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People exercising

Reduced Mortality in Cancer Survivors Who Exercise

Exercise is Medicine

In order to be a Survivor-Thriver and significantly reduce risk of recurrence, cancer patients must be encouraged to develop a life-long habit of regular exercise with clear guidelines, measurable goals and behaviors and coaching support if necessary to successfully integrate a new habit. Exercise has the potential to reduce all cause mortality in cancer survivors by 25%.

According to investigator, Lee W. Jones, PhD, of Memorial Sloan Kettering Cancer Center in New York City, in a study involving 11,480 survivors, with 16 year median follow up, patients who followed exercise guidelines enjoyed a 25% reduced risk of all-cause mortality compared with patients who did no exercise (HR 0.75, 95% CI 0.70-0.80).   [1]

Additionally, patients who followed exercise guidelines also showed a significant reduction in cancer mortality (HR 0.79, 95% CI 0.72-0.88), as well as mortality from other causes (HR 0.72, 95% CI 0.66-0.78).[1]

Exercise was associated with a reduction in all cause mortality (for breast, endometrial, head and neck, hematopoietic, prostate, and renal cancers), cancer-specific mortality (for head and neck, and renal cancers), and other cause mortality (for breast, colon, endometrial, hematopoietic, and prostate cancers).

In patients who adopt an active lifestyle and follow exercise guidelines, the benefits may last for two decades after diagnosis.  [2]  Meeting versus not meeting the exercise guidelines was associated with a 25% reduced risk of all-cause mortality, a 21% reduced risk of cancer mortality, and a 28% reduced risk of death from other causes. [2]  

“Compared with no exercise, there were statistically significant reductions in cancer-specific mortality among those exercising below the exercise guidelines and larger reductions for those meeting and exceeding the guidelines, 19%, 25%, and 33% reductions, respectively, which demonstrates that all levels of exercise are beneficial.” [2]

“The American Cancer Society guidelines recommend that physical activity assessment and counseling begin as soon as possible after diagnosis, to help patients prepare, tolerate, and respond to treatments, and manage symptoms and treatment side effects.” [3]

Exercise Guidelines in the study included moderate-intensity exercise 4 or more days per week, with each session, on average, 30 or more minutes in duration and/or strenuous-intensity exercise 2 or more days per week, with each session, on average, 20 or more minutes in duration.

On the very first patient visit I talk about the value and importance of exercise and include an exercise prescription in every patient’s care plan from day one.   I ask patients to accumulate 60 minutes of movement activity daily.  They can start with 10 or 15 minute sessions until they build up more fitness, strength and stamina.  

Unfortunately, only 38% of cancer patients in the study were classified as “exercisers”.    Some cancer patients think, mistakenly, that they should rest and convalesce and that exercise may do harm.  On the contrary, patients undergoing all types of treatments and those in remission and in recovery benefit from some type of appropriate movement.  Of course, each patient should be assessed individually and given appropriate guidelines, training and supervision.   Using apps that track activity can increase interest and compliance.

The reality is that the awareness of the positive impact of exercise is very low among cancer patients and cancer survivors.  Exercise is truly one of the “big levers”, a source of significant impact upon the health, well-being, mood, sleep, bone density, muscle mass, prognosis, quality of life and SURVIVAL of cancer patients.  

I envision all cancer treatment centers having an exercise room at their facility!!!

I propose a new specialty “Exercise Oncology”!  

The OutSmart Cancer System is a HEALTH MODEL.  Every patient receives exercise guidelines, support and coaching to develop and sustain lifestyle and self care habits that create a body where cancer cannot thrive.

Selected References

  1. Jessica Lavery, Lee Jones et al
    Pan-Cancer Analysis of Postdiagnosis Exercise and Mortality
    DOI: 10.1200/JCO.23.00058 Journal of Clinical Oncology  PMID: 37651670

  2.  Stacey Kentfield, June Chan
    Meeting Exercise Recommendations Is Beneficial for Cancer Survivors
    DOI: 10.1200/JCO.23.01528 Journal of Clinical Oncology
    Published online September 20, 2023. PMID: 37729601

  3. Rock CL, Thomson CA, Sullivan KR, et al:
    American Cancer Society nutrition and physical activity guideline for cancer survivors.
    CA Cancer  J Clin 72:230-262, 2022
anxiety-and-depression

Integrative Resources for Cancer-related Anxiety and Depression

The OutSmart Cancer® System is a WHOLE PERSON approach to supporting the health of cancer patients, survivors and their loved ones.  This includes addressing the psycho-social and spiritual needs of our patients.

Anxiety and depression are common human responses both for patients and loved ones  during every phase of the cancer journey, from diagnosis, active treatment, recovery, living with cancer as a chronic illness or as a cancer survivor long term.  Psychological and spiritual concerns often go untreated.

Most patients require some encouragement to talk about their emotional, psychological and spiritual challenges. It is vital to include thoughtful support and resources to all patients, family members and significant others

ASCO

Cancer is a collective experience and everyone close to the patient is touched by the diagnosis and the suffering.   Everyone is transformed by the depth and intensity of the experience.

“I very much like to frame the cancer journey as an opportunity, as a meaningful and sacred gateway in

 one’s life.  It is a time for reflection and inquiry and for clarifying one’s priorities and core values.  

Many patients and families find the depth and intimate nature of the experience to be ultimately transformational and healing, especially when shared.”

