Why You Should Think Twice About Neulasta Or Neupogen When On Chemotherapy

By Donnie Yance

“The most telling and profound way of describing the evolution of the universe would undoubtedly be to trace the evolution of love.” ― Pierre Teilhard de Chardin

Introduction

Cancer patients frequently experience weakened immune systems from both their tumor burden and aggressive conventional treatments. While medical advances like colony-stimulating factors and erythropoietin have helped address some complications from chemotherapy and radiation treatments, these solutions often provide only temporary relief from long-term immune system damage in both clinical and outpatient contexts.

Research has demonstrated that controlled endotoxin exposure can significantly boost immunity in immunocompromised cancer patients and other vulnerable populations by counteracting the suppression of the immune system by viruses. However, this presents a complex challenge, as cytotoxic cancer treatments typically cause prolonged suppression of the immune system, which increases patients’ vulnerability to secondary cancers and other complications.

This immune system suppression remains one of the most significant challenges in modern cancer treatment, requiring careful balance between aggressive therapy and maintaining the body’s natural defenses. The role of herbal, nutritional, and dietary medicine can fill a significant role in this otherwise huge dilemma.

Accumulating evidence exists for (1) an inverse correlation between the incidence of infectious diseases and cancer risk and (2) a correlation between febrile infections, a fever, and remissions of malignancies.

A fever awakens the immune system, and when our body temperature rises, cells produce heat shock proteins and various immune signaling pathways and cells which activate the immune system to fight off infection; and sometimes it goes after the cancer cells as well.

The phenomenon of spontaneous regression and remission from cancer has been observed by many physicians and was described in hundreds of publications. However, suggestive clues on cause or trigger are sparse and not substantiated by much experimental evidence. At least in a large fraction of cases a hefty feverish infection is linked with spontaneous regression in time and is investigated as a potential trigger.

I wrote an extensive blog on the benefits of a fever (March 2020) entitled, “Don’t Fear A Fever: The Importance of Working With, Not Against the Immune System in Warding Off Infection” you may want to review it here.

Don’t Fear A Fever: The Importance of Working With, Not Against the Immune System in Warding Off Infection

What Are Colony-Stimulating Factors?

The PEGylated human granulocyte-colony-stimulating factor, Neulasta (pegfilgrastim), and Neupogen (filgrastim), are both granulocyte-colony-stimulating factors (G-CSFs). The drugs have the same parent molecule, but Neulasta is a longer lasting formulation so that only one injection is needed per chemotherapy cycle, while Neupogen requires injections everyday for up to 14 days.

They are both most often given as subcutaneous injections after chemotherapy and are used clinically to help stimulate white blood cell (WBC) production and reduce the incidence and duration of severe neutropenia (low neutrophils) in patients who have received chemotherapy treatment. 

In theory, this may reduce bacterial infections and even sepsis.  Patients with neutropenia can become susceptible to infections with bacteria, viruses, or fungi. The FDA has approved Neulasta to be given at least 24 hours following initiation of chemotherapy. 

The recommended dosage of Neulasta is a single 6-mg subcutaneous injection once per chemotherapy cycle. Neulasta should be given approximately 24 hours after the administration of cytotoxic chemotherapy but no later than 14 days prior to the next cycle.

Sargramostim (Leukine ®) is a granulocyte macrophage-colony stimulating factor (GM-CSF), it is seldom used, but appears to be far better.

Both types of growth factors, G-CSFs and GM-CSFs, can improve WBC production.³ Most medical institutions use G-CSF, and this is the most established type and one that has been studied the most.  These growth factors are specifically used in chemotherapy-induced neutropenia to accelerate neutrophil recovery.  G-CSFs may be given during the first cycle of chemotherapy to help prevent neutropenia throughout all of the chemotherapy cycles. 

But, there is a dark side to these drugs that I want to share with you.

“If you meet an angel, you will have not peace, but a fever.” Stefano Benni

The Dark Side of Colony-Stimulating Factor Injections

By modulating the functions of innate immune cells, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. 

While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much GM-CSF can exhaust immune cells and promote cancer growth. 

G-CSF and GM-CSF have been shown to promote tumor growth due to their suppression of immune cells that fight tumors, and through the promotion of angiogenesis (formation of new blood vessels that can feed tumors).

How Did These Drugs Become Part Of Standard Practice With Many Chemotherapy Protocols?

The main reason to justify the use of Neulasta, is so cancer patients can stay on the recommended chemotherapy regimen and not delay treatment.  Often, after several rounds of chemotherapy, the marrow does not recover enough to stay on schedule, and cancer patients need to delay treatment in order to recover.

