinese medicine (TCM) monomers as anticancer agents that inhibit the metastatic colonization of ovarian cancer cells. TCM monomers exhibit various mechanisms of action, including (1) inhibiting epithelial-to-mesenchymal transformation by modulating cell adhesion molecules; (2) reducing extracellular matrix damage through inhibition of degrading enzymes; (3) affecting cytoskeletal dynamics to alter cell movement; and (4) preventing angiogenesis by downregulating angiogenic factors. Additionally, TCM monomers can reshape the tumor microenvironment, enhance immune responses, and induce oxidative stress, resulting in reduced proliferation and survival of cancer cells. The comprehensive action of TCM monomers makes them promising candidates for individualized, multi-target therapies in drug-resistant cases. This paper reviews the current research on the mechanisms through which TCM monomers combat metastatic colonization, aiming to provide insights for future studies and clinical applications in ovarian cancer treatment, ultimately offering hope to affected patients.

Effectiveness of the Traditional Japanese Medicine Goshajinkigan in Preventing Paclitaxel-Induced Peripheral Neuropathy: A Multicenter Randomized Comparative Trial

Objective: Development of chemotherapy-induced peripheral neuropathy (CIPN) poses significant challenges in cancer treatment, often leading to dose reductions or treatment discontinuation. Goshajinkigan (GJG), a traditional Japanese medicine, has shown promise for alleviating CIPN symptoms. This multicenter, randomized controlled trial aimed to prospectively examine the efficacy of GJG in preventing paclitaxel-induced peripheral neuropathy. Methods: This study enrolled 55 patients with ovarian cancer undergoing first-line chemotherapy using paclitaxel and carboplatin. The participants were randomized into Groups A (GJG initiation after onset of grade 2 neuropathy) and B (prophylactic administration of GJG from 1 week before chemotherapy). The primary endpoints were the proportion with a maximum sensory neuropathy grade and visual analog scale (VAS) scores. The secondary endpoints were the rate of chemotherapy completion and paclitaxel dose reduction due to neurotoxicity. Results: Prophylactic GJG administration (Group B) resulted in significant benefits. While both groups had a similar incidence of grade 2 sensory neuropathy, all patients in Group B with grade 2 neuropathy completed treatment without requiring additional analgesics. Group B exhibited lower VAS scores by the end of the study, reduced reliance on adjuvant analgesics (27.3% vs 66.7% in Group A), and significantly less frequent persistent CIPN 6 months post-chemotherapy (18.2% vs 55.6% in Group A). No differences were observed in the chemotherapy completion rates or CIPN-related changes between the groups. Conclusion: GJG, when administered prophylactically, showed potential for mitigating CIPN symptoms during paclitaxel chemotherapy. While promising, further research with placebo controls and objective measures is essential to comprehensively validate these findings.

ENhAncing Lifestyle Behaviors in EndometriaL CancEr (ENABLE): A Pilot Randomized Controlled Trial

Purpose: Endometrial cancer is associated with the highest comorbid disease burden of any cancer. The aim of this trial was to assess the feasibility and safety of an allied health intervention during adjuvant treatment. Methods: A mixed-methods pilot randomized (2:1) controlled trial with concealed allocation and assessor-blinding. Eligibility criteria: adjuvant endometrial cancer treatment scheduled, disease stage I-IIIC1, ECOG 0-2 and able to perform unsupervised physical activity (PA). Participants received usual care and 8 sessions of weekly, individualized, lifestyle education (diet and PA) with behavior change and social support (intervention group), delivered predominantly by telehealth, or usual care alone. Feasibility outcomes: recruitment and consent rates, decline reasons, program acceptability, intervention adherence and retention. Results: 22/44 eligible patients (50%, 95%CI: 36%, 64%) were recruited over 10 months (14 intervention, 8 usual care). The recruitment rate was 2.2 patients/month (95%CI: 1.4, 3.3). Patients who declined had too much going on (7/22, 32%) or were not interested (6/22, 27%). Mean (SD) age and BMI were 63.2 years (6.8) and 31.9 kg/m2 (6.7). A majority were FIGO stage I (15/22, 68%) and received vaginal brachytherapy (14/22, 64%). Adherence was high, 11/14 (79%, 95%CI: 52%, 92%) participants attended >70% of scheduled sessions. Retention was 100% (95%CI: 85%, 100%) at 9 weeks, however completion of objective measures was impacted by COVID-19 restrictions. Telehealth and online questionnaires enabled participation. No serious adverse events occurred. Conclusion: The intervention was acceptable to participants with high levels of adherence and retention. Trial findings will be used to design a future RCT. Trial registration: The trial was registered on www.anzctr.org.au (ACTRN12619000631101) 29/04/2019.