I ask  patients to ponder the questions:

  • What gives me strength?
  • What gives me courage?
  • What are my fears?
  • What are my hopes and dreams?

Patients and families are encouraged to take the opportunity to enter into a new phase of life with new learned self-care and lifestyle tools and resources in alignment with the health focused and proactive principles of my OutSmart Cancer® System.

patients-and-families

The Society for Integrative Oncology(SIO) and ASCO (The American Society of Clinical Oncology) have co-published a resource outlining an integrative approach and research supported resources and recommendations for patients during active treatment as well as post-treatment.

“ I think of post-treatment as the rest of your life, not a finite period of time.”

Recommended Interventions from SIO and ASCO include:

  • Mindfulness based interventions/meditation
  • Yoga
  • Tai Chi/Chi Gung
  • Hypnosis
  • Acupuncture
  • Music/Music Therapy
  • Reflexology (Massage)
  • Aromatherapy: Lavender Essential Oil

SIO and ASCO convened a multi-faceted and diverse expert panel. Their literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2023. This team developed evidence-based guideline recommendations. The literature search identified 110 relevant studies (30 systematic reviews and 80 randomized controlled trials) to inform their guidelines.

I also encourage patients to seek appropriate psychological and spiritual counseling, spend time in nature, engage in creative activities  through art, dance, movement, writing, journaling and poetry as well as the recommendations outlined above.

It is possible to transform challenges and suffering into the pearls of new insights, loving-kindness, compassion and wisdom that can richly inform our inner and outer lives at every phase of the cancer journey.

Additional information is available at www.asco.org/survivorship-guidelines

Reference:

Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults With Cancer: Society for Integrative Oncology–ASCO Guideline

Linda E. Carlson, Nofisat Ismaila, Elizabeth L. Addington, et al

Rhodiola

Rhodiola, Mitochondria and Cancer Chemoprevention

Rhodiola (rosea and crenulata spp.) is a botanical adaptogen with broad application in cancer chemoprevention and mitochondrial support for cancer patients undergoing and recovering from cancer therapies.

Rhodiola is considered an adaptogen. It supports multiple functions that enhance resilience, responsiveness and recovery in the face of stress.

mitochondriaRhodiola came to widespread prominence when it was used by Olympic athletes, high altitude mountain climbers and long distance runners to enhance endurance and sustained energy over 50 years ago.

Rhodiola rosea and its primary active phytochemicals, salidroside and rosavins, have been widely studied for effects on cellular metabolism, energy production, inflammation control, oxidative stress, autophagy and cell death.

Salidroside is known to bind to the cell membrane and enter the cytosol via a membrane transporter where it influences AMPK and improves endothelial function and nitric oxide production, enhances glucose uptake and fatty acid oxidation and inhibit and gluconeogenesis and glycogen synthesis.

AMPK activity is required for cells to respond to stress and changes in energy balance.  It is primarily through this pathway that Rhodiola appears to enhance normal mitochondrial function and energy metabolism.  

Salidroside is water soluble and highly bioavailable via oral administration and its metabolites are excreted in the urine.

Rhodiola has also been shown to inhibit tumor promoting mTOR pathway and reduce angiogenesis and metastasis by down-regulating expression of HIF1a/HIF2a signaling. Reducint mTOR expression is a goal in chemoprevention and in optimizing the tumor microenvironment.

Rhodiola has demonstrated positive synergistic effects when combined with the chemotherapy agent cyclophosphamide.  

Rhodiola metabolites are excreted through the urine and one human study showed that patients with superficial bladder carcinoma who consumed Rhodiola orally reduced the average frequency of recurrence by 50%. 

Murine studies have shown that Rhodiola has Immuno-stimulating properties and increases, CD3 and CD4 T cells, Interferon-g and IL-2 cytokines.

Rhodiola demonstrates anti-inflammatory activity by inhibition of COX2, PLA2, NfkB, TNFa, IL-1B and IL-6 which are all upregulated in the tumor microenvironment. Additionally Rhodiola has inhibits expression of the NLRP3 inflammasome which is activated in the lung epithelia both during viral infections as well as malignancy.  (As a side note, this property of Rhodiola may also enhance vaccine adjuvant effect and maturation of dendritic cells and promote immune response to vaccine innoculation)

rhoRhodiola rosea and Rhodiola crenulata  are available as liquid botanical extract and in capsule form. Rhodiola extracts typically contain 3% salidrosides and 1% rosavins.  A therapeutic dose of Rhodiola is 3000mg/day.

A maintenance dose for cell protection and healthy aging ranges from 200-1000mg per day. Always use professional grade supplements and suppliers.

Rhodiola has a wide range of applications in chronic syndromes, healthy aging, and chemo-prevention and recovery by positively influencing multiple pathways in the cancer terrain and tumor microenvironment.

Selected References

Rhodiola and salidroside in the treatment

of metabolic disorders                                               
Xiang-Li Bai, et al, DOI : 10.2174/1389557519666190903115424

Rhodiola rosea L.: an herb with anti-stress, anti-aging, and immunostimulating properties for cancer chemoprevention

Yonghong Li , et al DOI: 10.1007/s40495-017-0106-1

mTOR, AMPK, and Sirt1: Key Players in Metabolic Stress Management                            
Silvia Cetrullo
, et al DOI: 10.1615/critreveukaryotgeneexpr.2015012975 

KNOW

Knowledge in Integrative Oncology Website

KNOW is a tool that allows access to up-to-date research on natural agents in cancer care.