Individual patient data from 11 clinical trials and observational studies using chemotherapy regimens with a risk of febrile neutropenia (FN) compared Neulasta vs no G-CSF treatments. Overall, febrile neutropenia was less frequent with Neulasta than without.

One of the main studies used for the approval stated that “Patients in the placebo arm not only experienced significantly more neutropenic events than patients in the Neulasta arm, but more than 65 percent of these events occurred in the first cycle of treatment.”

I am not sure this is reason to justify approval when no long-term studies had been done.

One important fact is that skipping a week and waiting for a patient to recover from bone marrow suppressive effects of the chemotherapy treatment may not reduce the treatment effectiveness.  So, taking a week off is fine to allow your body to fully recover.  Although one study did find an association between treatment delay and reduced 5 year all-cause mortality in breast cancer patients.

G-CSF has provided disappointing results in primary prevention, and its use is only justified for patients receiving chemotherapy that causes febrile neutropenia in at least 40% of cases: patients with acute leukemia, elderly patients, and patients with cancer-related neutropenia or poor general status, etc. In these patients, G-CSF reduces the incidence of febrile neutropenia and, possibly, the risk of hospitalization.

The second point is that neutropenia from chemotherapy is associated with significantly better response and more importantly survival rates. 

For some reason, this immune system side-effect actually helps patients live longer. 

Chemotherapy-Induced Neutropenia and Treatment Efficacy

Chemotherapy-induced neutropenia (CIN) has been demonstrated to be a prognostic factor in several cancer conditions. Recent research has found a significant prognostic value of CIN on overall survival (OS), in a pooled dataset of patients with advanced non-small-cell lung cancer (NSCLC) receiving first line chemotherapy.

Many studies show that neutropenia can often lead to beneficial outcomes:

• Chemotherapy-induced neutropenia was a predictor of better survival for patients with advanced non-small-cell lung cancer.

• Early-onset CIN during perioperative chemotherapy is predictive of better overall survival (OS) and disease-free survival (DFS) in patients with completely resected cancers.

• Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer. 

• Neutropenia during chemotherapy is an independent predictor of increased survival in patients with advanced gastric cancer.
• Of patients with metastatic colon cancer, an early-onset of CIN predicted longer survival.
• Patients with metastatic colon cancer who have experienced large decreases in neutrophils have longer survival times than smaller decreased levels or patients with no neutropenia.
• Severe neutropenia is associated with better clinical outcomes in patients with advanced pancreatic cancer who receive modified FOLFIRINOX therapy.
• Both neutropenia and high blood pressure are independent markers that the biologic medication sunitinib is working better in metastatic renal cell carcinoma.
• Financially, it has been shown that primary prevention (giving G-CSF to all patients to try to prevent neutropenia) may not be cost effective compared to secondary prevention (giving G-CSF as a treatment only after the neutropenia has occurred). 

Known Common Side Effects Of Colony Stimulating Factors

• Bone pain, musculoskeletal pain, and deep bone pain affect 30-49% of patients
• Pain is likely caused by bone marrow expansion, altered bone metabolism, nerve sensitization, and histamine-induced inflammation
• Side effects peak around 24 hours post-injection when blood levels are highest

Laboratory Abnormalities

• Low RBCs (bone marrow anemia)
• Low Lymphocytes 
• High white blood cell counts (≥100 x 109/L) may occur
• Up to 20% experience elevated:
  • Lactate dehydrogenase
  • Alkaline phosphatase
  • Uric acid

Special Considerations

• Cancer risk: G-CSF receptors found on some cancer cells may promote growth 
• Not approved for stem cell mobilization
• Use with caution in sickle cell patients
  • Risk of severe or fatal sickle cell crisis
• Kidney disease – Glomerulonephritis possible
  • Usually resolves with dose reduction or discontinuation
• Inflammation of the aortic wall following G-CSF administration has been reported in 0.3-0.47% of cases.

Other Adverse Effects of G-CSF Supplementation Include:

• G-CSF Can Worsen Anemia in Early Breast Cancer Patients.

• Recent studies have found that G-CSF plays an important role in cancer progression. G-CSF expression is increased in different types of cancer cells, such as lung, gastric, colorectal, bladder, glioma, and breast cancers. 

• G-CSF Can Induce Blood-Building Dysregulation and the Progression of Solid Tumors.These immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (Tregs), actively suppress anti-tumor immune responses.

Signaling pathway of G-CSF in breast cancer. 

