Day: 02/17/2023

Patient-Reported Outcome Measures in Chemotherapy-Induced Peripheral Neurotoxicity: Defining Minimal and Clinically Important Changes

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Background

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a debilitating adverse event of neurotoxic cancer treatments and is particularly prominent with taxanes, platinum-based agents, vinca-alkaloids, proteasome inhibitors, and immunomodulatory drugs. CIPN produces numbness, tingling, and pain in a length-dependent manner, affecting the hands and feet, and may result in functional impairments, such as difficulty with fine motor tasks, problems with balance, and increased falls risk,1 that can persist long term and negatively impact on health-related quality of life.2 There are currently no interventions established to prevent CIPN development, and the only treatment moderately recommended is duloxetine.3,4 Consequently, evaluating CIPN with a valid, reliable, and responsive outcome measure is critical in identifying early signs of nerve damage and effects of intervention aimed at preventing long-lasting or severe neurotoxicity.

There are numerous approaches to assessing CIPN, with patient-reported outcome measures (PROMs) recognized as valuable tools that provide a patient-based perspective essential to accurate assessment.5 Previously demonstrated discordance between patient- and clinician-reported CIPN6 suggests that PROMs may depict a broader spectrum of CIPN severity than clinician-based assessments,7 enabling better understanding of symptom manifestation and effects on function.8

A number of PROMs have been developed to assess CIPN9; the 2 most commonly used and extensively validated are the EORTC Quality of Life – Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20)10 and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity questionnaire (FACT/GOG-NTX).11 Previous studies have demonstrated that both PROMs are responsive in identifying change in CIPN symptoms over time.7,11–15 However, the utility of these PROMs remains limited due to the lack of guidelines regarding thresholds for identifying the development of clinically relevant and functionally significant CIPN.

Estimates of the smallest meaningful change in an outcome measure (termed the minimally important difference [MID]) enable clinicians and researchers to assess the clinical significance of changes in outcomes over time. CIPN PROMs are currently used in multiple research settings, including observational studies and clinical trials, without clear guidelines on how to interpret change in scores. MID estimates will aid and increase interpretability for CIPN PROMs by helping guide clinical judgement about whether and when change in CIPN symptoms has reached clinical relevance, facilitating routine use of CIPN PROMs as clinical trial outcome measures and in clinical practice. Although previous studies have attempted to estimate MIDs for the QLQ-CIPN20 and FACT/GOG-NTX,16,17 methodological constraints remain that may affect the reliability, clinical interpretability, and utility of these estimates.18 Consequently, this study aimed to estimate MIDs for the QLQ-CIPN20 and FACT/GOG-NTX to provide guidance for clinical threshold of CIPN development. Furthermore, thresholds for clinically significant CIPN were also estimated.

Methods

Patients and Study Design

Patients were recruited into a prospective longitudinal study at 2 hospitals in Sydney, Australia, from August 2015 to March 2021. Patients were eligible if they were scheduled to commence treatment with neurotoxic agents, including taxanes, platinums, vinca-alkaloids, proteasome inhibitors, or immunomodulatory drugs, and were recruited at treatment commencement. Patients were assessed at baseline (prior to the second administration of neurotoxic agent), midtreatment (halfway through treatment protocol), and end-of-treatment (upon completion of neurotoxic treatment). Demographic and treatment dosing information were obtained from medical records.

The study was approved by the Sydney Local Health District (SLHD) and South-Eastern Sydney Local Health District (SESLHD) Human Research Ethics Committees, and all patients provided informed signed consent in accordance with the Declaration of Helsinki. This study followed the STROBE reporting guidelines.19

CIPN Assessments

At each timepoint, patients completed a comprehensive battery of CIPN assessments as reported in prior studies,20,21 including key assessment tools described later that were used for the threshold estimation analysis. CIPN assessments were undertaken by trained researchers following a standardized testing protocol to ensure reproducibility. Full details of outcome measures and scoring are provided in eAppendix 1 (available with this article at JNCCN.org).

PROMs included the QLQ-CIPN20, a validated CIPN PROM consisting of 20 items addressing symptoms and functional impacts of CIPN (https://qol.eortc.org/).10 A reduced variant of the QLQ-CIPN20, consisting of 8 items (termed CIPN8) from the original scale,22 was also examined due to its recent use in translational studies.22–24 Another validated PROM assessing CIPN, the FACT/GOG-NTX consisting of 13 items (https://www.facit.org/),11 and its reduced version with 4 items (NTX4),25 were also examined.

The NCI’s CTCAE (version 4) peripheral sensory neuropathy subscale26 was used to clinically grade CIPN and was adopted as the clinical anchor for MID estimations. Trained researchers graded each patient using the CTCAE scale immediately following each patient’s clinical review and comprehensive CIPN assessment to maximize the scale’s accuracy and reproducibility.27 The Total Neuropathy Score, clinical version (TNSc), which is a validated composite neurologic grading scale designed to evaluate peripheral neuropathy, was also used to evaluate CIPN severity.28,29

Statistical Analysis and Threshold Estimation Methods

Summary statistics are presented as mean and standard deviation. Mean change in PROM scores were calculated from baseline to midtreatment and to end-of-treatment timepoints, and their statistical significance from zero was assessed with unpaired t tests, with statistical significance defined at P<.05. Both anchor-based and distribution-based methods were used to estimate thresholds30 for the 4 PROMs as described later. All statistical analyses were performed using Stata, version 14 (StataCorp LP).

Anchor-Based Methods

Anchor-based methods express change in PROM scores for subgroups of patients defined by clinically relevant variables (clinical anchors). For this study, the CTCAE was chosen as the clinical anchor because it is the most commonly used method of CIPN assessment and also has clinical relevance, with dose-modifying decisions in clinical practice often made based on CTCAE neuropathy grade. To assess suitability of the clinical anchor, correlations between the CTCAE scores and PROMs were calculated at each timepoint using Spearman’s rank correlation and a correlation coefficient of r > 0.30 was required to determine plausibility of the anchor.30 PROMs and CTCAE score changes were computed between baseline to midtreatment and baseline to end-of-treatment, and correlations between PROM change scores and CTCAE grade changes were calculated using Spearman’s rank correlation to further assess anchor suitability and MID credibility.18

Three clinical change groups (CCGs) were defined: (1) CCG 0: no CIPN development (CTCAE grade 0 at all timepoints); (2) CCG 1: development of minimal CIPN (CTCAE grade 0 at baseline, developing to grade 1 at midtreatment/end-of-treatment)—this was deemed the MID, and mean changes from this group provided MID estimates for the PROMs31; and (3) CCG 2: development of clinically significant CIPN (CTCAE grade 0 at baseline, developing to grade 2 at midtreatment/end-of-treatment), sufficient to influence/inform important clinical management decisions such as dose reduction, because this was deemed the clinically important difference (CID).32 Patients who developed grade >2 neuropathy were excluded from analysis because this study aimed to estimate score changes that reflect the development of minimally important neuropathy (CCG 1) and the threshold for clinically significant neuropathy (CCG 2). TNSc scores were used as a validated neurologic score of CIPN to further examine quantitative CIPN severity between CCGs. The mean change method was used to calculate PROM score changes over time for each CCG, and statistical significance of change was assessed with paired sample t tests, expressed with a 95% confidence interval.

Distribution-Based Methods

Distribution-based methods of threshold estimation using the statistical distribution of PROM scores (such as SD or standard error of the mean [SEM]) are considered as supportive evidence to the anchor-based MID estimations.30 In this study, the distribution-based method was calculated using 0.5 SD of PROM scores at midtreatment and end-of-treatment as in previous studies.33,34 Data from patients who had completed a midtreatment or end-of-treatment timepoint were included in this analysis.

Results

A total of 478 patients were recruited to the study, with 406 patients completing a baseline and midtreatment or end-of-treatment assessment and suitable for inclusion in this analysis (Figure 1). For these 406 patients, mean [SD] age was 55.6 [12.6] years, 64.0% were female (n=260), and most were treated with taxane (38.9%; n=158), platinum (26.6%; n=108), or combination taxane/platinum-based (19.2%; n=78) neurotoxic regimens for breast (32.3%; n=131), gynecologic (19.2%; n=78), or colorectal/gastrointestinal cancers (17.7%; n=72) (Table 1).

Figure 1.

Figure 1.

Flowchart and clinical change groups across each timepoint.

Abbreviations: CCG, clinical change group; CTCAE, Common Terminology Criteria for Adverse Events.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7074

Table 1.

Patient Demographic and Clinical Characteristics (N=406)

Table 1.

At baseline assessment, most patients (79.3%; n=322/406) did not have neuropathy symptoms (CTCAE grade 0; Table 1). By midtreatment (8.9 ± 4.8 weeks from baseline), 62.2% (n=199/320) had CIPN symptoms (CTCAE grade ≥1), and by end-of-treatment (17.6 ± 10.1 weeks from baseline), 79.9% (n=274/343) had CIPN symptoms (Figure 2). Mean scores for all 4 PROMs similarly reflected statistically significant increased self-reported CIPN (P<.001) at each subsequent timepoint (supplemental eFigure 1).

Figure 2.

Figure 2.

Distribution of CTCAE grades for CIPN at each timepoint.

Abbreviations: CIPN, chemotherapy-induced peripheral neurotoxicity; CTCAE, Common Terminology Criteria for Adverse Events.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7074

Patients who received taxane- or platinum-only treatments did not have significantly different CTCAE grade at midtreatment or end-of-treatment (both P>.05). Similarly, patients with stage IV disease did not have significantly different CTCAE grade than those with stage 0–III disease at either midtreatment and end-of-treatment (both P>.05).

CTCAE grades were correlated with PROM scores at each timepoint and between timepoints (r = 0.42–0.82; supplemental eTable 1). All correlations were >0.3, indicating the CTCAE grade was an appropriate clinical anchor.28 Furthermore, all but 1 of the 20 correlations were >0.50, meeting the higher threshold set by Devji et al18 for MID credibility.