KNOW: Knowledge in Integrative Oncology Website

https://www.knowintegrativeoncology.org/

Phone & Fax: 1-800-908-5175

Email info@knowoncology.org

KNOWintegrativeoncology.org is dedicated to improving the lives of people with cancer through integrative cancer care.

KNOW shares current best evidence on the use of nutrition and natural health products in oncology. Our goal is to inspire collaboration among healthcare providers, researchers, and advocacy groups to support education, safety, and clinical decision-making.

KNOW is a tool that allows access to up-to-date research on natural agents in cancer care. KNOW systematically searches and presents relevant human studies, including clinical trials, from Medline and EMBASE.

In KNOW, data is searchable by tumor type, natural therapy, conventional treatment, and side effects. You can copy references into professional communications, academic projects or presentations, education materials, curriculum, and websites. KNOW provides convenient links to the publisher for full text review or access.

Key Benefits of KNOW

  • Efficient access to current best evidence
  • Improves clinical outcomes
  • Supports development of educational resources
  • Comprehensive and cost-effective
  • Answers questions about natural therapies in cancer care

KNOW also provides Resources for Patients and Provider Network 

  • COMPETENCY AND SAFETY Articles in KNOW provide important information about safety, tolerability, preparation, dosing, and side effects not readily available to clinicians

How KNOW supports you:

✔ Improved efficiency - Enormous energy is spent to distill current literature.

✔ Stay up-to-date - The volume of research in integrative oncology is ever increasing and it's nearly impossible to stay abreast. Our team keeps the website current with summaries of published studies that the average clinician cannot easily acquire.

✔ Knowledge sharing with providers - KNOW references can be pasted into letters, handouts, presentations, and websites..

✔ Evidence-informed practice - Informed decisions require access to relevant research.

✔ Knowledge base for teaching - A central repository of information supports curriculum for integrative residencies, fellowships, and other training programs.

✔ Collaboration for research and publication projects

Membership to KNOW is subscription-based, providing access for individuals, cancer care teams, research groups, academic project groups, hospitals, and public education organizations.

For more information: https://www.knowintegrativeoncology.org/

bone cancer

Higher Risk of Bone Fracture for Cancer Survivors

Cancer stage, chemotherapy treatment, hormonal treatment, menopause status, physical activity and smoking history increase risk of bone fracture for cancer survivors.

Adult cancer survivors, specifically those who have received chemotherapy, hormonal blockade therapy and/or a diagnosis within five years, are at an increased risk for bone fractures.

bone-fracture

Recent studies published JAMA Oncology, also demonstrated decreased risk for physically active survivors and increased risk for smokers.

“These findings are important as the number of cancer survivors living in the United States is projected to rise to 26.1 million by 2040. Research like this seeks ways for cancer survivors to have a better quality of life after their diagnosis,” said Dr. Erika Rees-Punia, senior principal scientist, behavioral and epidemiology research at the American Cancer Society and lead author of the study, in a press release. “Fractures of the pelvis and vertebrae are more than just broken bones – they are serious and costly.”

Rees-Punia, et al analyzed the association between cancer stage and time of diagnosis with risk of pelvic, radial and vertebral fractures compared to adults without a history of cancer including behavior, lifestyle and type of cancer treatment. 

Among 92,431 participants included in the study, 12,943 experienced a frailty-bone fracture. Cancer survivors who were diagnosed with an advanced cancer stage within five years were at the highest risk for bone fractures compared to those without a history of cancer. Osteoporotic fractures occurred in vertebrae, pelvis and hip.

Additionally, cancer survivors who received chemotherapy had a higher rate of fracture, compared to those who did not receive chemotherapy. 

“We hope our findings will inform clinical guidance on fracture prevention, which could incorporate physical activity with exercise cancer professionals and smoking cessation programs, to improve quality of life after a cancer diagnosis,” Rees-Punia added.

Additional risks related to loss of bone density include malnutrition, persistent stress and elevated cortisol, use of steroid hormones, hyperthyroidism, estrogen and androgen hormone blockade therapies, oophorectomy, menopause, extended convalescence.

While clinicians primarily focus on risk of osteoporosis and bone fracture in women, men can also develop fracture risk and loss of bone mass. Men with low testosterone and androgens as well as men with prostate cancer being treated with androgen deprivation therapy should also be monitored for fracture risk and bone health.

Recommended Patient Guidance and Screening to reduce risk of bone fracture include

  • Bone Mineral Supplements Daily. (Copper free and including bone minerals and co factors)
  • Adequate intake of protein daily 
  • Regular weight bearing and resistance exercise
  • Active vs. Sedentary Lifestyle Support
  • Stop Smoking Support
  • Appropriate Bone Density Scans (DEXA)
  • Appropriate N-Telopeptide Crosslinks Urine Tests to assess rate of turnover of bone minerals
  • Consultation with physician to determine if anti-resorptive or hormonal                   medication may be of benefit to manage bone density and fracture risk

Selected References 

Rees-Punia E, Newton CC, Parsons HM, et al. Fracture Risk Among Older Cancer Survivors Compared With Older Adults Without a History of Cancer. JAMA Oncol. Published online November 03, 2022. doi:10.1001/jamaoncol.2022.5153

Suarez-Almazor ME, Pundole X, Cabanillas G, Lei X, Zhao H, Elting LS, Lopez-Olivo MA, Giordano SH.