In the breast cancer microenvironment: 1) CEACAM1 downregulation promotes G-CSF secretion by TAMs, thereby promoting tumor angiogenesis and initial tumor establishment. 2) By acting on G-CSFR on TAMs, G-CSF increases transforming growth factor-α secretion to promote tumor cell migration. 3) G-CSF increases Ly6G+Ly6C+ granulocytes, which are a type of MDSC and further promotes the production of the proangiogenic factor Bv8 to enhance breast tumor metastasis. 4) BMP4 inhibits the expression and secretion of G-CSF by inhibiting NF-κB, resulting in decreases in the number and activity of MDSCs. 5) In a hypoxic environment, HIF1/2 upregulates CAIX and increases G-CSF expression by activating the NF-κB signaling pathway, which then promotes the mobilization of MDSCs and eventually leads to the lung metastasis of breast cancer. 6) Activation of the AKT-mTOR signaling pathway increases G-CSF expression in tumor cells, thereby promoting the accumulation of MDSCs. MDSCs promote the expression of stem-associated genes, including Nanog, LGR5 and MSI-1, in cancer cells via Notch signaling to promote tumor progression. Direct effect of G-CSF on breast cancer: 7) Stable expression of G-CSF induced by H-Ras upregulates the expression of MMP-2 by activating Rac 1 and promotes the migration/invasion of breast epithelial cells. In addition, overexpression of G-CSF activates other signaling pathways, including MKK3/6, p38 MAPK, ERK1/2 and AKT, thus promoting an invasive phenotype in breast epithelial cells. 8) TNF-α promotes the expression of G-CSF by activating the ERK2 signaling pathway to promote tumor invasion. TNF, tumor necrosis factor; AKT, protein kinase B; G-CSF, granulocyte-colony stimulating factor; HIF, hypoxia inducible factor; MAPK, mitogen associated protein kinase; NF, nuclear factor; mTOR, mammalian target of rapamycin; MDSC, myeloid-derived suppressor cell; CAIX, carbonic anhydrase IX; MMP, matrix metalloproteinase; ERK, extracellular signal regulated kinase; TAM, tumor-associated macrophages; CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1. 

When we force rapid white blood cell production through G-CSF agents, we’re essentially creating an inexperienced immune army.

This premature immune system lacks the sophistication needed to handle complex tasks like fighting cancer cells and defending against diverse pathogens. More concerning is that these agents primarily boost neutrophil production at the expense of the lymphocytes – a critical oversight since lymphocytes are the white blood cell subset most crucial for both viral defense and cancer cell elimination.

By artificially skewing the balance of white blood cells, we may inadvertently be compromising the immune system’s ability to mount an effective, coordinated response against both cancer and infections. 

The complexity of immune function requires a balanced, mature approach – not just raw numbers of neutrophils.

More Research That Substantiates All Of What I Just Said

• G-CSF has tumor-promoting effects on both tumor cells and the tumor microenvironment. G-CSF has a direct effect on tumor cells to promote tumor-stem-cell longevity, and overall tumor-cell proliferation and migration. 
• It may promote pro-tumorigenic immune cell phenotypes such as M2 macrophages, myeloid-derived suppressor cells, and regulatory T cells.
• GCSF suppresses interleukin (IL)12 and/or IL2 induced interferon (IFN)gamma production and cytotoxicity of decidual mononuclear cells.
• G-CSF decreases IFN-γ and increases IL-4 production in vitro and in vivo and likely modulates a balance between TH1 and TH2 cells.

• GM-CSF activates four main signaling networks including the JAK/STAT, PI3K, MAPK, and NFκB pathways. 

The mechanism of abnormal differentiation in hematopoietic stem cells driven by tumor-derived G-CSF and GMCSF. Granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) have high affinity for their receptors, and then downstream signaling pathways are activated, including JAK/STAT, PI3K/AKT, and RAS/Raf1/MEK pathways. These signaling pathways play a significant role in regulating the differentiation and proliferation of hematopoietic stem cells (HSCs) by inducing the transcription of target genes such as Bcl-xl, C-myc, Cyclin D1, Survivin, S100A8, and S100A9.

G-CSF Can Increase Red Blood Cell Aggregation, Which Isn’t Good For Cancer Patients

Red blood cell (RBC) aggregation is the reversible clumping of red blood cells under low shear forces or at stasis. The prognostic value of RBC aggregation indices has been demonstrated in various diseases.

The level of RBC aggregation is a marker for inflammation, and is used in one of the most fundamental standard blood tests, the erythrocyte sedimentation rate (ESR). 

RBCs play an important but complex role in blood clotting and hemostasis. While RBCs can support normal clotting by helping platelets move toward vessel walls (margination), inducing RBC aggregation in cancer patients is not recommended. 

