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Book Review: You Finished Treatment-Now What?

 

A Field Guide for Cancer Survivors.
By Dr. Amy Rothenberg

You-Finished-Treatment-Now What

You Finished Treatment, Now What? A Field Guide for Cancer Survivors by Dr. Amy Rothberg is a roadmap for lifestyle and natural medicine approaches to address health challenges that persist after cancer care, and to reduce the risk of recurrence.

Dr Rothenberg wrote this guide for cancer survivors and those on their support and care team.

You Finished Treatment, highlights the evidence for an integrative approach to healing that Dr. Rothenberg has used for over 37 years practicing as a licensed naturopathic doctor.

She is also a breast and ovarian cancer survivor/thriver herself. She wrote this book to make sense of an overwhelming topic, in a user-friendly, accessible way, providing both actionable information and inspiration.

As a survivor/thriver of both ovarian cancer and breast cancer she speaks both from the physician’s and the patient’s point of view with heart, levity and solid, practical advice.

When diagnosed with cancer in 2014, Dr. Rothenberg sought and received state-of-the-art care at a renowned teaching hospital and had her own naturopathic medical team to help her best handle treatment, and rebound afterward.

Her writing is evidence-informed, while also bringing her personal experience as a doctor, patient, wife, mother, sister, and friend. Offering a natural, integrative medicine perspective on items in the news, find Dr.

This is an example of the principles employed in Dr. Chilkov’s OutSmart Cancer® System which is an integrative approach to combining the best of modern oncology with the best of research informed modern and traditional naturopathic systems of medicine for the very best outcomes.

This approach allows patients to have not only a plan for their disease, but also a plan to support their health during and after treatment and to support recovery, restoration and rejuvenation in support of both healthspan and lifespan.

Dr. Rothenberg’s both personal experiences and medical expertise combine to form a heartful and pragmatic approach with clear guidelines and recommendations. This book is a wonderful resource for both patients and families as well as care providers.

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Breast-Cancer

Changing the Management of Cancer with Personalized Testing

 

Personalized cDNA surveillance for patients with high-risk breast cancer

Is there a more sensitive technology that can detect preclinical breast cancer progression?

It is now possible to monitor fragments of cell free tumor DNA (ctDNA) circulating in the blood. This falls under the umbrella of “liquid biopsies” which monitor tumor burden, tumor response to treatment and early signs of recurrence or progression without a scan or need for a new surgical or biopsy tissue sample.

  • “Up to 30% of patients with breast cancer relapse after primary treatment.
  • There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence.
  • Breast cancer cell free tumor DNA blood test (liquid biopsy) can detect recurrence up to 2 years earlier than currently available conventional serum tumor markers and radiologic studies.
  • Cell free tumor DNA assays predict breast cancer recurrence earlier and with greater accuracy than traditional tools by using a highly-personalized molecular residual disease assay.

A cell free tumor DNA (ctDNA) assay is a personalized, tumor-informed assay with the power to give you earlier, clearer insight into your patient's disease. By detecting and quantifying ctDNA, you can optimize your ability to assess risk, predict recurrence, and monitor treatment response in those most at risk for progression.

This technology can be used to monitor a wide range of cancers. While this type of monitoring has not yet been widely adopted as “standard of care” I encourage you to educate all of your patients and their care providers to adopt the use of this highly reliable screening tool now.

Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.”

Cell free tumor DNA assays use a sample of the patient’s tumor tissue to develop a unique DNA fingerprint. After that, follow-up blood draws capture changes in the level of ctDNA, giving clinicians a better picture of a patient’s risk of recurrence without the need for another tissue sample and may decrease the need for frequent scans and repeated frequency of exposure to radiation and contrast material.

neodjuvant

A recent study “demonstrates that patient specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention. “(1)