Feasibility of Measuring Context Specific Sedentary Behavior and Pulse Wave Velocity in Endometrial Cancer Survivors

Purpose: Sedentary behavior (SB) contributes to the heightened risk of cardiovascular disease (CVD) in endometrial cancer survivors (ECS). This feasibility study aimed to evaluate key outcomes to assess the practicality of SB reduction interventions for ECS. Secondary aims included SB domain assessment and preliminary efficacy testing of the relationship between SB and arterial stiffness. Methods: Forty stage-1 ECS (BMI ≥ 25.0 kg/m², aged 50-80, <12 months post-treatment) participated in the study, which measured total and domain-specific SB using accelerometry and ecological momentary assessment (EMA). Aortic pulse wave velocity (PWV) was estimated via Mobil-O-Graph, and linear regression models examined the association between SB and PWV. Results: The study achieved 4 of 5 assessed outcomes, with a 63% consent rate in 10 months. Retention was high, with 90% of participants completing all aspects. Fidelity was strong, though EMA compliance was 69%, slightly below the 70% target. Self-reported SB was 71.4% lower than accelerometer-measured SB [MD: −5.00 hours/day (95% CI: −6.57 to −3.43), P  < .001]. ECS exhibited a PWV of 9.04 ± 1.80 m/s, 13.4% higher than normative values, with occupational SB significantly associated with PWV. Conclusions: This study highlights high SB and PWV levels in ECS, indicating the need for interventions, particularly for occupational SB. The high retention and consent rates suggest ECS are willing to engage in behavior change, pointing to future research focusing on strategies to reduce SB and improve cardiovascular health.

Metabolic Effects of Healing Touch During Cervical Cancer Treatment: An Exploratory Analysis

Introduction: Cancer treatment with chemotherapy frequently leads to side effects such as fatigue, pain, nausea, and anxiety. Healing Touch is a non-invasive complementary therapy often used by cancer patients to address side effects of treatment. To better inform the use of complementary therapies, there is a need to understand the biological mechanisms underlying the effects of such treatments. Methods: This study included 44 patients with cervical cancer undergoing chemoradiation randomized into a Healing Touch (HT), a relaxation training (RT) and a usual care (UC) group. An exploratory metabolomics analysis was conducted on plasma samples taken at baseline, 4, and 6 weeks of ongoing treatment (4 sessions per week). Results: A multivariate data analysis revealed no significant separation in metabolites between the 3 groups. Univariate data analysis revealed changes in metabolites between baseline and week 6 within each group. The main findings were lower levels of acylcarnitines, bile acids and proline in the HT group, higher levels of fatty acids in the HT and RT groups, and lower levels of kynurenine and quinolate in the UC group. The network of correlations between metabolites shows clear differences in correlations between steroids, fatty acids, sphyngomyelins, amino acids, and γ glutamyl peptides between the 3 groups, suggesting a more flexible and resilient metabolism in the HT and RT groups compared with UC. Conclusion: This first exploratory study investigating metabolic effects of Healing Touch in cancer patients indicated suggestive differences in metabolic signatures which need further investigation in a larger study.