Cancer patients already face increased risks of thrombosis, and promoting RBC aggregation could potentially exacerbate clotting complications in this vulnerable population.

G-CSF Promotes New Blood Vessels By Releasing Vascular Endothelial Growth Factor (VEGF) From Neutrophils 

G-CSF promotes angiogenesis through multiple mechanisms. Research has shown that neutrophils, but not monocytes, release vascular endothelial growth factor (VEGF) when pre-stimulated with G-CSF. 

This G-CSF stimulation leads to increased neutrophil counts in circulation along with elevated plasma VEGF levels leading to increased angiogenesis and potential cancer growth. 

The importance of the VEGF pathway in this process is demonstrated by the fact that blocking VEGF signaling prevents G-CSF-induced angiogenesis. Additionally, G-CSF increases circulating VEGF receptor-2 (VEGFR2) endothelial progenitor cells (EPCs) compared to controls.

This research suggests that G-CSF administration to ischemic tissue represents a promising and safe therapeutic approach for improving neovascularization. 

This process of neovascularization can be good for wound repair or heart disease, but is terrible for cancer patients.

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis Via Cancer Stem Cell Activation 

In neuroblastoma there exists a special group of cells called cancer stem cells (CSCs). These cells can be identified by a specific receptor called G-CSF receptor (G-CSFR).

When G-CSF binds to this receptor, it activates a protein called STAT3 specifically in these cancer stem cells. 

This activation helps these cells multiply both in lab experiments and in living organisms.

When we added extra G-CSF to neuroblastoma models in mice, the tumors grew larger and spread more easily. We discovered that STAT3 creates a continuous cycle by increasing the production of G-CSFR, which helps maintain the cancer stem cell population.

When G-CSF-STAT3 cycle was blocked using either antibodies against G-CSF or drugs that inhibit STAT3, we observed three important effects:

• The number of cancer stem cells decreased
• Tumor growth slowed down
• The cancer became more responsive to chemotherapy
• The cancer spread less

These findings show that G-CSF is a key factor in activating cancer stem cells in neuroblastoma. This suggests we should carefully reconsider the clinical use of G-CSF in neuroblastoma patients. 

Other Studies Show the Detrimental Effects of G-CSF Including: 

• Neutrophils pre-modified by IL-6 and G-CSF induce changes that ultimately promote tumor angiogenesis and growth, revealing a previously unknown role for G-CSF and IL-6 in modifying neutrophil behavior.
• Treating resistant tumors with both anti-VEGF and anti-G-CSF was more effective at slowing tumor growth than using anti-VEGF alone. Anti-G-CSF treatment greatly reduced certain immune cells linked to tumors and slowed the tumor’s blood vessel growth.
• G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth. Research clearly suggests it might help tumors create new blood vessels through various methods. This could reduce the effectiveness of chemotherapy.
• The use of G-CSF was associated with a doubling in the risk of subsequent acute myeloid leukemia or myelodysplastic syndrome among the population that was studied.
• G-CSF’s effects on nerve outgrowth promote prostate cancer growth and progression.
• The G-CSF appears to be a suppressor of antitumor immunity. Routine administration of G-CSF to cancer patients may not be recommended, except for febrile neutropenia.
• G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions. 

Now that I have presented you with all this data exposing the truth regarding G-CSF agents with chemotherapy, I am sure you are shocked and want to know why this information isn’t presented to the FDA, the Oncologists, or the patients. 

I hope this paper helps people to weigh the risk-to-benefit ratio of using G-CSF to make the best clinical decision.

The other side of the coin is the immense benefits of herbal medicine for bone marrow nourishment and immune restoration during and after chemotherapy. 

Herbal Medicine For Integrative Cancer Care

Chemotherapy, radiotherapy, biologics, and surgery are treatments used in all stages of cancer that weaken the entire body and specifically the bone marrow and immune system.

More specifically, these therapies either alone or in combination have been shown to have numerous limitations and drawbacks including: overall marrow suppression, gastrointestinal tract reaction, cardiac damage, liver and kidney dysfunction, rash, hand-foot syndrome, local radiation damage, and so on.

Herbal medicines have emerged as a promising complementary approach in cancer treatment, offering multiple therapeutic benefits. These natural remedies demonstrate remarkable capabilities in inhibiting tumor growth while simultaneously enhancing the effectiveness of conventional cancer treatments such as chemotherapy and radiation. 