Currently, there are no sensitive and specific clinical tests available to follow patients with breast cancer after primary treatment. Signatera developed a patient-specific method to analyze circulating tumor DNA (ctDNA) that allows for monitoring of these patients regardless of molecular genotype. In this study, we analyzed 208 blood samples from 49 patients monitored longitudinally for up to 4 years after completion of adjuvant chemotherapy to determine whether personalized ctDNA assays can allow for more effective monitoring than current clinical tests such as CA 15-3. Remarkably, for the patients that recurred, our test detected molecular relapse up to 2 years ahead of clinical relapse (median, 8.9 months) with 89% sensitivity and 100% specificity. This may provide a critical window of opportunity for additional therapeutic intervention.” (1)

hope

Data from a retrospective cohort analysis of EBLIS, a study designed to determine the lead interval between ctDNA detection and clinical metastatic disease, and to determine whether ctDNA in plasma can detect recurrent disease earlier than traditional methods, demonstrated that Signatera can accurately predicts metastatic relapse with a significant lead time over imaging and CA 15-3 (200 days on average)

Neoadjuvant

“…our study shows promise that early response prediction by highly sensitive ctDNA analysis in high-risk early breast cancer patients may facilitate a timely and judicious change in treatment to improve patients’ chances of achieving favorable long-term outcomes.(2)

Surveillance

Patients undergoing treatment as well as those who have completed their course of treatment can be assessed both for response to treatment during a course of therapy as well as for early signs of reurrence after treatment has been completed. In a study of patients undergoing treatment with Pembrolizumab, a checkpoint inhibitor.

“Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.” (3)

Recommended labs offering this technology include Natera, INVITAE, Foundation One, Caris Life Sciences. All of these labs are highly regarded in the oncology community. (Disclosure: I have no financial relationships with any of the labs recommended in this article.)

How often should these assays be performed?
I recommend monitoring monthly during active treatment to determine if the current treatment is effective and continuing to be effective. This is a way to identify treatment resistance early.

top10-badgeI recommend monitoring every three months during the first two years after completing treatment or for patients with advanced receiving ongoing treatments. (For example advanced breast cancer patients receiving hormonal treatments, immunotherapy treatments, checkpoint inhibitor treatments or chemotherapy treatments over long periods of time.)

For long term survivors I recommend monitoring every 6 months until the 10 year No Evidence of Disease anniversary.

This is the same schedule of monitoring that we use in the OUTSMART CANCER® System to follow measurable biomarkers in the tumor microenvironment.

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References

  1. Coombes C, Page K, Salari R, et al. Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence. Clinical Cancer Research. 2019;25(14):4255-4263.
  2. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival M. J. M. Magbanua. https://doi.org/10.1016/j.annonc.2020.11.007
  3. Bratman, S.V., Yang, S.Y.C., Iafolla, M.A.J. et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer 1, 873–881 (2020). https://doi.org/10.1038/s43018-020-0096-5
  4. https://www.natera.com/info/know-breast-cancer/?utm_source=cancer-therapy-advisor&utm_medium=email&utm_campaign=breast-cancer-launch
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breast-cancer

Should PreMenopausal Breast Cancer Patients Receive Endocrine Therapy?

 

Endocrine Therapy Provides TwentyYear Benefit in ER+ Breast Cancer

Integrative and Individualized cancer care is the best cancer care and yields the best long term outcomes. Making individualized care decisions and including a health model, not just a disease model and following the OutSmart Cancer® Diet Guidelines are core principles of the OutSmart Cancer® System.

Two years of adjuvant endocrine therapy in premenopausal patients with estrogen receptor-positive (ER+) breast cancer can reduce the risk of recurrence at 20 years, according to a study published in the Journal of Clinical Oncology. (2)  This study is meaningful because many oncologists recommend five to ten years of endocrine therapy.  This study clearly demonstrates that only two years is sufficient to significantly reduce risk of breast cancer recurrence 20 years after completion of conventional oncology treatment.  This study also demonstrates that women who are candidates for and who do not receive endocrine therapy have worse outcomes. 

Furthermore this study demonstrates that women with low genomic risk should receive tamoxifen and women with high genomic risk should receive goserilin for best long term outcomes.

By including an integrative approach utilizing the health principles of the OutSmart Cancer® System, we can further manage the side effects of these treatments and support healthy function and quality of life for these women.