Figure 1 shows the number of patients with PROM and CTCAE data that allowed them to be categorized as CCG 0, CCG 1, or CCG 2 at midtreatment and end-of-treatment. TNSc scores significantly worsened with increasing CCG both at midtreatment and end-of-treatment timepoints (P<.001; supplemental eTable 2), further supporting the CTCAE as an appropriate clinical anchor of CIPN severity.

PROM change scores for each CCG and timepoint are shown in Table 2. As expected, the CCG 0 group had the smallest mean score changes and the CCG 2 group had the largest mean score changes at midtreatment and end-of-treatment. The end-of-treatment means were larger than the midtreatment means for all PROMs and CCGs.

Table 2.

Mean Score Changes for Each CCGa

Table 2.

Distribution-based MID estimates were based on PROM data provided by 320 patients at midtreatment and 343 patients at end-of-treatment. These supportive MID estimates were smaller than the definitive MID estimates based on anchor-based methods at both time points for all PROMs (Table 3).

Table 3.

Comparison of Definitive Anchor-Based MID Estimate (CCG 1) With Supportive Distribution-Based MID Estimatea

Table 3.

Discussion

This study established score changes associated with minimal (grade 1) and clinically significant (grade 2) neuropathy development for 2 commonly used CIPN PROMs and their abbreviated versions. CIPN PROMs are widely used in clinical research and these data will enable better understanding of the PROM score differences that reflect development of minimally emergent neuropathy as well as development of significant neuropathy that would warrant consideration of dose modification. These corresponding sets of mean score changes serve as thresholds to guide clinical interpretation of score changes on these commonly used CIPN PROMs.

The reported prevalence of CIPN in this study is within the range reported by previous studies.35 However, some studies have reported lower prevalence of CIPN, which may be due to the methodology of CIPN assessment. In the present study, neuropathy grades were evaluated by trained researchers after completing a battery of CIPN assessments. This comprehensive investigation provided researchers with in-depth CIPN information and may have resulted in increased sensitivity in capturing CIPN compared with other studies.

This study used anchor-based methods, which are preferred over distribution-based estimations because they are underpinned by clinical relevance that enriches the interpretation and utility of the MIDs.30 The CTCAE peripheral sensory neuropathy subscale was used as the clinical anchor, and accordingly these MID estimations reflect development of grade 1 sensory CIPN. MIDs were estimated for both midtreatment and end-of-treatment timepoints, providing estimations of thresholds for CIPN development during treatment and quantifying overall treatment toxicity.

Choice of Clinical Anchor: Limitations and Future Directions

Choosing an appropriate clinical anchor is essential in MID estimation. The MIDs we estimated have high credibility according to the criteria developed by Devji et al18 (supplemental eTable 3), supporting the CTCAE peripheral sensory neuropathy subscale as an appropriate and robust anchor. An appropriate anchor needs to identify the threshold of a small but meaningful change in a patient’s symptoms: grade 1 of the CTCAE meets this requirement because it represents emergence of perceptible CIPN. In addition, we used the clinical significance of the higher grades to provide PROM thresholds for treatment modification indications, given that grade ≥2 CIPN often results in treatment modification. Finally, it is familiar to clinicians and researchers, further emphasizing its utility as a clinical anchor to aid interpretation of CIPN PROM scores.

Prior MIDs estimation studies for non-CIPN PROMs used more than one clinical anchor,34,36 whereas this study used only the CTCAE sensory subscale—arguably a limitation of this study. We considered other measures as additional anchors, including the TNSc.28 However, despite being a validated CIPN outcome measure, the TNSc lacks defined clinically significant cutoff values, resulting in ambiguity when benchmarking clinical significance. Although a recent study estimated MIDs for TNSc,37 the TNSc is not commonly used in routine oncology clinical practice, and accordingly there is a lack of treatment modification indications attributed to TNSc grades.

The CTCAE also has limitations as a clinical anchor, because it can have low interobserver reliability38 and low sensitivity to change,39 with the scale’s 4 grades not being able to accurately capture the spectrum of CIPN severity. Despite these shortcomings, Cavaletti et al27 demonstrated that standardized training in CTCAE grading and interpretation increases accuracy and reproducibility of results, and this has been adopted in the present study. Furthermore, in our study, the CTCAE grading was completed by trained researchers following the comprehensive CIPN assessment and discussion with the patient, which may explain the high correlations between the change scores compared with previous literature on MIDs.33,34,36 In addition, our study found significant worsening of TNSc scores between clinical change groups, further verifying the CTCAE as an appropriate proxy of CIPN severity.

This study estimated MIDs for the development of CIPN, but was not designed to estimate MIDs for CIPN improvement posttreatment, which we acknowledge may differ. Future studies estimating improvement MIDs for the QLQ-CIPN20, FACT/GOG-NTX, and their abbreviated versions will provide important thresholds, because these PROMs are also increasingly used in CIPN treatment intervention studies to ameliorate chronic CIPN symptoms. Furthermore, use of an anchor based on patient-reported perceived change in future work would provide an MID estimate better linked to patient perceptions of importance.18

Comparison With Previous MIDs Studies

Two prior studies have investigated MIDs for both the QLQ-CIPN2016 and FACT/GOG-NTX.17 However, there were some methodological differences that may limit the comparability of findings. First, the 3 timepoints used by Yeo et al16 (baseline, at second cycle of chemotherapy, and at 12-month follow-up) may not allow accurate capturing of CIPN symptom development. Because CIPN develops cumulatively with neurotoxic treatment, these timepoints may have missed the apex of CIPN symptoms, as suggested by the low proportion of their patient cohort (6.2%–6.6%) that developed CIPN. Consequently, although Yeo et al16 aimed to estimate MIDs for QLQ-CIPN20 using anchor-based methods, final estimates were based solely on distribution-based methods because their anchor-based estimates were found to be inconsistent due to the low rate of CIPN development. Cheng et al17 also used solely distribution-based methods to estimate MIDs for FACT/GOG-NTX. As discussed earlier, distribution-based methods are limited in clinical utility, lacking a direct link to a clinically relevant anchor. Furthermore, MIDs were estimated separately for the sensory and motor subscales of the QLQ-CIPN20.16 However, due to a lack of demonstrated structural validity for these QLQ-CIPN20 subscales,9 it has been recommended that the PROM be used in its entirety, rather than individual subscales.40

Utility in Different Clinical and Research Settings

Clinically relevant thresholds for PROMs have utility in both research settings and routine clinical care.41 The QLQ-CIPN20 and FACT/GOG-NTX are currently used in a wide range of research settings, including CIPN observational and natural history studies, CIPN treatment and intervention studies, and cancer treatment clinical trials. Although not as extensively validated as the original versions, the abbreviated CIPN8 and NTX4 have been used as outcome measures in observational studies22,23 and clinical trials.42,43 However, without guidelines on clinical thresholds, interpretation of observed changes in PROM scores is limited. The application of estimated MID scores in the research setting will amplify the utility of PROMs, guiding researchers to determine whether the PROM score changes are clinically meaningful and helping to define appropriate endpoints for clinical trials when assessing CIPN.

CIPN PROMs also have an important role in routine clinical care during treatment, particularly because clinician-rated CIPN grades are known to consistently underreport severity compared with patient self-report.44 Given that development of CIPN is a major reason for dose modification, it is critical that clinicians have the most accurate representation of CIPN severity when making these decisions. CIPN PROMs provide a promising data source, but to date, the use of CIPN PROMs in clinical practice has received little attention. We have estimated thresholds for clinically significant (grade 2) CIPN, because this level of CIPN often impacts on management, including dose modification. Careful considerations need to be made when adapting PROMs developed and validated for use in research to individual patient care,45 but the clinically significant thresholds we have provided are an important first step to introducing these PROMs to routine clinical practice. Furthermore, other interventions, such as increasing patient involvement in their symptom management46 and use of decision support algorithms to promote adherence to evidence-based CIPN management,47,48 may also provide clinicians with additional information and aid in treatment modification decisions. However, further studies are needed to determine how to best implement these methods into clinical practice.

Conclusions

MIDs and other clinical thresholds estimated in this study provide guidance on the meaningful interpretation of score changes for CIPN PROMs. These results will assist clinicians and researchers in identifying minimal and clinically significant CIPN development when these PROMs are used in research settings, and potentially in clinic.

Effect of Yoga and Mediational Influence of Fatigue on Walking, Physical Activity, and Quality of Life Among Cancer Survivors

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Background

Cancer is the second leading cause of death in the United States.1 With advances in cancer screening and treatment, survival rates have increased by 20% over the past 4 decades.2 Despite increased survival rates, quality of life (QoL) is often dramatically diminished due to cancer-related and treatment-related toxicities.3–6

Cancer-related fatigue (CRF) is one of the most pervasive toxicities experienced by survivors.5,7–11 Although most patients experience CRF during treatment, up to 40% of survivors continue experiencing this debilitating fatigue after completion of treatment.12–17 These survivors often report a lack of energy, tiredness, and a need to slow down and rest, which interferes with their ability to work, resume daily routines (eg, walking), and engage in physical activity (PA).6,18

Evidence suggests that yoga alleviates a variety of cancer-induced and treatment-induced toxicities, and could, therefore, improve QoL among cancer survivors.19–32 We previously showed that our yoga intervention, Yoga for Cancer Survivors (YOCAS), effectively improves CRF, insomnia, cognitive impairment, arthralgias, and pain among cancer survivors.33–37 To our knowledge, no nationwide, multicenter, phase III randomized controlled trial (RCT) has studied how reducing CRF through yoga consequently influences CRF’s interference with survivors’ daily activities such as walking and engaging in PA and QoL. Here we report the effect of YOCAS on CRF’s interference with survivors’ walking, PA, and QoL as secondary outcomes from our phase III RCT, and examine whether yoga-induced improvements in CRF mediate changes in CRF’s interference with walking, PA, and QoL among survivors.

Patients and Methods

Study Design

We used data collected from our nationwide, multicenter, phase III RCT (ClinicalTrials.gov identifier: NCT00397930) conducted via the University of Rochester Cancer Center NCI Community Oncology Research Program Research Base (URCC NCORP RB) to examine the effect of YOCAS on CRF’s interference with walking, PA, and QoL (as secondary outcomes) among cancer survivors. The primary and other secondary outcomes along with detailed study design and methods have been published previously.33–37 See supplemental eAppendix 1 (available with this article at JNCCN.org) for information on study recruitment and randomization.