Efficacy of Rikkunshito on Chemotherapy-Induced Nausea and Vomiting in Patients With Uterine Corpus or Cervical Cancer Treated With Cisplatin-Based Regimen-Placebo-controlled, Double-Blind, Randomized Confirmatory Study (JORTC-KMP03)

Background: The current standard treatment for chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics is insufficient. Rikkunshito, a Japanese traditional herbal medicine, has been shown to improve cisplatin-induced anorexia and functional dyspepsia, and our exploratory study found that rikkunshito has an additive beneficial effect on CINV in patients with uterine corpus and cervical cancer receiving cisplatin containing chemotherapy (JORTC KMP-02). Methods: One hundred eighty patients with uterine corpus or cervical cancer who were scheduled to receive treatment with a cisplatin based regimen as initial chemotherapy were enrolled across 17 Japanese institutions. Patients were randomized with a 1:1 equal allocation ratio to the rikkunshito group or placebo groups and given oral administration on days 1 to 5 with standard antiemetics (granisetron, aprepitant, and dexamethasone). The primary endpoint was complete response (CR; no vomiting or rescue medication) during the delayed phase (24-120 hours after cisplatin treatment). The secondary endpoints were complete control (CC; CR without significant nausea) and total control (TC; CR without nausea) rates during the overall (0-120 hours), acute (0-24 hours), and delayed phases, as well as the CR rate during the overall and acute phases, time to treatment failure, degree of nausea and appetite during the overall phase, and adherence to the intervention. Results: The CR rate in the delayed phase was similar between the rikkunshito group and control groups (50.6% vs 58.9%, P  = .2631), as were the secondary endpoints: CR rates in the overall and acute phases, CC and TC rates in the overall, acute, and delayed phases, degrees of nausea and appetite, and time to treatment failure. Conclusion: Rikkunshito had no additive effect on CINV prevention in patients with uterine corpus or cervical cancer who were treated with a cisplatin based regimen and standard antiemetics. Clinical Trial Registration: https://jrct.mhlw.go.jp/re/reports/detail/66957 , identifier jRCT1011190007

Effect of Zingiber Officinale in the Management of Nausea and Vomiting Induced by Treatment With Cisplatin Associated With Radiotherapy: A Randomized Controlled Trial

Objective: evaluate the efficacy of Zingiber Officinale in the management of nausea and vomiting induced by treatment with cisplatin associated with radiotherapy in patients with uterine cervical neoplasms. Methods: a triple-blind, randomized, placebo-controlled trial. Interventions: Comparing the effects of ginger with institutional antiemetic therapy (ondansetron with dexamethasone). Patients with cervical cancer who started treatment with cisplatin with an indication of 40 mg/m² associated with radiotherapy, aged over 18 years, and with the ability to tolerate swallowing a capsule were recruited and equally allocated (1:1:1) into 3 groups of 16 patients each (the ginger capsules 250 mg group, ginger capsules 500 mg group, and placebo group). Nausea and vomiting were measured on baseline, 7 days after the first dose of medication and every seven consecutive days during a treatment break. Results: The 250 mg ginger group had an 8.0% greater chance of experiencing nausea within 24 h after the chemotherapy infusion than the placebo group, although there is no statistical significance ( P = .92986). The 500 mg ginger group showed a 63.9% reduction in nausea under the same conditions ( P = .40460). No change was detected in the occurrence of nausea episodes during the 6 weeks ( P = .8664) or between the groups ( P = .2817). No change was detected in acute or late vomiting during the 6 weeks ( P = .3510) or between the groups ( P = .8500 and P = .5389, respectively). Conclusion: Ginger supplementation does not reduce the intensity of acute and late nausea and vomiting. REBEC (RBR-47yx6p9).