Association of Bone Mineral Density Testing With Risk of Major Osteoporotic Fractures Among Older Men Receiving Androgen Deprivation Therapy to Treat Localized or Regional Prostate Cancer.

JAMA Netw Open. 2022 Apr 1;5(4):e225432. doi: 10.1001/jamanetworkopen.2022.5432.

PMID: 35363269 

Daya NR, Fretz A, Martin SS, et al. Association Between Subclinical Thyroid Dysfunction and Fracture Risk. JAMA Netw Open. 2022;5(11):e2240823. doi:10.1001/jamanetworkopen.2022.40823

Bauer DC. Clinical Use of Bone Turnover Markers. JAMA. 2019;322(6):569–570. doi:10.1001/jama.2019.9372

Acupuncture

Acupuncture Provides Long Term Pain Relief for Breast Cancer Patients

Acupuncture Provides Long Term Pain Relief for Joint Pain Caused by Aromatase Inhibitors

In a randomized study conducted in November 2022 by a research team headed by Dr. Dawn Hershman MD,  asked


Does short-term acupuncture confer long-term reduction of joint pain related to aromatase inhibitors among women with breast cancer?

acupuncture-for-breast-cancer

This study demonstrated the benefits and highlights the durability of response to Acupuncture which significantly relieved joint pain caused by aromatase inhibitors in women diagnosed with early-stage, hormone receptor-positive breast cancer for one year.

Patients received 18 acupuncture treatments over 12 weeks.

This is a typical and traditional course of acupuncture applied to achieve a  real pattern change and durable outcome.  Controls included an second set of patients who received sham acupuncture and a third group of patients were told their were on a waiting list and received no treatment.   All patients had been receiving AI therapy for at least 30 days at inception. 


Patients were monitored for another 40 weeks and thus were followed for a full year.

“The study was conducted at 11 academic and community sites within the National Cancer Institute Community Oncology Research Program. Sites were required to have 2 trained acupuncturists for the duration of the trial.” (1)

 

Aromatase Inhibitors (AI) are widely used in the treatment of estrogen receptor positive breast cancers.    AI inhibit the transformation of androgens in the tissue into biologically active estrogens which can bind to the receptors on breast cancer cells sending a growth signal. Aromatase inhibitors are usually prescribed after surgery for five to ten years to reduce risk of recurrence in post-menopausal women.  


Commonly used first line AI include Arimidex (anastrozole), Aromasin (exemestane) and Femara (letrozole).


However a common adverse effect is joint pain and stiffness which contributes to non-compliance with therapy for more than 50% of breast cancer patients.  Many patients do not disclose to their physicians that they have discontinued AI therapy due to poor quality of life and persistent pain.

Researchers concluded that “Acupuncture was associated with a statistically significant decrease in aromatase inhibitor–related joint pain that persisted at 40 weeks after discontinuation of the intervention, suggesting long-term benefits of this therapy.”  

acupuncture-for-breast-cancer

(1) The study showed that a full course of therapeutic acupuncture over three months led to a durable change in perceived pain at 52 weeks compared to controls. This study did not follow women past 52 weeks.

Subsequent systemic reviews and meta-analyses (2, 3) of acupuncture trials have also demonstrated efficacy and long term beneficial effect. 

1.Hershman, D. Et al Comparison of Acupuncture vs Sham Acupuncture or Waiting List Control in the Treatment of Aromatase Inhibitor-Related Joint Pain: A Randomized Clinical Trial. JAMA Netw Open. 2022 Nov 1;5(11):e2241720. doi: 10.1001/jamanetworkopen.2022.41720. PMID: 36367721; PMCID: PMC9652759.

2. Liu X, Lu J, Wang G, et al. . Acupuncture for arthralgia induced by aromatase inhibitors in patients with breast cancer: a systematic review and meta-analysis. Integr Cancer Ther. 2021;20:1534735420980811. doi:10.1177/1534735420980811 - DOI - PMC - PubMed

 

3. MacPherson H, et al. ; Acupuncture Trialists’ Collaboration . The persistence of the effects of acupuncture after a course of treatment: a meta-analysis of patients with chronic pain. Pain. 2017;158(5):784-793. doi:10.1097/j.pain.0000000000000747 - DOI - PMC - PubMed

 

Prostate-Cancer-Control

Boron and Prostate Cancer Control

Aside from non-melanoma skin cancer, prostate cancer is the most common cancer among men in the United States. It is also one of the leading causes of cancer death among men of all races and Hispanic origin populations.(1)

Dietary Boron intake is inversely correlated with prostate cancer incidence. (5)

Prostate risk is  52% lower in men whose diets contain at least 1.8mg boron daily. Prostate cancer risk reduction is correlated with boron intake.  Recommended optimal daily dose of elemental boron is 3 mg/day for health maintenance.