Participants

Participant inclusion criteria included (1) any type of cancer diagnosis, excluding a metastatic diagnosis; (2) completion of primary treatment 2 to 24 months prior to enrollment; (3) persistent sleep disturbance (≥3 on symptom inventory scale); (4) age ≥21 years; and (5) ability to read and understand English. Participants were excluded if they (1) regularly practiced yoga within 3 months or planned to start a new yoga program during the study period; (2) were diagnosed with sleep apnea or metastatic cancer; and (3) were currently receiving any form of cancer treatments except hormonal therapy.

Yoga Intervention

YOCAS is a standardized 4-week yoga intervention that is based on gentle hatha and restorative yoga consisting of breathing exercises, physical alignment postures, and mindfulness exercises.33 Participants in the YOCAS group received 8 yoga sessions (75 minutes per session, twice per week) at low to moderate intensity. Each yoga session was delivered by a Yoga Alliance–registered instructor in a group setting (10–15 participants per group) at community-based sites (eg, community centers, cancer centers, and yoga studios).33

To ensure the standardization, quality, and fidelity of the yoga intervention, each instructor completed a 2-hour training session conducted by the URCC NCORP RB and was instructed to follow the provided intervention manual and a DVD to deliver YOCAS sessions. The study coordinator from each participating NCORP community oncology practice also attended a randomly selected yoga session to observe and verify whether proper content was delivered.

Standard Care Control

Participants in the standard care control group continued their usual follow-up clinic visits with their oncologists and primary care providers. They received the same amount of time and attention from the research team regarding study measures but had no yoga exposure.

Measures

Medical records were reviewed to confirm participants’ eligibility and collect clinical information (eg, cancer type, previous treatment). Demographic data were collected via the study-specific form. Race data were collected using the NCI Clinical Trials Reporting Program criteria for clinical trials. For data reporting purposes, we condensed racial categories to White, Black, and Other (comprising Native Hawaiian or Other Pacific Islander, Asian, American Indian, Alaska Native, and unknown).

Adherence and compliance were monitored by patient-reported daily diaries and yoga attendance logs completed by yoga instructors. A feedback form was used to collect the helpfulness of the YOCAS intervention and whether yoga participants would recommend the intervention to other survivors experiencing similar symptoms. Adverse events were monitored using NCI’s Common Terminology Criteria for Adverse Events and were reported to the URCC Data Safety Monitoring Committee.

CRF’s Interference With Walking, PA, and QoL

The symptom inventory is a commonly used and widely accepted tool for both research and clinical assessments of the severity of symptoms and how symptoms interfere with patients’ daily living.38 We modified the MD Anderson Symptom Inventory and included 12 common symptoms and 8 interference items.36,37 Participants were asked to rate the severity of each symptom on a scale of 0 to 10 (0 = not present; 10 = as bad as you can imagine) and how much their fatigue interfered with the 8 items of their life (including daily living, mood, work, relations with other people, general physical activity, walking, exercise, and quality of life) with a scale of 0 to 10 (0 = did not interfere; 10 = completely interfered). In this study, we used 3 Symptom Inventory interference items to assess CRF’s interference with walking, PA, and QoL. Higher scores indicate worse interference.

CRF

CRF was measured via the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI),39,40 a validated, 30-item, commonly used fatigue instrument that generates a total score indicating overall CRF level and 5 subdomain scores indicating general, physical, emotional, and cognitive fatigue and vigor levels. Higher scores indicate worse fatigue levels. CRF results were previously published.34,37 In this study, the total MFSI scores were used for mediation analysis.

Statistical Analyses

Among 410 participants who consented and were randomized, 328 provided complete baseline and postintervention symptom inventory and MFSI data. A sample size of 328 (YOCAS: n=168; standard care: n=160) provided >90% power to detect an effect size of 0.33 in between-group differences in CRF’s interference with walking, PA, and QoL scores assuming a correlation coefficient of 0.5 between baseline and postintervention at a significance level of 5% with a 2-tailed F test using analysis of covariance (ANCOVA).

Between-group differences in baseline demographic data and characteristics were examined with 2-tailed t tests for continuous variables and chi-square tests for categorical variables. Within-group differences in CRF’s interference with walking, PA, and QoL were assessed using 2-tailed t tests. Between-group intervention effects on CRF’s interference with walking, PA, and QoL at postintervention were assessed using ANCOVA with the intervention arm as the group factor and baseline value as a covariate. Two-tailed t tests and ANCOVA were performed using SAS 9.4 (SAS Institute Inc.). The effect size was calculated using the between-group mean change (postintervention minus baseline) in CRF’s interference with walking, PA, and QoL divided by the standard deviation of baseline scores.

The mediation analysis was conducted using path modeling on change scores in CRF with change scores in CRF’s interference with walking, PA, and QoL as the dependent variables to derive path coefficients. The path modeling included a direct path between the intervention arm (YOCAS vs standard care) and each outcome variable (CRF’s interference with walking, PA, and QoL), a path between the intervention arm and CRF, and a path between CRF and each outcome variable. Statistical significance of mediation was assessed using nonparametric bootstrap 95% confidence intervals for the indirect path coefficient from the intervention arm to each outcome variable on CRF. Statistical significance was determined as P≤.05.

Data analyses followed the intent-to-treat principle and were based on complete cases (see supplemental eAppendix 1 for the description of intent-to-treat, multiple imputation, and mediation analysis).

Results

Figure 1 shows the CONSORT diagram. Among 413 survivors who consented to participate in the study, 3 were excluded due to ineligibility, 410 were randomized to either YOCAS (n=206) or standard care (n=204), 357 provided complete baseline symptom inventory and MFSI data, and 328 provided complete baseline and postintervention symptom inventory and MFSI data. Eighty-one enrolled participants, including 37 YOCAS participants and 44 standard care controls, dropped out of the study due to medical issues (n=12), personal issues (n=47), unknown reasons (n=20), and starting their own yoga program (n=2). One YOCAS participant did not provide complete baseline data. The proportion of dropouts between YOCAS (18%) and standard care (22%) was not significantly different.

Figure 1.

Figure 1.

CONSORT diagram.

Abbreviations: MFSI, Multidimensional Fatigue Symptom Inventory; YOCAS, Yoga for Cancer Survivors.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7080

Demographics and Baseline Characteristics

Table 1 shows the demographics and baseline characteristics of 357 participants (YOCAS: n=176; standard care: n=181) who provided complete baseline symptom inventory and MFSI data. Mean [SD] age of participants was 54.3 [10.2] years; most were female (96%), White (93%), married or in a committed relationship (73%), educated at a college level or higher (81%), employed (81%), and breast cancer survivors (77%). Participants had completed surgery (90%), chemotherapy (71%), and/or radiation therapy (67%) prior to enrollment. On average, there was a mean [SD] of 15.7 [8.2] months since their first cancer treatment. No significant between-group differences were found in demographics and baseline characteristics.

Table 1.

Demographics and Baseline Characteristics

Table 1.

Adherence, Compliance, and Adverse Events

YOCAS participants attended an average of 6.5 of 8 prescribed yoga sessions and reported practicing 1 additional session per week on their own. The average rating of exertion was 3.4 on a 0 to 10 scale (with 0 = “nothing at all” and 10 = “very, very strong”), indicating that the intensity of the YOCAS session was low to moderate. YOCAS participants, on average, practiced 182 minutes of yoga each week or 728 minutes across the 4-week intervention period, which was 128 minutes more than the prescribed yoga dose (eight 75-minute sessions = 600 minutes). No significant yoga contamination was found in the standard care group; 7 standard care controls reported an average of 20 minutes of yoga practice weekly during the intervention period. No study intervention–related adverse events were reported.

CRF’s Interference With Walking, PA, and QoL

YOCAS participants reported significant improvements in CRF’s interference with walking (−0.6 ± 0.2; P=.01), PA (−0.9 ± 0.2; P<.01), and QoL (−1.0 ± 0.2; P<.01) from baseline to postintervention, whereas standard care controls reported no change in these outcomes. In addition, ANCOVA revealed significantly greater improvements in CRF’s interference with walking (−0.9 ± 0.3; P<.01; effect size = −0.33; 95% CI, −0.54 to −0.11), PA (−0.9 ± 0.3; P<.01; effect size = −0.33; 95% CI, −0.52 to −0.15), and QoL (−0.9 ± 0.3; P<.01; effect size = −0.33; 95% CI, −0.51 to −0.14) in YOCAS participants than in standard care controls at postintervention, controlling for baseline values (Figure 2, Table 2). More than 90% of YOCAS participants found these changes to be clinically meaningful; they explicitly stated that the YOCAS intervention was helpful and they would recommend it to other survivors for managing these side effects.

Figure 2.

Figure 2.

Changes in CRF’s interference with walking, PA, and QoL. Data are presented as effect size and its 95% confidence limits.

Abbreviations: CRF, cancer-related fatigue; PA, physical activity; QoL, quality of life; YOCAS, Yoga for Cancer Survivors.

*P≤.05.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7080

Table 2.

Changes in CRF’s Interference With Walking, Physical Activity, and Quality of Life

Table 2.

Mediational Effect of CRF on CRF’s Interference With Walking

YOCAS participants, compared with standard care controls, reported significantly greater improvements in CRF from baseline to postintervention.34 Mediation analysis revealed that improvements in CRF significantly mediated the intervention effect on CRF’s interference with walking. The path mediation model of CRF and CRF’s interference with walking adjusted with the intervention effect is demonstrated in Figure 3. The total effect of YOCAS compared with standard care on symptom inventory walking interference score was −1.01 points (P<.01), indicating that YOCAS improved CRF’s interference with walking by 1.01 points compared with the effect of standard care on walking. Improvements in CRF significantly mediated the YOCAS effect on CRF’s interference with walking by 0.45 points in addition to the direct YOCAS effect on CRF’s interference with walking of 0.57 points, suggesting that 44% (95% CI, 24%–100%) of the improvements in CRF’s interference with walking was mediated through improvements in CRF.