Hydroethanolic Extracts of the Aristotelia Chilensis (Maqui) Berry Reduces Cellular Viability and Invasiveness in the Endometrial Cancer Cell Line Ishikawa

Cancer of the reproductive tract includes diseases with higher prevalence in the female population. This investigation examined whether an anthocyanin-enriched extract of Aristotelia chilensis, commonly known as “maqui,” could affect some hallmarks of endometrial cancer. Cultures of the human endometrial cancer cell line Ishikawa were treated with a hydroethanolic maqui extract at 1, 3, 10, 30, 100, 300, or 1000 µg/mL to determine the effect on cell viability by MTT assay. Then, we used the 50% Effective Concentration (EC50) to evaluate whether the effect of the maqui extract is mediated via an arrest of the cell cycle or induction of apoptosis using flow cytometry or Annexin V-FITC assays, respectively. The effects of sublethal doses of the maqui extract on migration and invasiveness of Ishikawa cells were also evaluated by the wound healing and Boyden Chamber assay, respectively. Our results show that the hydroethanolic maqui extract inhibits the cell viability with an EC50 of 472.3 µg/mL via increased apoptosis, and that reduces the invasive capacity but not migration of Ishikawa cells. These findings suggest that the hydroethanolic maqui extract has antineoplastic properties for endometrial cancer and merits further studies to corroborate its efficiency as anticancer therapy in reproductive organs.

Inhibitory Effects of Digoxin and Digitoxin on Cell Growth in Human Ovarian Cancer Cell Line SKOV-3

Background: Cardiac glycosides (CGs) possess a chemical structure similar to steroids, and are inhibitors of the sodium potassium pump. An anti-tumor effect of CGs in breast and prostate cancers has been reported, but the effect of CGs on ovarian cancer is still unclear. Aims: In this study, the effects of CGs on proliferation, cytotoxicity and cell cycle of ovarian cancer cell line (SKOV-3) have been investigated. Procedure: The cell proliferation and cytotoxicity were detected by MTT assay and LDH activity assay, respectively. CGs, at concentrations higher than IC50, decreased cell proliferation and showed increased cytotoxicity toward SKOV-3 cells. The colony-formation ability was reduced after treatment with digoxin and digitoxin for 10 days. Furthermore, we explored the effect of digoxin and digitoxin on the distribution of cell cycle by flow cytometry. Results: Results revealed that both digoxin and digitoxin led to cell cycle arrest in G0/G1 phase with 24 or 48 hours, but the arrest of G0/G1 phase was not observed at 72 hours. We evaluated the percentage of hypodiploid cell population as an index of the cellular fragments through flow cytometry. The data indicated that cellular fragments were significantly increased by treating with digitoxin at the concentrations of IC50 and 10−6 M for 72 hours. Conclusion: Taken together, these data suggest that CGs decreased cell proliferation and increased cytotoxicity through cell cycle arrest at the G0/G1 phase. CGs have anti-tumor effect in SKOV-3 cells and might be a potential therapeutic drug for ovarian cancer. Since this study is a preliminary investigation of CGs on SKOV-3 cells, more experiments might be performed in the future. Furthermore, more ovarian cancer cell lines might also be employed in the future studies to confirm the effect of CGs in ovarian cancer.

Mindfulness-Based Interventions in Recurrent Ovarian Cancer: A Mixed-Methods Feasibility Study

A recurrence of cancer is a traumatic and stressful experience, and a number of approaches have been proposed to manage or treat the associated psychological distress. Meditative techniques such as mindfulness may be able to improve an individual’s ability to cope with stressful life events such as cancer diagnosis or treatment. This single-arm mixed-methods study primarily aimed to determine the feasibility of using a mindfulness-based intervention in managing psychosocial distress in recurrent ovarian cancer. Twenty-eight participants took part in a mindfulness-based program, involving six group sessions, each lasting 1.5 hours and delivered at weekly intervals. The study found that the mindfulness-based intervention was acceptable to women with recurrent ovarian cancer and feasible to deliver within a standard cancer care pathway in a UK hospital setting. The results suggested a positive impact on symptoms of depression and anxiety, but further study is needed to explore the effectiveness of the intervention.