Mechanisms of Action

Boron-containing compounds interfere with the physiology and reproduction of cancer cells through diverse mechanisms, including inhibition of serine proteases, NAD-dehydrogenases, mRNA splicing and cell division, receptor binding mimicry, and induction of apoptosis. (2) 

normal-prostate

In several studies Barranco et al (7, 8, 9, 10) demonstrate that increased boron intake is associated with lower levels of Prostate Specific Antigen (a biomarker for prostatitis and prostate cancer) as well as modulation of serum estradiol leading to increased expression of ER-beta receptors and decrease of ER-alpha receptors on tumor cells decreasing proliferation and growth signaling.  Furthermore boron supplementation increased regulation of cell cycle arrest, increased apoptosis, decreased cell adhesion, migration and metastatic progression. 

Boron decreases cancer associated inflammatory factors including hs CRP, TNFa, Interleukin-6 all of which are elevated in the tumor microenvironment.   “Elevated hs-CRP is associated with an increased risk for breast cancer, obesity and metabolic syndrome (MetS) in children, atherosclerosis, unstable angina, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), metastatic prostate cancer, lung cancer, adult depression, depression in childhood and psychosis in young adult life, coronary heart disease, and stroke." (2)

In  murine study Insulin Like Growth Factor was significantly reduced in the prostate tumor cells in boron dosed animals. The IGF-1 signaling pathway promotes cancer progression and its down regulation is associated with lower risk of prostate cancer. (6)

“Increased intracellular concentration of borate activates borate transporters and leads to growth inhibition and increased apoptosis. “ (2) (3) (11)

Boron may act as a Histone De-acetylase Inhibitor (HDI).  HDI’s act as therapeutic agents for cancer due to their impact on gene expression on growth arrest signaling, cell differentiation and apoptosis in cancer cells. (2)

Boronic Acid has been shown to inhibit hypoxia inducible factor (HIF) which is a physiological stimulus for tumor induced angiogenesis.  Inhibition of HIF leads to inhibition of Vascular Endothelial Growth Factor (VEGF) and the production of capillary blood supply to tumor cells. Angiogenesis leads to exponential tumor growth and to metastatic progression of solid tumors. (11)

Plant foods rich in boron include Avocados, dried apricots, dried prunes, raisins, red kidney beans, lentils, almonds, hazelnuts, brazil nuts, pistachios, cashews and walnuts.

In summary, dietary and supplemental oral boron intake should be optimized to create a tumor microenvironment and cancer terrain that decreases risk of prostate carcinogenesis,proliferation and disease progression through angiogenesis and metastasis. 

 

Selected References

1. American Cancer Society Statistics https://cancerstatisticscenter.cancer.org/

2. Scorei RI, Popa R Jr. Boron-containing compounds as preventive and chemotherapeutic agents for cancer. Anticancer Agents Med Chem. 2010 May;10(4):346-51. doi: 10.2174/187152010791162289. PMID: 19912103.

3. Romulus Ion Scorei and Radu Popa, Sugar-Borate Esters –Potential Chemical Agents in Prostate Cancer Chemoprevention  DOI: 10.2174/18715206113139990124 Volume 13, Issue 6, 2013 Page: [901 - 909]

4. Kiliccioglu I, Konac E, Varol N, Gurocak S, Yucel Bilen C. Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines. Genet Mol Res. 2014 May 9;13(2):3721-31. doi: 10.4238/2014.May.9.17. PMID: 24854658.

5. Cui Y, Winton MI, Zhang ZF, et al. Dietary boron intake and prostate cancer risk. Oncol Rep. 2004;11(4):887-892.

6. Pizzorno, L.  Review: Nothing boring about boron. Integrative Medicine Vol. 14, No. 4 August 2015

7. Barranco WT, Hudak PF, Eckhert CD. Evaluation of ecological and in vitro

effects of boron on prostate cancer risk (United States). Cancer Causes Control. 2007;18(1):71-77.

8. Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett. 2004;216(1):21-29.

9. Barranco WT, Eckhert CD. Cellular changes in boric acid-treated DU-145 prostate cancer cells. Br J Cancer. 2006;94(6):884-890.

10. Barranco WT, Kim DH, Stella SL Jr, Eckhert CD. Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells. Cell Biol Toxicol. 2009;25(4):309-320.

11. Shimizu K, Maruyama M, Yasui Y, Minegishi H, Ban HS, Nakamura H. Boron-containing phenoxyacetanilide derivatives as hypoxia-inducible factor (HIF)-1alpha inhibitors. Bioorg Med Chem Lett. 2010;20(4):1453-1456.

OutSmart-Cancer-Immuno-Therapy

Modulating Extreme Adverse Effects of Immunotherapy Treatments

Today, more and more patients are avoiding toxic chemotherapy in favor of targeted cancer therapies.  Among the many new therapies available are a class of immunotherapy drugs that take the brakes off of the immune system and mobilize T cells against tumor cells.

Because tumor cells have the capacity to disable T cells, this therapy addresses the huge problem of immune resistance in many cancers.  Drugs in the class of PD1 and PDL1 inhibitors were some of the first to be developed.  These drugs bind to PD1 or PDL1 receptors on the tumor surface and unleash the fury of the immune system upon the tumors by removing the inhibitory function of these ligands.

Nature has designed the immune system with both a gas pedal and a brake.  The PD1 and PDL1 inhibitors are the brakes.  Take off the brakes and the immune system is activated.