Figure 3.

Figure 3.

Mediational effect of CRF on its interference with walking. Data are presented as regression coefficient ±SE.

Abbreviations: CRF, cancer-related fatigue; YOCAS, Yoga for Cancer Survivors.

*P≤.05.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7080

Mediational Effect of CRF on CRF’s Interference With PA

Mediation analysis revealed that improvements in CRF significantly mediated the intervention effect on CRF’s interference with PA. The path mediation model of CRF and CRF’s interference with PA adjusted with the intervention effect is demonstrated in Figure 4. The total effect of YOCAS compared with standard care on symptom inventory PA interference score was −1.02 points (P<.01), indicating that YOCAS improved CRF’s interference with PA by 1.02 points compared with the effect of standard care on PA. Improvements in CRF significantly mediated the YOCAS effect on improvements in CRF’s interference with PA by 0.54 points in addition to the direct YOCAS effect on CRF’s interference with PA of 0.47 points, suggesting that 53% (95% CI, 34%–100%) of the improvements in CRF’s interference with PA was mediated through improvements in CRF.

Figure 4.

Figure 4.

Mediational effect of CRF on its interference with PA. Data are presented as regression coefficient ±SE.

Abbreviations: CRF, cancer-related fatigue; PA, physical activity; YOCAS, Yoga for Cancer Survivors.

*P≤.05.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7080

Mediational Effect of CRF on CRF’s Interference With QoL

Mediation analysis revealed that improvements in CRF significantly mediated the intervention effect on CRF’s interference with QoL. The path mediation model of CRF and CRF’s interference with QoL adjusted with the intervention effect is demonstrated in Figure 5. The total effect of YOCAS compared with standard care on symptom inventory QoL interference score was −0.96 points (P<.01), indicating that YOCAS improved CRF’s interference with QoL by 0.96 points compared with the effect of standard care on QoL. Improvements in CRF significantly mediated the YOCAS effect on improvements in CRF’s interference with QoL by 0.43 points in addition to the direct YOCAS effect on CRF’s interference with QoL of 0.52 points, suggesting that 45% (95% CI, 26%–100%) of the improvements in CRF’s interference with QoL was mediated through improvements in CRF.

Figure 5.

Figure 5.

Mediational effect of CRF on its interference with QoL. Data are presented as regression coefficient ±SE.

Abbreviations: CRF, cancer-related fatigue; QoL, quality of life; YOCAS, Yoga for Cancer Survivors.

*P≤.05.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7080

Discussion

To our knowledge, this is the first nationwide, multicenter, phase III RCT demonstrating how reducing fatigue through a standardized, 4-week, yoga intervention (YOCAS) has broader implications on survivors’ daily activities and QoL. Our findings suggest that YOCAS, the gentle hatha and restorative yoga–based, low- to moderate-intensity yoga intervention, practiced 2 to 3 times per week (182 minutes per week; 32–75 minutes per session) for 4 weeks significantly improves CRF’s interference with walking, PA, and QoL among cancer survivors. A significant proportion (44%–53%) of the YOCAS effect on CRF’s interference with walking, PA, and QoL is due to improvements in CRF. By practicing YOCAS, survivors not only reported less CRF but consequently improved their engagement in daily activities such as walking and PA, and overall QoL, suggesting the broader therapeutic impact of yoga on symptom management in cancer survivors.

Although most oncology guidelines41–45 mention that it is reasonable to recommend the use of yoga for treating CRF, compelling level 1/category 1 scientific evidence from multiple blinded phase III RCTs is insufficient to make yoga a gold standard treatment. Results of this study add substantial value to the scientific evidence supporting the use of yoga for treating CRF and its interference with essential daily activities such as walking, PA, and QoL.24–26,28–30,32–37,46–48 In addition, our YOCAS participants demonstrated high adherence and compliance to the yoga intervention, found the yoga intervention helpful, and claimed they would recommend it to other survivors experiencing similar side effects, which underlines the clinically meaningful effect of yoga on symptom management.33 Because these were secondary exploratory analyses, future phase III RCTs designed a priori with CRF and its interference with walking, PA, and QoL as primary outcomes are needed.

Although the results of this study are compelling regarding the use of yoga for treating CRF and its interference with daily activities and QoL, yoga remains underprescribed as an element of supportive care among cancer survivors.49,50 Improving awareness and enhancing accessibility of yoga therapy in cancer care and collaborations with yoga therapists and integrative medicine can lead to dissemination and implementation of yoga therapy in the oncology setting and extension of the benefits of yoga to greater numbers of cancer survivors.50–53 We understand that not all survivors will want to use yoga for treating CRF and other side effects. For those patients, it is reasonable to recommend the use of other behavioral interventions noted in oncology supportive care treatment guidelines (eg, exercise, cognitive behavioral therapy).

Certain limitations should be considered when interpreting our results and developing future studies, including (1) the generalizability of the results: most of our study participants were White, female, educated at a college level or higher, and breast cancer survivors, who do not represent the diversity of the cancer population; (2) the lack of a comparison with an active behavioral placebo: the study design did not compare YOCAS with an active behavioral placebo controlling for subject contact time and attention of the intervention; therefore, we cannot assess whether the improvements in CRF and in CRF’s interference with walking, PA, and QoL are specific to YOCAS; (3) use of only 3 items of the self-reported symptom inventory questionnaire to evaluate CRF’s interference with walking, PA, and QoL might not comprehensively evaluate the true interference level; (4) CRF and the 3 main outcomes were assessed only at baseline and postintervention: this assessment arrangement could not capture temporal changes for mediation analysis and evaluate sustainability of the intervention effect; (5) although compliance with YOCAS was good in this study, the effective dose of yoga might be challenging for survivors with more severe medical, physical, financial, or environmental barriers; and (6) 20% of enrolled participants dropped out due to personal, medical, and other reasons.

Future phase II/III RCTs should consider testing yoga intervention among survivors with diverse demographic backgrounds and various cancer types and treatment histories, and develop strategies to improve participant retention. Comparing yoga intervention to known effective treatments such as exercise or psychosocial interventions for alleviating CRF and its interference with daily activities and QoL could further elucidate the magnitude of each yoga component or their combination (breathing, postures, and mindfulness) versus the active component from other interventions, provide more direct clinical evidence, and identify multiple treatment options for symptom management. Collecting and analyzing objective biophysiologic data and assessing mediational relationships might help reveal the etiologic and pathophysiologic mechanisms of CRF and its connection to survivors’ walking, PA, and QoL. The study of temporal and dose–response relationships can help oncologists and yoga therapists prescribe yoga doses more precisely. Combining yoga with other behavioral interventions can also be considered to elicit greater improvements in CRF and its interference with walking, PA, and QoL among cancer survivors.

Conclusions

Our findings suggest that the standardized 4-week YOCAS yoga program improved CRF’s interference with walking, PA, and QoL among cancer survivors. More importantly, 44% to 53% of the improvements in CRF’s interference with walking, PA, and QoL are attributable to improvements in CRF resulting from yoga. Our findings provide strong clinical evidence for oncologists to include yoga as a treatment option when designing a cancer care plan for survivors experiencing CRF and its interference with walking, PA, and QoL.

Comanaging Chronic Lymphocytic Leukemia and Chronic Myeloid Leukemia: A Case Report

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Background

Agents that target B-cell signaling pathways, such as ibrutinib, idelalisib, and venetoclax, provide durable responses while drastically changing the adverse effect profile in the management of chronic lymphocytic leukemia (CLL).1–4 Ibrutinib is a first-generation Bruton’s tyrosine kinase inhibitor (BTKi) that has been shown to be effective in frontline and relapsed/refractory CLL, including in patients harboring a 17p deletion.2,5 Ibrutinib irreversibly binds to BTK, which is stimulated by the B-cell receptor and other cytokine receptors. Ibrutinib and other targeted agents have modified the landscape in the management of CLL.

Similar to CLL, the use of small-molecule tyrosine kinase inhibitors (TKIs) for the management of chronic myeloid leukemia (CML) has led to significant improvement in outcomes. These TKIs (eg, imatinib, dasatinib, nilotinib, bosutinib) have transformed CML from a fatal malignancy to a chronic disease with which most patients achieve a normal life expectancy.6–10 Despite the success of these therapies, some patients will either not tolerate first-line TKI or not achieve response milestones.11,12 Second- and third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib, asciminib) have been shown to be efficacious for second and later lines of therapy, allowing patients to remain on oral therapy for long periods of time, even after other TKIs have failed.13–17 Nonetheless, these agents are affected by prevalent drug–drug interactions.18

One potential common target for both CLL and CML is inducing apoptosis through BCL-2.4,19 The BCL-2 family of proteins regulates the mitochondrial apoptotic response. Constitutionally elevated expression of BCL-2 leads to resistance to apoptosis. Venetoclax, a small molecular inhibitor, mimics BH3 and binds to the BCL-2 protein, causing a displacement of proapoptotic proteins, restoring apoptosis, and causing subsequent malignant cell death. Aberrant BCL-2 activity has been implicated in many types of cancer, including CLL, acute myeloid leukemia, and CML.4,19–27 Venetoclax is now an established therapeutic option in CLL, for use as first-line therapy or in relapsed/refractory disease.3,4,28–30 This report presents a case of concomitant use of venetoclax and imatinib for the comanagement of concurrent CLL and CML.