A Novel Approach of Intraneural Facilitation Versus Standard Physical Therapy for the Prevention of Chemotherapy-Induced Peripheral Neuropathy: A Randomized Controlled Trial

This study compared Intraneural Facilitation (INF ® ) therapy and standard physical therapy (PT) in preventing chemotherapy-induced peripheral neuropathy (CIPN) in women with newly diagnosed breast and gynecologic cancer. Thirty-eight women undergoing platinum and/or taxane-based chemotherapy, without prior peripheral neuropathy, were randomized into INF ® therapy (n = 20) and PT (n = 18). Treatments lasted 45 minutes, twice weekly, for 6 weeks. Neuropathy severity was evaluated using the Pain Quality Assessment Scale. Assessments were at baseline, 3 weeks, 6 weeks, and 3 months post-intervention. Acceptability, burden, and satisfaction were evaluated after 6 weeks. Among 38 patients, 12 (32%) experienced CIPN, with mean pain scores remaining mild (≤3) and no pharmacotherapy required until week 6. No adverse events were reported from the interventions. The INF ® therapy arm showed significant changes in numbness ( F  = 6.030, P  = .001, partial η 2  = 0.262) after week 6, while the PT arm showed significant changes in numbness ( Z  = −2.39, P  = .017), tingling ( Z  = −2.84, P  = .004), cramping ( Z  = −2.120, P  = .034), surface pain ( Z  = −2.75, P  = .006), and deep pain ( Z  = −1.99, P  = .046) between weeks 3 and 6. Nearly 80% of patients completed chemotherapy cycles with an average relative dose intensity of 90.4% (INF ® therapy: 87.73% vs PT: 73.44%). Ninety-four percent of patients were satisfied with their care, accepted the treatments, and perceived them as a low burden. The results demonstrated that INF ® therapy and PT are feasible options for CIPN, improving treatment adherence, outcomes, and quality of life for women with newly diagnosed breast and gynecological cancers. Trial Registration - The study was pre-registered on ClinicalTrials.gov (NCT03272919). August 8, 2017.

Enhancement of Conventional and Photodynamic Therapy for Treatment of Cervical Cancer with Cannabidiol

Cervical cancer (CC) is the fourth most diagnosed cancer in women worldwide. Conventional treatments include surgery, chemo- and radiotherapy, however these are invasive and may cause severe side effects. Furthermore, approximately 70% of late-stage CC patients experience metastasis, due to treatment resistance and limitations. Thus, there is a dire need to investigate alternative therapeutic combination therapies. Photodynamic therapy (PDT) is an alternative CC treatment modality that has been clinically proven to treat primary CC, as well as to limit secondary metastasis. Since PDT is a non-invasive localized treatment, with fewer side effects and lessened resistance to dose repeats, it is considered far more advantageous. However, more clinical trials are required to refine its delivery and dosing, as well as improve its ability to activate specific immune responses to eradicate secondary CC spread. Cannabidiol (CBD) isolates have been shown to exert in vitro CC anticancer effects, causing apoptosis post treatment, as well as inducing specific immune responses, which obstruct tumor invasion and angiogenesis, and so hinder CC metastatic spread. This review paper discusses the current conventional and alternative PDT treatment modalities for CC, as well as their limitations over the last 10 years. It has a particular focus on the combinative administration of CBD with these treatments in order to prevent CC secondary migration and so possibly encourage future research studies to focus on this synergistic effect to eradicate CC.

Extracts of the Medicinal Plants Pao Pereira and Rauwolfia vomitoria Inhibit Ovarian Cancer Stem Cells In Vitro

Ovarian cancer has an enrichment of cancer stem cells (CSCs) which contribute to the treatment resistant tumor’s high rate of recurrence and metastasis. Here we investigated 2 plant extracts from the medicinal plants Pao Pereira (Pao) and Rauwolfia vomitoria (Rau) each for their activities against ovarian CSCs. Both Pao and Rau inhibited overall proliferation of human ovarian cancer cell lines with IC50 ranging from 210 to 420 μg/mL and had limited cytotoxicity to normal epithelial cells. Ovarian CSC population was examined using cell surface markers and tumor spheroid formation assays. The results showed that both Pao and Rau treatment significantly reduced the ovarian CSC population. Pao and Rau had similar activities in inhibiting ovarian CSCs, with IC50s of ~120 μg/mL for 24 hours treatment, and ~50 μg/mL for long-term tumor spheroid formation. Nuclear β-catenin levels were decreased, suggesting suppression of Wnt/β-catenin signaling pathway. Taken together, data here showed that Pao and Rau both inhibited ovarian cancer stem cells, probably in preference to the bulk of tumor cells. Further mechanistic studies and in vivo investigation validating these findings are warranted, given that inhibition of cancer stem cells holds the promise of comprehensively inhibiting cancer metastasis, drug resistance and recurrence.