The best of outcomes with these treatments may result in complete tumor eradication, a truly miraculous outcome for some patients.  I have a patient who came to me with Stage 4 Endometrial Cancer with Lung Metastases some years ago.  After reduction of some of her tumor burden with surgery and rather brutal chemotherapy, her very forward-thinking Gynecologic Oncologist included a course of Keytruda (Pembrolizumab), which was a new immunotherapy treatment at the time. 

The historical prognosis for this patient would have been certain eventual mortality for her metastasized aggressive cancer.  However, she achieved a complete response and has been in remission and designated NED or No Evidence of Disease for many years now.   This is a patient who most likely would not be alive today without the advent of PD1 -PDL-1 inhibitor therapy.

The problem with this class of drugs is that their use is very unskillful and very unpredictable. Some patients will respond with a modicum of mild to moderate systemic autoimmune inflammation while other patients will be disabled by furious, extreme, and damaging autoimmune syndromes.  Some patients may die from extreme autoimmune activity.  I had one patient who developed myocarditis and died within a few days of receiving his first dose.  This was a prostate cancer patient whose sudden death was completely unexpected and not predicted.   

These patients require a health model and safe, effective modulation of extreme auto-immune inflammation not provided by their oncology teams. 

Some patients will have immune activation similar to a nice warm burning ember.  They get the therapeutic benefit without extreme adverse effects.  While other patients will respond with a forest fire of inflammation that must be suppressed aggressively with steroid medications for long periods of time.  The adverse effects of long-term steroid therapy then become part of the clinical picture and challenge for these patients.  In these circumstances, it IS reasonable to ask if the cure is worse than the disease itself? 

My patient developed such severe colitis (a common adverse effect) that she visited the emergency room multiple times for fluid and electrolyte replacement due to extreme persistent watery diarrhea.  Additionally, the nutritional status of this patient was also compromised and she became depleted in both calories and nutrients and developed sarcopenia.

Many cancer patients receiving PD1 and PDL 1 inhibitors are left with lifelong autoimmune disease.   Most common are autoimmune arthritis, colitis, thyroiditis, dermatitis, pneumonitis, and associated loss of normal tissue and organ function.  Some patients suffer ongoing chronic inflammatory pain syndromes.

Less prevalent, but also part of the long list of adverse effects are myocarditis, pericarditis, nephritis, hepatitis, pancreatitis, neuritis, vasculitis. Essentially, any tissue or organ can be impacted with associated loss of function and sequelae.

It is my practice to screen and monitor patients receiving cancer immunotherapies for the development of autoimmune syndromes and intervene early.  If I have a patient with a history of inflammatory or autoimmune disorders I can predict that such patients are more likely to develop adverse effects. 

Additionally, high levels of inflammation not only lead to pain syndromes but are also contributors to ongoing chronic fatigue as well as agitation,  cognitive changes, sleep disruption, anxiety, and depression, and the stress of living not only as a cancer survivor but with a chronic and distressing autoimmune syndrome difficult to control and manage.  It is my firm goal that Quality of Life must be a goal in all treatment plans for cancer patients and survivors.

 If a patient has NO inflammatory adverse effects it is assumed that the patient is not going to benefit from the PD1/PDL1 inhibitor because there is no sign or symptom indicating immune activation.   I always tell patients we should celebrate if they develop a rash or diarrhea because we know the drug is working!   

In fact, it is my observation over many years of following patients who have received these therapies that when the course of immunotherapy treatment is completed those patients who continue to have low levels of inflammation continue to have the therapeutic benefit of tumor control.  This is only an empirical observation on my part.  For example, the endometrial cancer patient described above continues to have mild colitis and has remained in remission.  Before the availability of these therapies, we would expect this patient to have a recurrence and to die of her advanced stage 4 metastatic disease within a few years of her diagnosis.   Patients such as this with lung metastases historically had very poor prognoses and very high mortality rates.  Patients with powerful and manageable responses to PD1 and PDL1 inhibitors may live a long time.  While some patients do recur, some have not.  We have not had decades of time to follow these patients as these treatments are relatively new.  If nothing else, these treatments do extend the life of many patients.

How can we modulate the auto-immune adverse effects of these potentially curative immunotherapy treatments?   I have taken the approach that we employ in Functional and Naturopathic Medicine in the management of auto-immune syndromes to turn down the volume on the immune inflammation just enough to reduce extreme side effects, damage, and loss of function without losing the therapeutic benefit of these immunotherapy treatments.   

While we can rely on studies that have demonstrated that Omega 3 Fatty Acids, Vitamin D3, and Curcumin and a healthy microbiome can modulate auto-immune inflammation, there is a paucity of research on managing autoimmune syndromes related to immunotherapy adverse effects with the exception of steroids. (See selected references below.)

I share with you here my empirical clinical experience.  I have employed this approach with several hundred patients since immunotherapies have come into wider use in oncology.  Clinicians experienced in managing autoimmune syndromes will recognize the basic principles of care.

  • Anti-Inflammatory, Low Antigen Diet
  • Support for the healthy intestinal microbiome 
  • Specific Nutriceutical-Phytochemical Interventions
    • Omega 3 Fatty Acids (EPA DHA)  recommended dose 4-6 grams daily SPMs Specialized ProResolving Mediators can also be considered 1-2grams daily
    • Fat soluble Curcumin recommended dose 2-6 grams daily
    • Vitamin D3 5,000-25,000iu daily  (125mcg-625mcg). 
      • Consider a loading dose of 50,000iu (1.25mg)

I always start at the lower end of the dose range and spread the dosing out into 3-4 doses over the day.  The goal is to MODULATE but not SUPPRESS the therapeutic impact.  It is also important to be mindful of the anticoagulant/platelet aggregation inhibitory effect of such an approach and to determine which patients may NOT be a candidate for high dosing due to thrombocytopenia or anticoagulant pharmaceutical therapies.