Case Report

The patient was a 73-year-old woman with a remote history of stage I breast cancer status post a partial mastectomy and brachytherapy in 2008, gastroesophageal reflux disease, dyslipidemia, and hypertension. She was diagnosed with CLL in 2012 at an outside facility, and initial immunophenotype, cytogenetics, indications for therapy, and staging were not known. She received one cycle of bendamustine + rituximab, which was complicated by severe anemia. She refused further bendamustine + rituximab therapy and was maintained on active surveillance. Her CLL remained quiescent until August 2018, when she was found to have a worsening WBC count of 31,000/mcL along with worsening lymphadenopathy of the neck, chest, abdomen, axilla, and pelvis. PET/CT imaging showed a new prevertebral soft tissue mass in the nasopharynx with a maximal standardized uptake value of 5.8. This mass was not biopsied. Flow cytometry on a bone marrow biopsy was variably positive for CD20 and CD23 (Figures 1 and 2). Fluorescence in situ hybridization (FISH) on bone marrow was positive for trisomy 12 and 14.q32.3, but negative for TP53 and ATM. It was determined that the patient had Rai stage I CLL. She was started on ibrutinib at 420 mg orally once daily, but the dose was reduced to 280 mg once daily shortly after initiation due to the development of skin rashes. After the dose reduction, her skin rashes resolved. Two years into therapy, restaging CT chest scan showed improvement but not resolution of lymphadenopathy, consistent with partial response.

Figure 1.

Figure 1.

Peripheral blood smear showing chronic lymphocytic leukemia/small lymphocytic lymphoma, August 2018. (A) Lymphocytes with numerous smudge cells are visible. (B, C) Bone marrow core biopsy shows diffuse infiltration of small lymphocytes with CD20 expression. On high magnification, a diffuse increase in small lymphocytes is seen.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Figure 2.

Figure 2.

Bone marrow aspirate flow cytometry using CD45 versus side scatter (August 2018) separates the cells into regions: granulocytes (R4: 9%), monocytes (R3: 1.4%), and lymphocytes (R8: R2 + R5 + R7 = 83%). Within the lymphocyte population, 78% of clonal B cells (R2: green) represent lambda-restricted CD5(+) and CD23(+). Proliferation index showed 5% positivity.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

In October 2020, the patient presented to our lymphoma service for management and was found to have leukocytosis and mediastinal lymphadenopathy but no organomegaly, remaining Rai stage I. At presentation, the patient reported fatigue; otherwise the physical examination was unremarkable. She was found have a resolved hepatitis B infection, and tenofovir was initiated. A subcarinal lymph node biopsy was completed in January 2021 (Figure 3), which was positive for CD45, CD5 (dim), CD11c (dim), CD19, CD20, CD22, CD52, and monotypic surface lambda light chain, consistent with persistent CLL via flow cytometry. Due to worsening lymphadenopathy and flow cytometry results, a decision was made to change therapy to venetoclax with rituximab. Shortly before the initiation of venetoclax in late February 2021, the patient underwent a PET scan, but no PET-avid disease was identified. A FISH panel on peripheral blood was found to be normal.

Figure 3.

Figure 3.

Lymph node core needle biopsy from patient in January 2021 after 2 years of therapy using ibrutinib, 280 mg once daily. (A, B) Hematoxylin-eosin staining from subcarinal lymph node biopsy reveals effacement of the lymph node architecture by medium-sized CD20-positive lymphocytes.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

At the initiation of venetoclax in early March 2021, the patient’s WBC count was 66,900/mcL. After completing only week 1 of venetoclax at 20 mg once daily, her WBC count increased to 74,400/mcL, with increases in neutrophils and metamyelocytes (Table 1). Given her peripheral blood FISH and PET scan results and increasing absolute neutrophil count and basophilia during week 2 of venetoclax at 50 mg once daily, a bone marrow biopsy was performed. Results showed hypercellular bone marrow (95%) with CML with 1% blasts, and flow cytometry showed residual low-grade B-cell lymphoma (<5%) (Figure 4). A karyogram of this sample showed 46,XX,t(9;22)(q34;q11.2), and FISH identified 182/200 nuclei positive for BCR::ABL1 fusion (Figure 5). The final diagnosis was confirmed as chronic phase CML, in addition to the already known CLL. When the ramp-up phase was completed, ibrutinib was stopped, imatinib was started at a dose of 400 mg daily, and venetoclax was continued at a maintenance dose of 200 mg daily, given that imatinib is an inhibitor of cytochrome P450 3A4 (CYP3A4).

Table 1.

Blood Counts

Table 1.
Figure 4.

Figure 4.

Peripheral blood smear, bone marrow biopsy, and aspirate particles in March 2021. (A, B) Leukocytosis with granulocytic left shift, nontoxic neutrophilia, and basophilia (inset, A) and rare blast (inset, B) are the classic features of BCR::ABL1–positive chronic phase CML. (C) Megakaryocytes in CML are small and hypolobated in contrast to other classic myeloproliferative neoplasms. (D) Low- and high-power magnification of hypercellular bone marrow core biopsy with increased myeloid-to-erythroid ratio. MPO staining highlights left-shifted myeloid element (inset, D).

Abbreviations: CML, chronic myeloid leukemia; MPO, myeloperoxidase.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Figure 5.

Figure 5.

Karyogram and FISH studies from bone marrow sample, March 2021. Karyogram highlights the classic chromosome 22 (Philadelphia) in CML. (A) The reciprocal translocation involves 9q34 and 22q11.2 juxtaposing the ABL1 and BCR genes at the molecular examination. (B) FISH using dual-fusion probe shows the presence of a BCR::ABL1 gene fusion (arrows).

Abbreviations: CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Rituximab was added to venetoclax therapy, with the last rituximab dose being given in November 2021. She is currently continuing imatinib and venetoclax therapy for comanagement of her CML and CLL. She has tolerated both imatinib and venetoclax very well with only mild leukopenia, anemia, neutropenia, and nausea managed with ondansetron. At the time of writing, her response to venetoclax therapy is unknown because restaging imaging has not occurred. Regarding her CML, she has experienced a major molecular remission (Table 2).

Table 2.

BCR::ABL Transcript-Level Trends and Response to Imatinib Therapy

Table 2.

Discussion

Several aspects of this case report are noteworthy. Venetoclax dosing with imatinib requires consideration. After daily administration under fed conditions, the venetoclax maximum concentration is reached within 5 to 8 hours and is oxidized by cytochrome P450 3A to its inactive metabolite.31 After single and multiple doses, strong inhibitors of CYP3A4 have resulted in a 2.3- to 2.4-fold increase in maximum concentration and a 6.9- to 8.1-fold increase in the area under the curve.31–33 Imatinib is a known substrate and a moderate inhibitor of CYP3A4 and cytochrome P450 3A5.34,35 For this reason, the venetoclax dose was chosen to be 200 mg once daily for this patient. To date, she has tolerated concomitant therapy well.

Synchronous occurrence of CLL and CML is rare. Although secondary malignancies with CLL are common, most are found to be skin, prostate, and breast cancers.36 In addition, malignancy post-BTK therapy can also be problematic in CLL.37,38 Secondary CML has been reported, but it does not have additional cytogenetic abnormalities typically found with other secondary cancers, such as acute myeloid lekemia.39 A handful of concurrent CML and CLL cases have been reported in the literature spanning 30 years that have successfully been comanaged.40–44 Targeted therapies have also been used successfully in a few cases, strengthening the argument that combination therapies can be safely and effectively administered in these rare patients.45,46

The most compelling component of this case report is that it highlights the safety and efficacy of concomitant venetoclax and imatinib. Both are well-established therapies in their respective diseases; however, concurrent CML and CLL are exceptionally rare. In preclinical models, venetoclax and navitoclax have activity in CML.19 Venetoclax activity is related directly to the expression of BCL-2 in CML but is modest at best as a single agent in several CML cell lines. When combined with imatinib, venetoclax enhanced imatinib-induced apoptosis in cell lines higher in BCL-2 expression. The present case report also corroborates a reported case series demonstrating that the concomitant use of venetoclax and TKIs is safe and effective.47 In addition, venetoclax has been shown to target leukemia stem cells,48,49 which are believed to be responsible for the initiation and perpetuation of leukemias and are known to be resistant to traditional chemotherapy and TKIs. And finally, adding TKIs to venetoclax has been shown to overcome venetoclax resistance through inducing Lck/Yes-related novel tyrosine kinase–mediated proapoptotic BCL-2–like protein 11 expression and inhibiting the upregulation of antiapoptotic MCL-1.50

Given all of this information, a compelling argument can be made for combination therapy using venetoclax plus TKIs as a novel and attractive approach for CML to obtain treatment-free remission and potentially a cure. However further studies, particularly prospective in nature, are needed to evaluate this combination from a treatment perspective and for treatment-free remission attempts.

Conclusions

This case report represents the second report on the use of venetoclax plus TKIs for CML and is the first report on the use of venetoclax plus TKIs for concomitant CLL and CML. Concomitant oral BCL-2 and TKI therapy was shown to be safe and efficacious, but given the unique pharmacokinetic and pharmacodynamic profiles of these drugs, careful monitoring and management of adverse events with this combination is warranted. Future studies of this novel treatment combination are needed.

