Chemotherapy resistance remains one of the greatest challenges in oncology.
Resistance occurs when cancer cells adapt to survive despite the presence of chemotherapy, rendering treatments less effective over time. This allows cancer to continue to proliferate and spread, making it more difficult to treat.
To counter resistance, higher doses or drug combinations are often used, but these escalate side effects, such as immune suppression and organ toxicity.
Many aggressive cancers including pancreatic cancer, ovarian cancer, and brain cancer (glioblastoma) have demonstrated high rates of chemotherapy resistance, contributing to poor outcomes and mortality.
Resistance has been observed with nearly all major chemotherapy drugs used to treat the deadliest cancers.
For example:
- Platinum-based chemotherapy initially works in 70–80% of ovarian cancer patients, but 25–30% develop resistance within six months, drastically reducing survival rates.
- Around 30% of breast cancer patients develop resistance to chemotherapy, making it a leading cause of mortality in breast cancer.
- In colorectal cancer, up to 50% of patients develop resistance to drugs like oxaliplatin and 5-fluorouracil, leading to disease progression.
- Chemotherapy resistance affects up to 90% of pancreatic cancer patients, a major factor in the five-year survival rate of less than 10%.
Chemotherapy resistance can be classified into two categories: intrinsic and acquired. Intrinsic resistance occurs when tumors fail to respond to chemotherapy from the very beginning, affecting up to 50% of cancers. Acquired resistance develops after an initial response to treatment, as cancer cells adapt to evade the effects of chemotherapy. This form of resistance, seen in an additional 20–50% of cases, often leads to relapse and treatment failure.
Doctors can sometimes predict whether a cancer will resist chemotherapy based on certain factors, but it’s not always definitive. Predicting intrinsic resistance (when a cancer is resistant from the start) requires a combination of diagnostic tools, tumor profiling, and understanding the biology of the cancer. For example, mutations in genes like TP53 (tumor suppressor gene) are associated with resistance to several types of chemotherapy.
Mechanisms of Chemotherapy Resistance:
- Cancer stem cells (CSCs): CSCs are a small subpopulation of cancer cells with properties like self-renewal, enhanced cell repair, and metabolic reprogramming. These cells often survive chemotherapy and contribute to relapse, metastasis, and mortality.
- Tumor microenvironment:
- Hypoxia: Low oxygen levels in tumors reduce chemotherapy effectiveness.
- Metabolic changes: Cancer cells reprogram their metabolism, relying on alternative fuels like glutamine or fatty acids to survive, bypassing pathways targeted by chemotherapy.
- Vascular barriers: Poor blood supply in tumors prevents drugs from reaching cancer cells effectively.
- Acidosis: Tumors often have acidic environments due to high lactate production, which can deactivate certain chemotherapy drugs and promote resistance.
- Drug inactivation: Enzymes like glutathione S-transferase (GST) and cytochrome P450 (CYP) can deactivate chemotherapy drugs, reducing their effectiveness. For instance, changes in CYP enzymes can prevent drugs like irinotecan (used in colon cancer) from reaching therapeutic levels.
- Efflux transporters: Efflux transporters are proteins in cell membranes that pump substances, including chemotherapy drugs, out of cells. Overexpression of efflux pumps allows cancer cells to expel drugs, lowering intracellular drug concentrations.
Because chemotherapy is non-selective (it targets both cancer and healthy tissue) it is extremely hard on the body. Many patients experience severe side effects and complications from these drugs, including fatigue, nausea, immune suppression, and organ damage.
In advanced cases, chemotherapy can also cause cachexia, a severe wasting syndrome characterized by muscle loss and metabolic dysfunction. Cachexia significantly weakens patients, increasing the risk of death.
When faced with resistance, many oncologists will increase dosages, switch chemotherapy drugs, or use a combination of therapies, which can intensify these side effects.
Over half of all cancer patients will receive chemotherapy at some point during treatment, so there is an urgent need for more targeted, less toxic alternatives, and adjunct therapies. Researchers have considered options that enhance drug delivery and minimize collateral damage to healthy tissue. Some options we use at the Center for New Medicine:
- High-dose IV vitamin C, which selectively targets cancer cells through oxidative stress while sparing healthy tissues.
- Mistletoe therapy, a plant-based treatment that has shown potential to stimulate the immune system and improve quality of life.
- Repurposed drugs, such as ivermectin or aspirin, which may inhibit cancer growth by targeting metabolic or inflammatory pathways.
- Nutritional support, including high-dose nutrients like thiamine, niacinamide, and vitamin D, which strengthen the body’s ability to fight cancer and recover from treatment.
- Hyperthermia therapy, which uses heat to enhance the effects of radiation or chemotherapy and potentially kill resistant cancer cells.
Chemotherapy should be reserved for cases where it will be beneficial. Advanced testing, such as the RGCC test, can help identify which treatments are most likely to work with a specific patient’s cancer, avoiding unnecessary toxicity
At the center, we use low dose chemotherapy-Fractionated Chemotherapy with Biological Response Modifier (FCBRM) which can be massively beneficial in lieu of traditional chemo treatments. For this procedure, we use 1/10th of the traditional chemotherapy dose, using specific anti-cancer agents that test best for each patient. Insulin is administered in an IV, followed by glucose and the drug to help enhance delivery into cells. Because of the dose, patients typically do not experience hair loss, vomiting, or other side effects.
Many of our protocols involve strengthening the entire terrain of the body, so that the patient can receive and respond to the drug well.