Effects of Vigorous Versus Restorative Yoga Practice on Objective Cognition Functions in Sedentary Breast and Ovarian Cancer Survivors: A Randomized Controlled Pilot Trial

Purpose: Many cancer survivors experience cancer-related cognitive impairment (CRCI). We conducted a randomized controlled pilot trial of 2 types of yoga practice and evaluated their effects on participants’ objective cognitive function. Methods: Sedentary breast or ovarian cancer survivors were randomized to practice either restorative yoga (with more meditative practice and minimal physical exertion) or vigorous yoga (with considerable physical exertion and minimal meditative practice) in 60-minute supervised sessions 3 times a week for 12 weeks, followed by 12 weeks of home practice. We used the NIH Toolbox Cognition Domain to evaluate participants at baseline, week 12, and week 24. Results: We enrolled 35 participants. For women in the restorative yoga group, overall cognitive function was statistically significantly improved at weeks 12 and 24 compared to baseline ( P = .03 and 0.004; Cohen’s D = 0.3 and 0.5). Fluid cognitive function also significantly improved at weeks 12 and 24 ( P = .02 and 0.0007; Cohen’s D = 0.3 and 0.6), whereas improvements in crystallized cognition were not significant. For women in the vigorous yoga group, significant improvement was only seen in tasks of crystallized cognition at week 24 ( P = .03; Cohen’s D = 0.5). Between-group comparisons showed that at week 24, women in the restorative yoga group had significantly higher scores on fluid cognition tasks. Conclusions: Patients who participated in yoga practice demonstrated improvement in objective cognitive function over time. Restorative yoga may be more effective in improving fluid cognitive function at week 24 when compared to vigorous yoga. These promising findings should be confirmed in definitive studies. Trial registration: Clinicaltrials.gov; NCT02305498 (Date Registered: December 2, 2014)

Adjunctive Chinese Herbal Medicine Treatment is Associated With an Improved Survival Rate in Patients With Cervical Cancer in Taiwan: A Matched Cohort Study

Background Cervical cancer is one of the most common cancers in Taiwan. Some patients take Chinese herbal medicine (CHM). However, very few current studies have ascertained the usage and efficacy of CHM in patients with cervical cancer. The aim of this study was to investigate the benefits of complementary CHM among patients with cervical cancer in Taiwan. Methods We included the newly diagnosed cervical cancer patients who were registered in the Taiwanese Registry for Catastrophic Illness Patients Database between 2000 and 2010. The end of follow-up period was December 31, 2011. Patients who were less than 20 years old, had missing information for age, withdrew from the National Health Insurance (NHI) program during the follow-up period, or only received other TCM interventions such as acupuncture or tuina massage were excluded from our study. After performing 1:1 frequency matching by age and index date, we enrolled 7521 patients in both CHM and non-CHM user groups. A Cox regression model was used to compare the hazard ratios (HRs) of the risk of mortality. The Kaplan-Meier curve was used to compare the difference in survival time. Results According to the Cox hazard ratio model mutually adjusted for CHM use, age, comorbidity, treatment, and chemotherapeutic agents used, we found that CHM users had a lower hazard ratio of mortality risk (adjusted HR = 0.29, 95%CI = 0.27-0.31). The survival probability was higher for patients in the CHM group. Bai-Hua-She-She-Cao ( Herba Oldenlandiae, synonym Herba Hedyotis diffusae) and Jia-Wei-Xiao-Yao-San were the most commonly prescribed single herb and Chinese herbal formula, respectively. Conclusions Adjunctive CHM may have positive effects of reducing mortality rate and improving the survival probability for cervical cancer patients. Further evidence-based pharmacological investigations and clinical trials are warranted to confirm the findings in our study.