Partial Breast Irradiation for Breast Cancer. Comparative Effectiveness

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Objectives: To evaluate the comparative effectiveness and harms of partial breast irradiation (PBI) compared with whole breast irradiation (WBI) for early-stage breast cancer, and how differences in effectiveness and harms may be influenced by patient, tumor, and treatment factors, including treatment modality, target volume, dose, and fractionation. We also evaluated the relative financial toxicity of PBI versus WBI. Data sources: MEDLINE®, Embase®, Cochrane Central Registrar of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and various grey literature sources from database inception to June 30, 2022. Review methods: We included randomized clinical trials (RCTs) and observational studies that enrolled adult women with early-stage breast cancer who received one of six PBI modalities: multi-catheter interstitial brachytherapy, single-entry catheter brachytherapy (also known as intracavitary brachytherapy), 3-dimensional conformal external beam radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), proton radiation therapy, intraoperative radiotherapy (IORT). Pairs of independent reviewers screened and appraised studies. Results: Twenty-three original studies with 17,510 patients evaluated the comparative effectiveness of PBI, including 14 RCTs, 6 comparative observational studies, and 3 single-arm observational studies. PBI was not significantly different from WBI in terms of ipsilateral breast recurrence (IBR), overall survival, or cancer-free survival at 5 and 10 years (high strength of evidence [SOE]). Evidence for cosmetic outcomes was insufficient. Results were generally consistent when PBI modalities were compared with WBI, whether compared individually or combined. These PBI approaches included 3DCRT, IMRT, and multi-catheter interstitial brachytherapy. Compared with WBI, 3DCRT showed no difference in IBR, overall survival, or cancer-free survival at 5 and 10 years (moderate to high SOE); IMRT showed no difference in IBR or overall survival at 5 and 10 years (low SOE); multi-catheter interstitial brachytherapy showed no difference in IBR, overall survival, or cancer-free survival at 5 years (low SOE). Compared with WBI, IORT was associated with a higher IBR rate at 5, 10, and over 10 years (high SOE), with no difference in overall survival, cancer-free survival, or mastectomy-free survival (low to high SOE). There were significantly fewer acute adverse events (AEs) with PBI compared with WBI, with no apparent difference in late AEs (moderate SOE). Data about quality of life were limited. Head-to-head comparisons between the different PBI modalities showed insufficient evidence to estimate an effect on main outcomes. There were no significant differences in IBR or other outcomes according to patient, tumor, and treatment characteristics; however, data for subgroups were insufficient to draw conclusions. Eight studies addressed concepts closely related to financial toxicity. Compared with conventionally fractionated WBI, accelerated PBI was associated with lower transportation costs and days away from work. PBI was also associated with less subjective financial difficulty at various time points after radiotherapy. Conclusions: Clinical trials that compared PBI with WBI demonstrate no significant difference in the risk of IBR. PBI is associated with fewer acute AEs and may be associated with less financial toxicity. The current evidence supports the use of PBI in appropriately selected patients with early-stage breast cancer. Further investigation is needed to evaluate the outcomes of PBI in patients with various clinical and tumor characteristics, and to define optimal radiation treatment dose and technique for PBI.

The efficacy of intra-articular triamcinolone acetonide 10 mg vs. 40 mg in patients with knee osteoarthritis: a non-inferiority, randomized, controlled, double-blind, multicenter study.

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BACKGROUND: Intra-articular (IA) corticosteroid injection is recommended in refractory knee osteoarthritis patients. However, 40-mg of triamcinolone IA every 3 months for 2 years reduces cartilage volume as compared to saline IA.

OBJECTIVE: To determine the non-inferiority of 10-mg versus 40-mg of triamcinolone acetonide (TA) for treatment of pain in symptomatic knee osteoarthritis at week 12.

METHODS: This was a double-blind, randomized, controlled trial conducted in 84 symptomatic knee osteoarthritis patients. The 10-mg or 40-mg of TA were 1:1 randomized and injected to the affected knees. The primary outcome was the 12-week difference from baseline in pain VAS, with a pre-specified lower margin for non-inferiority of 10 mm. The measuring instruments used were: Visual analog scale (VAS: 0-10), modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), EuroQol Group 5 Dimensions (EQ5D), Knee Injuries and Osteoarthritis Outcome Score (KOOS) questionnaire, chair standing test and 20-m walking time at baseline, at week 4, and week 12 after randomization. Adverse events were recorded.

RESULTS: Baseline characteristics were similar between two groups. The mean differences of pain VAS (95% confidence interval: CI) between the two groups at baseline and week 12 were 0.8 (-0.8, 2.4) with p of 0.002 for non-inferiority. There were no differences in pain reduction and quality of life improvement between 10-mg and 40-mg groups. The mean differences (95%CI) of WOMAC, KOOS pain, EQ5D and KOOS quality of life between baseline and week 12 were 0.4 (-1.1, 1.9). -8.7 (-21.3, 3.9), 1.3(-7.1, 9.6) and 1.8 (-11.5, 15.0), respectively. There were significant improvements in pain and quality of life between baseline and week 12 in both groups.

CONCLUSION: The 10 mg of TA is non-inferior to 40 mg TA in improving pain in patients with symptomatic knee OA. Both 10 mg and 40 mg of TA significantly improved pain and quality of life in patients with symptomatic knee OA.

Learn How to Identify Nutrient Deficiencies

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Our body requires vitamins, minerals, and other nutrients for optimum functional efficiency. Any kind of deficiency is a serious problem and should be recognized and treated without delay. The good news is that the human body is like a mirror, reflecting deficiencies within external symptoms.

If you are vigilant and make it a point never to ignore these symptoms, you can easily detect a deficiency at an early stage and correct it. A blood test can confirm certain vitamin deficiencies, but as mentioned, nutrient deficiency symptoms are reflected in five important parts of the body.

1. Head

  • Hair loss is a sign of vitamin deficiency. Common deficiencies include folic acid, vitamin B5, vitamin B6, and EFAs (essential fatty acids). Vitamin A toxicity or other environmental toxicities may also cause hair loss.
  • Dandruff problems indicate EFA, antioxidant (especially selenium), or B-complex deficiencies.
  • Premature greying is a sign of pantothenic acid (vitamin B5) deficiency.

2. Face

  • Dark circles under the eyes can indicate low levels of quercetin and vitamin C.
  • Acne is mostly caused by zinc, EFA, and vitamin A deficiency and may be triggered by the over-consumption of bad fatty acids like those present in fried, oily food.
  • Tooth decay is a sign of deficiency of vitamin B6 and minerals like boron, calcium, and silica.
  • Bleeding gums are a result of inadequate intake of vitamin C and bioflavonoids.
  • Cracks at the corners of the mouth are a sign of deficiencies in B2 (riboflavin) and other B-complex vitamins.
  • Sore tongue may be a sign of B12, folic acid, iron, and/or zinc deficiency.
  • Pale tongue may indicate low iron levels, so an iron test is recommended.

3. Skin

  • Dry skin is often caused by deficiencies in EFAs, vitamin A, and/or vitamin E.
  • Skins tags around the neck, arms, and back are a sign of glucose intolerance or reactive insulin levels.
  • Small red bumps on the back of arms may be indicative of deficiencies in vitamin A, vitamin E, zinc, and EFAs.
  • Easy bruising of the skin may indicate low levels of vitamins K, C, or E, and/or bioflavonoids.
  • Slow wound healing is a sign of deficiencies in vitamin A, vitamin C, zinc, and/or EFAs. It may also indicate the presence of diabetes.

4. Hands and Nails

  • Hangnails and cuticle inflammation may be a sign of zinc deficiency.
  • Skin cracking at the tips of fingers showcases deficiencies in zinc, vitamin E, or EFAs.
  • Cold hands are a sign of deficiencies in EFAs, niacin (vitamin B3), vitamin E, vitamin B12, or iron.
  • Flat angle/spooning of nails may be a result of iron deficiency.
  • Ridged nails are caused by low levels of minerals.

5. Feet

  • Nail abnormalities in the feet and toes similar to those found in hands (such as ridged nails), may indicate the same vitamin deficiencies.
  • Tingly feet with poor circulation are a sign of vitamin D3 deficiency. You may need to get more sunlight!

Deficiencies of essential vitamins, minerals, and other nutrients are usually a result of poor dietary habits like low intake of fruits and vegetables. If you eat a balanced diet, you can easily prevent vitamin deficiencies. For example, eating more foods rich in vitamin E (like almonds) can help to overcome skin and hair hassles that are very common nowadays.

If you have one or more symptoms highlighted above, consider discussing them with a healthcare provider. Some of these symptoms may also point to a deeper issue, such as venous blood clots, kidney disorders, or thyroid disease. Take a stand and protect your body from vitamin deficiencies by eating healthy!

5 Simple Tricks to Get Rid of Irritating Nighttime Leg Cramps

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Leg cramping during vigorous exercise is one thing, but leg cramping in the middle of the night is something else entirely. It’s perplexing, it’s painful, and it keeps you awake!

Poor sleep causes a poor mood and low functionality the next day, so this is a no-brainer; it’s essential to figure out how to get rid of leg cramps. To that end, we’ve compiled a handy list of DIY methods for treating and preventing painful leg cramps. But first, let’s make sure we’re all on the same page; what exactly are nighttime leg cramps?

Nighttime, or “nocturnal,” leg cramps are pains in the legs that occur most frequently when you are lying in bed at night. They can happen to both men and women but mostly occur in people over the age of 50. Painful cramps occur when the leg muscles tighten for between several seconds and several minutes, and the pain is often localized to the calf muscles, thighs, or feet.

Now that we’re clear on what they are, what causes nighttime leg cramps? Well, we certainly know the triggers. Sitting still for long periods of time, or conversely, overexerting the muscles, can cause cramping later in the day. TipHero suggests that standing or working on concrete floors and sitting with poor posture may also contribute.

You might also experience leg cramps if you have a pre-existing medical condition such as alcoholism, chronic dehydration, Parkinson’s disease, diabetes, or a neuromuscular disorder. Also, nighttime cramps are quite common for pregnant women.

So, you’re experiencing nighttime leg cramps; what can you do? The pain of leg cramping may well leave you immobilized, but acting immediately will diffuse the pain and residual soreness more quickly. And we all know what that means: better sleep.

Epoch Times Photo
Extend both legs on the floor in front of you. Flex your feet at the ankles and draw your toes toward your knees.

Try These Five Techniques for Relieving Leg Cramps:

1. Extend both legs on the floor in front of you. Flex your feet at the ankles and draw your toes toward your knees. Deepen the stretch by pulling your feet gently further toward you; use a scarf or towel if you have difficulty touching your toes.

2. Get up and take a gentle walk around the bedroom, shaking your legs as you go.

3. Massage the painful area, rubbing in firm circles with your thumbs to increase blood circulation.

4. Loosen blankets and bedsheets to ensure that your legs are not compressed.

5. Take a tablespoon of yellow mustard. This one may sound a little “out there,” but it does seem to work! Mustard contains acetic acid, which prompts the body to produce more acetylcholine, the chemical that motor neurons release in order to activate (de-cramp) the muscles.

mustard
Mustard contains acetic acid, which prompts the body to produce more acetylcholine, the chemical that motor neurons release in order to activate (de-cramp) the muscles.

How Can You Prevent Nighttime Leg Cramps?

But we all know the old adage “prevention is better than a cure.” Try any number of these five easy rituals and see if you can banish painful cramping for good.