OUTSMART CANCER SYSTEM® Integrative Approach and Health Focussed Model

chinese-characterEspecially supportive to management of adverse menopausal effects of endocrine therapy include acupuncture therapy(3), copper free bone mineral formula and optimized Vitamin D as well as traditional Chinese Herbal Tonics

 that nourish yin and blood and support kidney qi to modulate menopausal symptoms without estrogenic effects such as Er Xian Tang (Two Immortals Formula)  and also formulas to address hormone depletion related mood dysregulation, depression and irritability such as Shu Gan Tang (Buplerum and Evodia Combination) to harmonize the liver qi and relieve stagnation of blood and emotions.  Furthermore, patients with estrogenic cancers should be given guidance on restricting estrogenic foods from their diets as part of a lifelong plan to prevent recurrence. For example,  both red meat (7) and alcohol (6) are known carcinogens linked to promotion of breast cancer and should be restricted.  Following the OutSmart Cancer® Diet Guidelines is recommended 

Monitoring for complications of endocrine therapies

Patients receiving Tamoxifen therapy  (an oral selective estrogen receptor modifier) should have semi-annual uterine ultrasound to measure endometrial thickness to assess risk of uterine hyperplasia and neoplasm as a risk of tamoxifen therapy.

Patient receiving goserilin  (an injectabl luteinizing hormone releasing hormone antagonist administered subcutaneously either every month or every 3 months) should monitor bone density by having a baseline DEXA bone density scan at inception and at 2 years and also Urine N-Telopeptide assay to monitor rate of loss of bone minerals due to medical menopause and estrogen blockade.

Results of Study

Researchers observed significant improvements in long-term distant recurrence-free interval (DRFI) for patients who received goserelin alone, tamoxifen alone, or the combination of goserelin and tamoxifen, when compared with patients who did not receive endocrine therapy. 

However, combination goserelin and tamoxifen did not improve DRFI when compared with either agent alone.

Researchers assessed the 20-year benefit of endocrine therapy by analyzing data from the Stockholm trial (1990-1997). The analysis included 584 patients with ER+ breast cancer. The median age at baseline was 47 (range, 26-55) years, 91% of patients had progesterone receptor-positive tumors, and 88% had HER2-negative tumors.

Patients were randomly assigned to 2 years of goserelin (n=155), tamoxifen (n=135), combined goserelin and tamoxifen (n=149), or no adjuvant endocrine therapy (n=145).

In a multivariable analysis, any endocrine therapy was associated with a significant improvement in long-term DRFI, when compared with no endocrine therapy. 

There was a significant improvement in DRFI with goserelin alone (hazard ratio [HR], 0.49; 95% CI, 0.32-0.75), tamoxifen alone (HR, 0.57; 95% CI, 0.38-0.87), and goserelin plus tamoxifen (HR, 0.63; 95% CI, 0.42-0.94). 

However, there was no significant long-term benefit from the combination of goserelin plus tamoxifen, when compared with either agent alone. There was a significant interaction between goserelin and tamoxifen (P =.016). 

The researchers also assessed the long-term benefit of endocrine therapy in patients with low genomic risk (n=305) and those with high genomic risk (n=158). 

Patients with low-risk genomics had a significant improvement in DRFI with tamoxifen (HR, 0.24; 95% CI, 0.10-0.60), and patients with high-risk genomics had a significant improvement in DRFI with goserelin (HR, 0.24; 95% CI, 0.10-0.54).

Patients with high-risk genomics had significantly worse DRFI when tamoxifen was added to goserelin (HR, 3.36; 95% CI, 1.39-8.07). The interaction between goserelin and tamoxifen was significant in high-risk patients (P =.006) but not in low-risk patients (P =.080). 

“This study demonstrates long-term benefit from 2 years of adjuvant endocrine therapy in ER-positive premenopausal patients,” the researchers concluded. “Furthermore, it suggests long-lasting benefit from tamoxifen in genomic low-risk patients with long-term risk of distant recurrence, whereas genomic high-risk patients have early risk and benefit from goserelin.”