This approach has few negative drug-nutrient interactions. I have continued these inflammation-modulating therapies continuously for many years with most patients.  Dosing is highly individualized to each patient towards the goal of supporting and promoting healthy function and quality of life.

For front-line clinicians interested in supporting the health of cancer patients and cancer survivors and learning and implementing my OutSmart Cancer® System developed over 35 years in practice, I encourage you to join our training program, Foundations of Integrative Oncology, self-paced online training with clinical supervision and mentoring.  Go to aiiore.com.  

There is a huge population of patients whose lives have been touched by cancer searching for a health model and skilled and knowledgeable clinicians.

Selected References:

Vitamin D and autoimmune diseases.
Illescas-Montes R, Melguizo-Rodríguez L, et al Life Sci. 2019 Sep 15;233:116744. doi: 10.1016/j.lfs.2019.116744. Epub 2019 Aug 8. PMID: 31401314 

Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.
Grover S, Dougan M, et al Cancer. 2020 Aug 15;126(16):3758-3767. doi: 10.1002/cncr.32966. Epub 2020 Jun 22. PMID: 32567084

Therapeutic Potential of omega-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases.
Li X, Bi X, Wang S, Zhang Z, Li F, Zhao AZ.
Front Immunol. 2019 Sep 27;10:2241. doi: 10.3389/fimmu.2019.02241. eCollection 2019.  PMID: 31611873 

Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases.
Abdolmaleki F, Kovanen PT, et al 
Clin Rev Allergy Immunol. 2020 Feb;58(1):82-91. doi: 10.1007/s12016-019-08754-9. PMID: 31267470 

Curcumin in Autoimmune and Rheumatic Diseases.
Yang M, Akbar U, Mohan C.
Nutrients. 2019 May 2;11(5):1004. doi: 10.3390/nu11051004.
PMID: 31052496 

Curcumin and autoimmune disease.
Bright JJ.
Adv Exp Med Biol. 2007;595:425-51. doi: 10.1007/978-0-387-46401-5_19. PMID: 17569223  

Curcumin as an Adjuvant to Cancer Immunotherapy.
Paul S, Sa G.
Front Oncol. 2021 Aug 16;11:675923. doi: 10.3389/fonc.2021.675923. eCollection 2021.
PMID: 34485117 

Gut Bacteria Influence Effectiveness of a Type of Immunotherapy. https://www.cancer.gov/news-events/cancer-currents-blog/2018/gut-bacteria-checkpoint-inhibitors. Feb 2018  NCI Staff

cancer-patient

VITAL TALK: Learn to Communicate Effectively with Patients Experiencing Serious Illness

“Just as no doctor is born knowing how to handle a scalpel, the same is true for how to communicate effectively with seriously ill patients and their families. We believe every clinician can become a better communicator.”

dr-tony

I met oncologist Dr. Tony Back, MD at a meditation retreat focused on working skillfully and mindfully with patients with serious, life changing illnesses as well as end of life care.  Dr. Back is affiliated with the Center to Advance Palliative Care at Fred Hutchinson Cancer Center in Seattle, Washington and has combined his years of clinical oncology experience with his recognition that patients and clinicians require more skillful and effective conversations in the midst of emotionally charged and medically complex discussions. Dr. Back has developed online and in person trainings called Vital Talk for clinicians to LEARN TO COMMUNICATE EFFECTIVELY WITH PATIENTS EXPERIENCING SERIOUS ILLNESS. His mission is “To Elevate Patient Care with better communication”.

Dr. Back and the Vital Talk mission is “that every seriously ill patient will be surrounded by clinicians who can speak about what matters most and match care to values.”

Vital Talk Trainings help clinicians to Master Tough Conversations

Whether in person or online, clinicians feel safe practicing newly learned skills through VitalTalk’s evidence-based training methodologies.

Some tips from a Vital Talk trained physician

Dr. Nalini

  • Give yourself grace
  • Lean in with emotion, heart and feeling
  • Respond with empathy.  
  • Explore and ask the patient to tell you more.  
  • Ask permission to talk about a topic (scan results, disease progression, end of life care)

[READ MORE]

EVIDENCE-BASED SKILLS Vital Talk TRAINING COURSES 

  • Elevate patient care with better communication
  • Explore best-practice communication methodologies and tools, as well as our rich community of support to better serve the needs of patients with serious illness and their families.
  • Support clinicians in learning to communicate effectively and compassionately with patients living with serious illness. 

We are living in the midst of an aging patient population in the United States. Therefore our patients are increasingly at risk of developing more serious illnesses, experiencing co-morbidities and facing many life changes of loss and limitation, frailty and mortality.   Cancer patients of all ages face immense challenges and must redefine their sense of self and examine their values and relationship to life, suffering, death and dying. These challenges may be turned into gateways to transformation.  I counsel my patients to reframe their cancer journey so that the challenges that they face become opportunities for growth, insight and wisdom and not just suffering, grief and loss.   These conversations require clinicians to develop greater communications skills and the ability to be comfortable engaging in these dialogues.