1. Enjoy a warm bath before bed, or apply a heat pack to problem areas before you go to sleep.

2. Perform some gentle stretching exercises so that your muscles can relax between the sheets.

3. Go swimming or join an aqua aerobics class a couple of evenings a week to promote strength in your leg muscles.

4. Avoid wearing high heels during the daytime.

5. Consider using a supplement containing horse chestnut seed or leaf. It can help increase blood flow to the legs.

No list of health hacks would be complete without a sensible disclaimer, however: If all else fails, or symptoms persist, see your doctor. If you are so inclined, they may even be able to refer you to alternative therapists such as an acupuncturist. But with consideration, self care, and this handy how-to guide, it may not come to that.

Sleep easy, and make nighttime leg cramps a thing of the past!

How Garlic Can Help Clogged Arteries

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This powerful food does so much more than add flavor to your meal

(NIKCOA/Shutterstock)

(NIKCOA/Shutterstock)

Garlic is one of the most powerful foods around, and for good reason. Apart from its known antibacterial, antifungal, and antimicrobial properties, garlic has been documented in studies to prevent and treat cardiovascular diseases, high blood pressure, and diabetes, to name a few. It’s also famed for helping to unclog arteries.

Atherosclerosis is a complex disease in which plaque, which is made up of fat, cholesterol, calcium, and other substances, builds up inside the arteries. In the long run, plaque hardens and narrows the arteries, limiting the flow of oxygen-rich blood to the organs and the rest of the body.

The condition can lead to serious conditions such as heart attack and stroke. Here are five ways that garlic assists in treating or preventing clogged arteries.

1. Inhibits Vascular Calcification

Aged garlic extract has been shown to reduce multiple cardiovascular risk factors such as high blood pressure. A 2004 study published in Preventive Medicine evaluated its ability to inhibit vascular calcification, which serves as a marker of plaque formation in coronary arteries.

In the double-blind, small pilot study conducted for a year, aged garlic extract demonstrated the ability to inhibit the rate of coronary calcification in patients on statin therapy compared to placebo.

Finding a three-fold reduced progression in coronary calcification in those taking an aged garlic supplement versus a placebo, researchers wrote that should their findings be confirmed in larger studies, garlic may prove beneficial for patients who are high-risk for future cardiovascular events.

2. Increases Vascular Elasticity and Endothelial Function

A stressful lifestyle is a known risk factor for the presence and worsening of atherosclerosis. A study published in Nutrition (Burbank, Los Angeles County, California) probed the effect of aged garlic extract in tandem with coenzyme Q10 (CoQ10) on vascular elasticity (how much our blood vessels can expand and contract) in a group of firefighters.

The combination was linked to significant benefits to vascular elasticity as well as endothelial function among the firefighters, who experience high stress at work. The combination emerged as a potential way to prevent atherosclerosis in such individuals.

Separate research published in Journal of Cardiovascular Disease Research evaluated the effects of garlic and CoQ10 on coronary atherosclerosis and inflammatory biomarkers, concluding that participants taking the combination had significant improvements in their coronary artery calcium as well as C-reactive protein levels. The results suggested improved heart health.

3. Inhibits Nanoplaque Formation

In a 2004 study published in Wiener Medizinische Wochenschrift (1946), garlic successfully inhibited lipoprotein associated arteriosclerotic nanoplaque formation. The experiments showed that garlic extract strongly inhibited calcium ions binding to proteoheparan sulfate, resulting in the blunting of the formation of what is responsible for “nanoplaque” composition and ultimately for the arteriosclerotic plaque generation.

4. Protects Against Aortic Stiffness

A cross-sectional observational study published in Circulation evaluated healthy adults taking standardized garlic powder for at least two years and a control group, then measured the elastic properties of their aorta.

Blood pressure levels, heart rate, and plasma lipid levels were similar in the groups. However, chronic garlic powder consumption slowed age-related increases in aortic stiffness, supporting the protective effects of garlic intake.

5. Reduces Atherosclerotic Progression

Aged garlic extract was combined with supplements to check the effects on inflammatory and oxidation biomarkers, vascular function, and the progression of atherosclerosis in a study published in Preventive Medicine.

In the trial, 65 subjects with intermediate risk for the disease were treated with either a placebo or a capsule containing aged garlic extract plus vitamin B12, folic acid, vitamin B6, and l-arginine, given daily for a year. The garlic and supplement mix were associated with improved oxidative biomarkers and vascular health, and a reduced progression of atherosclerosis.

A related study published in International Journal of Cardiology found aged garlic extract therapy plus supplementation with vitamin B12, folic acid, vitamin B6, and L-arginine were associated with a lack of progression in coronary artery calcium, along with increased ratio of brown adipose to white adipose tissue.

These are only some ways that garlic displays therapeutic properties against calcification problems of the cardiovascular system.

NICE recommends genetic test to prevent deafness from antibiotics in newborn babies

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A genetic test to establish whether a newborn baby is vulnerable to deafness if treated with gentamicin has been recommended in draft guidance by the National Institute for Health and Care Excellence (NICE).1

The Genedrive kit works by detecting the m.1555A>G variant from a swab of DNA from inside a newborn’s cheek, with results available in under an hour. If the m.1555A>G variant is found the baby can be treated with alternative antibiotics, which cannot be more widely used because of antibiotic resistance.

At present laboratory testing would not produce results within an hour in line with guideline recommendations, and babies who go deaf after being given gentamicin are discovered to have the variant only afterwards, with DNA testing. The estimated cost of treating hearing loss with a bilateral cochlear implant is around £65 000 (€73 200; $78 500) in the first year.

Evidence presented to the NICE committee from the Paloh study2 carried out in Manchester and Liverpool showed no statistically significant difference between the time to antibiotic treatment between standard care and when using the Genedrive device, suggesting that the test would not delay the time taken to administer antibiotics.

Gathering evidence

The Genedrive kit has been assessed through NICE’s Early Value Assessment pilot project, which has been created to enable earlier access to digital products, medical devices, and diagnostics to tackle national unmet needs in health and social care.

Once the kit is in use the NHS will collect real world evidence to ensure that the test can be applied in a variety of maternity settings and that it does not lead to increased use of antibiotics associated with higher risk of antimicrobial resistance or a longer time to antibiotic treatment. The results will then be scrutinised by the independent NICE committee as part of the kit’s full assessment.

Mark Chapman, interim director of medical technology at NICE, said, “The costs associated with hearing loss to the NHS are high, so driving an innovation like Genedrive into the hands of health and care professionals to enable best practice can also ensure that we balance the best care with value for money, delivering both for individuals and society as a whole.”

Susan Daniels, chief executive of the National Deaf Children’s Society and lay specialist committee member, said, “Speaking both as a deaf person and as chief executive of the National Deaf Children’s Society, it’s very encouraging that more evidence will be gathered on this important development. I hope this additional evidence will support the argument for the rollout of technology, which could play a pivotal role in preventing deafness in a small number of babies in the future.”

Is This the Biggest Threat to Our Survival?

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The pressing problems of water scarcity and water pollution

(michaeljung/shutterstock)

While some say ‘climate change’ is the No. 1 threat to humanity, this threat is capable of putting your life in immediate lethal peril. And it’s not just a third world issue – signs are popping up all over the US that we’re in trouble. Be prepared to face the unthinkable with these timely tips.

STORY AT-A-GLANCE

  • One key environmental threat facing mankind today is the increasing lack of potable water, worldwide, thanks to a combination of water pollution and scarcity. Infrastructure — especially in the U.S. but also elsewhere — is also in dire need of repairs and upgrades
  • During a single week in September, 2022, E.coli contamination was found in Baltimore, toxic arsenic levels were discovered in New York City, and in Jackson, Mississippi, 180,000 people are left without running water due to a water system breakdown
  • Hazardous water pollutants include but are not limited to arsenic, fluoride, nitrate, pharmaceutical drugs, pesticides, per- and polyfluoroalkyl substances (PFAS) and microplastics
  • In San Francisco, wastewater from 37 sewage plants has turned the San Francisco Bay a murky brown, and dead fish litter its shores. The cause for the die-off is a toxic algae bloom, triggered by the nitrogen and phosphorous from the feces and urine in the discharged wastewater
  • NASA mapping of groundwater storage trends for the earth’s 37 largest aquifers reveals 21 aquifers have already exceeded their sustainability tipping points and are being depleted, and 13 of them are considered “significantly distressed, threatening regional water security and resilience”

While the globalist cabal claims “climate change” is the No. 1 threat to humanity, necessitating radical quality of life sacrifices and the total relinquishing of privacy and freedom, there are far more pressing problems. One key environmental threat facing mankind today is the increasing lack of potable water, thanks to a combination of water pollution and scarcity. Without potable water, we’re in immediate lethal peril.

Groundwater aquifers rapidly depleting, resulting in water scarcity, higher prices, land cave-ins and water wars. On top of that, much of the world’s remaining water supply has become too contaminated to drink or even bathe in, and infrastructure — especially in the U.S. but also elsewhere — is nearing the end of its useful life and is in dire need of upgrades.

Water Contamination Commonplace Even in Developed Countries

News of dangerous water contamination in the U.S., reported in the first week of September 2022 alone, include:

•E.coli contamination in Baltimore, Maryland, thanks to aging water pipes and poorly maintained wastewater infrastructure.1

•Toxic arsenic levels in New York City tap water rendering it unsafe to drink.2

•The complete breakdown of the water infrastructure in Jackson, Mississippi, after the treatment plant got flooded, leaving some 180,000 people without running water.3 When something does come out of the tap, it’s mud brown.

As in Baltimore and Flint, Michigan,4 this crisis could have been avoided if proper maintenance and upkeep of infrastructure had been prioritized.

The Biden administration has now earmarked $429 million to help repair Jackson’s crumbling water and wastewater systems, but the final price tag has been quoted to run into the billions, and will take many months, if not years, to complete. In the meantime, residents are in a life-or-death crisis.5

According to the World Health Organization, more than 2 billion people worldwide drink water contaminated with feces,6 resulting in hundreds of thousands of deaths due to preventable diseases each year.