Isoflavones genistein and daidizen are phytochemicals derived from soy act  that act as MILD selective estrogen receptor modulators. These isoflavones need to be taken in very high doses on a long term basis to achieve a clinical impact and are mild in comparison to pharmaceuticals.  A recommended daily dose of genistein is 1000mg 3x/day

This study will help us support patients in making educated and informed choices and in making sure that their oncologists are practicing in accordance with the most current research and guidelines and that patients 

 

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Using Phytochemicals

Using Phytochemicals Synergistically with Chemotherapy to Improve Efficacy and Outcomes

 

The role of polyphenols in overcoming drug resistance. 

In a paper published in January 2022, Maleki Dana et al, engage in a thorough review of multiple polyphenols which, when used concurrently with chemotherapy, can inhibit the development of chemo-resistance, rendering treatment more effective and for a longer duration of time.    

Most oncologists are wary of negative drug-herb, drug nutrient interactions. 

 

polyphenols-fruits

This review shows that we can use polyphenol phytochemicals synergistically with chemotherapy treatments to support efficacy and outcomes.

 

The Outsmart Cancer® System is an Integrative Cancer Care model seeking to develop highly individualized care plans that include the best therapeutic approaches and tools from multiple disciplines, combining a disease focused targeted pathology model with a whole biosystem health model to support the best outcomes for patients.

 

Acquired drug resistance has become a challenge that may result in treatment failure.  Multiple factors contribute to chemo-resistance in cancer cells. Acquired drug resistance occurs when cancer cells fail to respond to a previously effective treatment.  Intrinsic  chemo-resistance occurs when a pre-existing factor causes a drug to be inefficient or ineffective.

 

Due to the inherent heterogeneity of tumors, subpopulations of cells may develop resistance while other subpopulations remain sensitive to treatment.  

This is the rationale for using multiple agents which impact multiple signally pathways and receptors to target a wide array of heterogeneous cells.  This is also the rationale for using multiple nutriceuticals, botanicals and phytochemicals concurrently to address multiple signaling pathways and functions.

In this excellent review paper the author focuses on the multiple synergistic functions of polyphenols citing multiple studies.

 

Polyphenols from medicinal plants and food plants form a large part of our Materia Medica. Polyphenols include several subclasses such as catechins, flavonoids, flavones, flavonols, anthocyanins, isoflavones, curcuminoids, chalcones and phenolic acids. These natural compounds are widely found found in deeply pigmented fruits, vegetables, cocoa, seeds and green and black teas,

 

Not only do polyphenols inhibit multiple pathways and mechanisms of drug resistance, but also act to  confront many of the Hallmarks of Cancer, thus inhibiting and controlling the activity and viability of malignant cells.

 

The multiple functional roles of

  • Resveratrol
  • EGCG Epigallocatechin gallate
  • Curcumin 

are discussed and examined in depth examining multiple pathways, mechanisms of action and dosing.

Also discussed are additional well researched polyphenols, many of which are sourced from food plants as well as medicinal plants including

  • Quercetin 
  • Baicalin
  • Baicalien
  • Apigenin
  • Chrysin
  • Luteolin
  • Kaempferol

Mechanisms which lead to drug resistance in tumor cells

Malignant cells are highly adaptive and respond to toxic stressors such as chemotherapeutic drugs in the tumor micro-environment in service to their own survival.  Essential malignant cells are “smart” and they can not only co-opt normal physiologic and metabolic functions within cells to respond to the presence of toxic drug therapies.

  • Decreased Drug Uptake by tumor cells
  • Drug Efflux from tumor cells (membrane pumps)
  • Alterations in drug metabolism
  • Epigenetic Modification and Signaling
  • Inhibition of Programmed Cell death via apoptosis, autophagy and necrosis in tumor cells
  • Alterations in DNA repair 
  • Activity of Cancer Stem Cells
  • Redox Capacity of cells in response to oxidative stress
  • Alterations in Epithelial to Mesenchymal Transition, Invasion and Metastatic Progression

Not only are polyphenols capable of addressing the common Hallmarks of Cancer, but they can also inhibit the multiple ways that malignant cells seek to survive in the face of drug therapies.  