It is my experience that clinicians who are inspired to work with cancer patients are motivated by the drive towards making a difference, the intellectual challenge of the complexity of cancer and the deep meaning that arises in meeting patients at the edge where  the rawness and overwhelm of being a cancer patient can be transformed into a profound healing journey of awareness and transformation.   

I highly recommend that all clinicians continue to develop their clinical skills so that they can be fully present, capable and comfortable for participating in these most tender, human and meaningful conversations.   

I always feel it is a privilege and an honor to be allowed to accompany a patient and their family on their journey and to be able to guide them into deeper meaning and a greater sense of connection to each other and to all of life.

I encourage you to explore The Vital Talk website where you will find information on their programs and trainings but also Free Downloadable Tools and Guides to get you started

https://www.chooseyourpath.vitaltalk.org/

https://www.vitaltalk.org/resources/

Please do share your stories with us!!  

Cancer-SARS

Inflammation, Cancer and SARS-CoV2

Managing Inflammation and Inflammasome in both the Cancer Terrain and SARS-Cov2

There is a subset of cancer patients who suffer significantly more inflammation as well as the sequela of increased inflammation including ongoing cancer related fatigue, increased pain, cognitive deficits.   Similarly there is a subset of COVID-19 patients who suffer a cytokine storm and the wildfire of inflammation that leads to respiratory distress syndrome and mortality. Identifying patients with a higher risk of increased inflammation can be assessed by taking a thorough history in search of historical tendencies and patterns and an analysis of single nucleotide polymorphisms (SNPs).  Patients with IL1B, IL6 and NFkB  SNPs are more prone to developing greater inflammation in both syndromes.

inflammationThe inflammatory drivers and cytokines are similar in both cases: NFkB, TNFa, IL1, IL6, IL8, Inflammasone NLRP3, TGFb1, STAT3, JAK2, p38MAPK, Nrf2, AMPK

Activation of Inflammasome NLRP3 is correlated with the development of the SARS CoV2 cytokine storm.  Inflammasome activation is an important component of innate immunity which enhances inflammation.  Inflammasome activity is correlated with destructive inflammation particularly in viral diseases.  Inflammsome NLRP3  increases IL-1B is also  upregulated in the cancer terrain, particularly in metastatic lung cancer, breast cancer, fibrosarcoma and gastric carcinoma.

curcuminCurcumin exhibits anti-inflammatory and anti-inflammasome properties and can be used in both syndromes.  Curcumin impacts all of the above named inflammatory drivers along with inhibition of COX2 transcription.    Furthermore curcumin acts as an antioxidant increasing control of reactive oxygen species present with increased inflammation.

I recommend Designs for Health Curcumevail, Thorne Research Meriva and Euromedica Curapro.  In managing both the cancer terrain and the SARS CoV2 terrain the dose range is 2g-6g curcuminoids per day.

Another actor, Nrf2, is a nuclear transcription factor that increases the presence of antioxidant proteins when cells are stressed.   Management of the cancer terrain also includes support for normal function of Nrf2.  Nrf2 is highly expressed in the lungs and is responsible for inhibiting the activity of Inflammasome NLRP3.  Sulforaphanes include Di-indole methane, Indole-3-Carbinol and  Sulforaphane glucosinolate.  Broccoli, broccoli sprouts and kale are dietary sources of sulforaphanes.  

antioxidant

I recommend Designs for Health Broccoprotect and Thorne Research Crucera for a high quality source of sulforaphane glucosinolate 50mg twice daily.

Ultimately we may find that the core foundation and targeted supplements used in the OutSmart Cancer System for managing the cancer terrain ALSO protect our patients in the midst of a viral pandemic.

Selected References 

Rajendra Karki et al Inflammasomes and Cancer                                                                                                             PMID: 28093447 DOI: 10.1158/2326-6066.CIR-16-0269

Saeedi‐Boroujeni  et al COVID‐19: A Case for Inhibiting NLRP3 Inflammasome, Suppression of Inflammation with Curcumin?  Ali  https://doi.org/10.1111/bcpt.13503 Volume128, Issue1 January 2021 Pages 37-45

Howrylak JA, Nakahira K. 

Inflammasomes: Key Mediators of Lung Immunity. 

Annu Rev Physiol. 2017;79:471‐494. doi:10.1146/annurev-physiol-021115-105229

James W.Pinkertona1Richard Y.Kima1Avril A.B.RobertsonbJeremy A.HirotacLisa G.WoodaDarryl A.KnightaMatthew A.CooperbLuke A.J.O’NeilldJay C.Horvata1Philip M.Hansbroa  Inflammasomes in the Lung

Molecular Immunology Volume 86, June 2017, Pages 44-55         

Shih-Yi Chuang,1,2 Chih-Hung Lin,3,4 and Jia-You Fang

Natural Compounds and Aging: Between Autophagy and Inflammasome

Biomed Research Int. Volume 2014 |Article ID 297293 | 10 pages | https://doi.org/10.1155/2014/297293                                                    

József Tőzsér1 and Szilvia Benkő

Natural Compounds as Regulators of NLRP3 Inflammasome-Mediated IL-1β Production

Mediators of Inflammation Volume 2016 |Article ID 5460302 | 16 pages                                               https://doi.org/10.1155/2016/5460302