Water sources in both developing and developed countries are also contaminated with toxic chemical pollutants that treatment plants are not prepared to filter. Among the most hazardous water pollutants are arsenic, fluoride, nitrate, pharmaceutical drugs, pesticides, per- and polyfluoroalkyl substances (PFAS) and microplastics.7

Algae Blooms Are a Costly Problem

According to a September 5, 2022, article in the San Francisco Chronicle,8 wastewater from 37 sewage plants dumped into the San Francisco Bay has turned the water a murky brown, and dead fish litter the shores. (While hard to believe, an estimated 80% of global wastewater is released into the environment untreated.9)

An estimated 10,000 yellowfin goby and hundreds of striped bass and white sturgeon have washed ashore so far. The cause for the die-off: toxic algae bloom, triggered by the nitrogen and phosphorous from the feces and urine in the discharged wastewater.

Harmful algae bloom (HABs) will turn the water red and release neurotoxic compounds that are then passed up the food chain. It also depletes the water of oxygen, eventually — if not properly addressed — creating a dead zone where no life can be sustained.10 As reported by the San Francisco Chronicle:11

“The regional water board has told agencies that it will probably require caps on nutrients in wastewater when their regional permit comes up for renewal in 2024.

But upgrading dozens of aging treatment facilities could cost $14 billion, which would double or triple ratepayers’ water bills, [executive officer of San Francisco Bay Regional Water Quality Control Board, Eileen] White said in an interview.

‘It’s a multibillion-dollar Bay Area issue that needs to be thought through very carefully, taking the science into effect,’ she said. ‘There’s all of sorts of different treatments, and none of them are cheap’ …

Federal, state and local governments and the treatment plants themselves have spent millions to research the issue, but like much of climate change planning, the science and policy are moving slower than the problem is progressing.”

Some water treatment plants could help address the problem using already existing infrastructure. The San Jose/Santa Clara Regional Wastewater Facility, for example, has been able to reduce the nitrogen load of its wastewater from 17 to 11 milligrams per liter, at no extra cost, simply by directing the water through a series of four tanks containing nitrogen-consuming bacteria before it’s discharged.

Wastewater Could Be a Source of Reusable Phosphorous

One of the important resources found in wastewater is phosphorus. This mineral is an essential nutrient for plant growth, which is why many fertilizers include it. And, while widespread across the Earth, there are limited areas where it is found in concentrated form.

However, wastewater contains a significant amount, as phosphorus is not only found in human excrement but also in detergents. Removing and reusing phosphorus from wastewater would not only increase supply, but would also reduce the risk of algae blooms.

The U.N. has proposed12 that removing and recovering phosphorus, nitrogen and other nutrients from wastewater could prevent hyper-growth of HEBs in lakes and rivers, while simultaneously providing a unique business opportunity to recuperate a finite resource essential for agriculture. The Blue Plains Advanced Wastewater Treatment Plant has been doing this for years already, as seen in the 2012 video report above.

Pharmaceutical Pollution Is Widespread

Anything and everything you flush down the drain ends up somewhere and, oftentimes, the end destination is your local waterways. Pharmaceutical drugs are particularly problematic, as water treatment plants are not equipped to filter out these compounds.

Water treatment plants fail to filter out an estimated 93% of the drug compounds in wastewater, and a 2017 U.S. Geological Survey found 80% of U.S. waterways contained pharmaceutical pollution,13 which can have a devastating impact on aquatic species.

Proper disposal of drugs, lotions, creams and perfumes is paramount to the reduction of water pollution. By using all-natural and unscented personal care products, dropping off unused and expired drugs at a drug take-back site and not flushing any medication down the toilet, you can reduce your personal pharmaceutical footprint.

If you’re in the U.S., the Food and Drug Administration has tools to help you find a local drug take-back location on its Drug Disposal: Drug Take Back Locations page.14

Firefighting Foam Contaminates Water Across the US

Firefighting foam also poses a serious threat to our water supplies. In 2015, investigative journalist Sharon Lerner published an extensive series15 of articles about the dangers of PFAS16 (two of the most well-known ones of which are PFOA and PFOS) and the industry’s attempts to cover up the damage.

Part 1517 addressed the U.S. military’s affinity for toxic flame retardants, despite the fact that billions of dollars are being spent trying to clean up drinking water contaminated by firefighting foam used on military installations. Many other PFAS chemicals18 — such as PFHxS, PFHpA, PFBA and PFBS — have also been detected in drinking water, yet the military is only attempting to clean up PFOA and PFOS contamination.

Around hundreds of U.S. military bases, PFAS have leached through the ground, contaminating surrounding groundwater. In addition to prostate cancer and thyroid problems, these chemicals have been linked to other types of cancer as well, including kidney, testicular and bladder cancer, as well as immune dysfunction, reproductive problems and hormone disruption.

Considering the public health threat posed by PFAS contamination, courtesy of firefighting foam, you’d think the U.S. government would take proactive measures to eliminate the use of these toxic chemicals. After all, other countries are using PFAS-free firefighting foam, and it works just as well. Alas, this is not happening.

Incomplete data make it very difficult to ascertain how widespread the PFAS-contamination might be, but drinking water near at least 46 military installations in the U.S. have been found to contain PFOA and/or PFOS at levels exceeding 70 parts per trillion (ppt), which is the EPA’s health advisory level for drinking water.19

If you live anywhere near a military installation or fire department fire-training area, consider getting your tap water tested for PFAS and other toxic contaminants. Water testing is a prudent step no matter where you live these days, as is filtering your water, as there are literally hundreds of potential water contaminants that can harm your health.

Factory Farm Contamination

Another major source of water contamination is runoff from factory farms. In addition to farming chemicals such as nitrates, which pose a serious threat to water quality, there’s the issue of drug-resistant bacteria, which are a result of antibiotic overuse in livestock.

When it comes to water pollution from farms, the problem is twofold. First, regular farming is exempt from the Clean Water Act. Second, while farms registered as concentrated animal feeding operations (CAFOs) are regulated under the Act, many simply don’t apply for the required National Pollutant Discharge Elimination System permits, which dictate what you’re allowed to discharge into national waterways.

Between 2011 and 2016, the number of CAFOs in the U.S. increased by 956, to a total of 19,496, yet the total number of CAFO discharge permits didn’t go up but actually declined by 1,806 during that period.20 Many farmers also don’t bother with nutrient management planning, which is voluntary, even though there are plenty of conservation practices that can help reduce water pollution.21

The Global Crisis of Vanishing Groundwater

Industrial farming also uses enormous amounts of potable water for irrigation, and in many areas, aquifers are being drained faster than they can be refilled, resulting in water scarcity.

NASA mapping of groundwater storage trends for the earth’s 37 largest aquifers reveals 21 aquifers have already exceeded their sustainability tipping points and are being depleted.

According to the U.S. Department of Agriculture, about 80% of U.S. consumptive water (and more than 90% in many Western states) is used for agricultural purposes.22

NASA mapping23 of groundwater storage trends for the earth’s 37 largest aquifers reveals 21 aquifers have already exceeded their sustainability tipping points and are being depleted, and 13 of them are considered “significantly distressed, threatening regional water security and resilience.” Considering groundwater accounts for 99% of potable freshwater,24 the depletion of aquifers is a serious concern. As reported by the Pacific Institute:25

“Depleted groundwater aquifers can take thousands of years to be replenished by rain, snow, and other sources. This option can be off the table when an aquifer becomes so depleted it loses its capacity to store water.

In the U.S., the Ogallala Aquifer, which stretches across parts of Colorado, Kansas, Nebraska, New Mexico, Oklahoma, South Dakota, Texas, and Wyoming, illustrates this concern.

A history of groundwater overdraft threatens to deplete the aquifer. Once depleted, it’s estimated the Ogallala Aquifer could take more than 6,000 years to be naturally replenished …

A 2021 Pacific Institute study26 highlighted connections between California groundwater management and local communities’ ability to access water — with significant water equity concerns.

California’s Sustainable Groundwater Management Act (SGMA) was created to help protect groundwater, but the study showed minimum groundwater thresholds defined by SGMA would leave many people vulnerable to losing their water access.”

What Are the Solutions?

There tends to be a “free-for-all” mentality at play where the one who can afford to drill the deepest well wins in the short term, but everyone loses in the long term. Groundwater as a resource needs proper governance and management. Farmers also need more efficient irrigation systems, and we need engineering solutions to improve the refill rate of aquifers.

On a personal level, we also need to make changes in how we use water, and how we grow crops. Selecting the most appropriate crops for any given area would result in more efficient water usage, and would reduce the amount farmers would have to draw from our aquifers. In short, we need to grow food with less water.

The good news is we already know how to do that, and it’s called regenerative agriculture. It’s been well-proven that regenerative agriculture biodynamic farming is far more water efficient than industrial farming. To learn how, see “Regenerative Food and Farming: The Road Forward.”

With water wars becoming a reality even in developed nations (just look at California, where the battle over water allocation has been ongoing for more than a decade27), you’d be wise to give serious thought to emergency water preparations.

Not only do you need a source of water, were your tap water to stop running, but you also need to have the proper supplies on hand to filter and decontaminate that water to make it safe to drink.

Filtering the water you use for drinking, cooking and bathing is, I think, an absolute necessity these days, no matter where you live — unless you’ve had your water tested and are satisfied that it’s pure (which is rare). I recommend installing a whole-house filter system to ensure optimal water quality from your tap.

In an emergency situation, however, when tap water is unavailable, you’ll need to source your water elsewhere and that can be a real challenge, as people in Jackson, Mississippi, are now finding out.

In “How to Secure Your Water Supply for Emergencies,” I review ideas for alternative water sources, such as collecting spring water, or water from a local stream or river, which is far from ideal but might work in the short-term, and setting up a rain catchment system, which is a far more sustainable, long-term solution.

I also go over basic water purification and disinfection guidelines. Rainwater is often thought to be pristine, but it’s not, so even rainwater needs to be properly filtered before drinking.

The time to sort out your emergency plans is now, while municipal water and supply chains are still operational. Once an emergency hits, it’s too late to start thinking about installing wells or rain barrels and buying water filters, as by then the things you need might be incredibly difficult to get.