 

Therefore, we should strategically combine chemo-therapeutic  agents with selected polyphenols to both enhance therapeutic effect as well as inhibit the development of drug resistance. 

 

This leads to greater therapeutic benefit, increased duration of action as well as skillful management of adverse effects.

I encourage you to read this paper in detail for a deep and detailed review of the mechanisms of these pleomorphic multitaskers polyphenols.  The polyphenols mentioned in this paper have a history of wide use and safety.

 

Our role is to both eradicate and inhibit neoplastic cells as well as nurture and support the health of the patient.  This is at the heart of the OutSmart Cancer® System.

 

References

 

The Role of Polyphenols in Overcoming Cancer Drug Resistance: A Comprehensive Review 

Maleki Dana et al

Cellular and Molecular Biology Letters (2022) 27:1

https://doi.org/10.1186/s11658-021-00301-9

 

Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg, 2011

https://doi.org/10.1016/j.cell.2011.02.013

 

Revisiting the hallmarks of cancer

Fouad YA, Aanei C.. Am J Cancer Res. 2017 May 1;7(5):1016-1036. PMID: 28560055; PMCID: PMC5446472.

 

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Clinical Pearl-cancer

Clinical Pearl: Chemotherapy Reduces Magnesium to Dangerously Low Levels

 

Hypomagnesia occurs in 29-100% of cancer patients receiving chemotherapy.

Magnesium deficiency is common in cancer patients, especially those receiving chemotherapy.  Magnesium is the second most abundant intracellular cation after potassium. It is involved in >600 enzymatic reactions in the body.

Hypomagnesia induces  fatigue , mitochondropathy (compromised mitochondrial function )and risk for neuropathy, nephropathy as well as abnormal cardiovascular function (arrhythmia, hypertension) immune dysfunction, headache and altered bone and Vitamin D metabolism.  Hypomagnesia is associated with nausea, vomiting, headache, myalgia, constipation, anxiety, insomnia and depression, all common complaints of cancer patients.

Long term and extreme hypomagnesia promotes cancer treatment related fatigue, cortical blindness, insulin resistance, prolonged QT interval, hypertension, seizures, tremor, psychiatric disturbances, migraine headaches and is associated with chronic inflammation and oxidative stress.

Magnesium status declines with age.

As cancer patients are typically over 50 years old, hypomagnesia may be present long before diagnosis. Pre-menopausal women and athletes also have higher needs of magnesium and may be deficient. 

This may influence the tumor microenvironment towards carcinogenesis, tumorogenesis, proliferation and progression.

Both oral and intravenous repletion relieve many of the hypomagnesia related adverse effects.

Adverse effects can be prevented by supplementing with magnesium in advance of as well as after chemotherapy. In a health model, keep patients replete with Magnesium at times to optimize function, prevent deficiency syndromes and adverse symptoms of chemotherapy.

Monitoring and Management of Magnesium Status

All patient care plans include oral Magnesium Glycinate Chelate

Daily Dose: 600-900mg daily in capsule, liquid or powder form

(Glycinate and Bis-Glycinate chelates are more well absorbed and less likely to have a laxative effect than other forms of magnesium chelate). Excess oral magnesium can lead to diarrhea. Spread out oral dosing over 3-4 doses per day to achieve repletion without loose stool.

Extreme Hypomagnesia can be quickly repleted by intravenous infusion.

All patients are monitored for Serum RBC Magnesium to assess magnesium status every 3-6 months long-term and monthly during active chemotherapy.

Serum Magnesium is not a reliable indicator of Magnesium deficiency.

 

Dietary Sources of Magnesium include:

Almonds, cashews, brazil nuts, pumpkin seeds, flaxseeds, cocoa, avocados, dark leafy greens, seaweed

 

Chemotherapeutic agents that induce hypomagnesia:

Platinum Chemotherapy Agents : Oxaliplatin, Cisplatin, Carboplatin and

Taxanes:  paclitaxel (Taxol) nab-paclitaxel (Abraxane), docetaxel (Taxotere),Cabazitaxel (Jevtana).

Vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine.

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