Integrative cancer care has shown the following positive outcomes:

• Strengthens the body’s immune system
• Helps alleviate fatigue and pain
• Improves management of respiratory infections
• Better gastrointestinal function
• Reduced diarrhea, nausea, and vomiting
• Increased protection of the liver and detoxification
• Reduced cachexia or muscle wasting

This comprehensive range of benefits makes herbal medicines an invaluable component of integrative cancer care, supporting patients’ overall well-being while enhancing the effectiveness of primary cancer treatments.

What Mederi Care Offers For Bone Marrow Immune Restoration

Astragalus membranaceus – one of the most well recognized bone marrow and immune enhancing herbs.

Astragalus Formula and Platinum-Based Chemotherapy Versus Chemotherapy Alone 

A meta-analysis of 34 randomized trials showed that astragalus improves survival, increases tumor response, improves performance status, and reduces chemotherapy toxicity.

Trametes Versicolor Extract Active Compounds Polysaccharide K (PSK) & Polysaccharide-Peptide (PSP)

Recently a review paper of nine studies reported the efficacy of medicinal mushrooms including Trametes versicolor (Turkey Tail), in treating symptoms, medication side effects, increased anti-tumor effects, and survival outcomes in gastric, breast, and colorectal cancers. 

Findings from this review suggest that medicinal mushrooms have the potential to reduce lymph node metastasis, prolong overall survival, decrease chemotherapy-induced side effects (e.g., diarrhea, vomiting), affect the immune system, and help maintain immune function and quality of life in patients with certain cancers.

Herbal medicine has been shown to improve blood counts in cancer patients, specifically leukopenia/neutropenia induced by chemotherapy. Meta-analysis showed that herbs significantly reduced the incidence of leukopenia induced by chemotherapy.

Comprehensive Evaluation of Traditional Herbal Medicine Combined With Adjuvant Chemotherapy on Post-Surgical Gastric Cancer 

• A total of 36 randomized controlled trials (RCTs) were included, and data were extracted according to study design.
• The primary outcomes evaluated in these studies included disease control rate (DCR) and overall response rate (ORR). 
• DCR is defined as the sum of complete response, partial response, and stable disease. 
• This measure provides a comprehensive assessment of the control over the disease progression. ORR is calculated as the sum of complete response and partial response, offering a focused view on the effectiveness of the treatment in reducing tumor size and progression. 

Herbal medicine impacts the global immune system, rather than just the neutrophils. Herbal medicine enhances both NK-cell and T-cell activity; increases IL-2 and IFN-gamma secretion from splenocytes, which helps to enhance the efficacy of chemotherapy.

Here is one of the recipes I provide for bone marrow nourishment, that really supports recovery during and after chemotherapy and radiation as well.

May you enjoy the benefits of a healthy immune system while also enjoying this deeply nourishing soup.

About the Author:

Donald R. Yance is the founder of the Mederi Center. A Clinical Master Herbalist and Certified Nutritionist, Donnie is renowned for his extraordinary knowledge and deep understanding of the healing properties of plants and nutrition, as well as of epigenetics, laboratory medicine, oncologic pathology, and molecular oncology. He is a professional member of the American Herbalists Guild, National Association of Nutrition Professionals, Academy of Integrative Health and Medicine, and the Society for Integrative Oncology.

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Over the past 30 years, the world has seen an increase in the rates of cancer in patients younger than 50. Many physicians and scientists around the world have joined in the great detective story to untangle the causes of this complex medical mystery.   

Since the pandemic began, oncologists have been noticing a disturbing rise in cancer cases, including rare cancers among younger adults. Early data from national sources and some large cancer institutions also suggests that there has been an increase in aggressive late-stage cancers. 

“We started noticing some very unusual patterns,” said Kashyap Patel from Carolina Blood and Cancer Care Associates. Patel and his colleagues have seen a 20% to 30% increase in new patients, multiple patients with several different cancers, couples and siblings developing cancers within months of each other, and patients relapsing after years of remission.¹ 

Continue reading “What’s Causing the Alarming Increases in Cancer Among Younger Adults? “

How St. Francis Inspired My Faith Journey

I always find it hard to describe my personal faith because there is so much to it. I was raised Roman Catholic, studied and learned from all the great religions, became a Third Order Franciscan in 1983 in the Eastern Byzantine Rite, and lived in an Eastern Rite Franciscan monastery studying to be a monk for almost three years. More recently, I have embraced a spiritual lifestyle practice called Mussar based in Judaism, and currently, I might say I am still Catholic but with some of the Jewish faith interwoven. At my core, I am a human spirit trying to be a better version of myself, bringing love and goodness to our troubled world. The rest – well, is truly a mystery.

Continue reading “Celebrate St Francis of Assisi Feast Day October 4th”