Colorectal Cancer And Mistletoe

In 2015, 1 in 14 men and 1 in 16 women were diagnosed with colorectal cancer. It is the second most likely cause of death from cancers for males, with a 1 in 29 chance of dying from it, and the third most common cause of death for females with cancer.^[1] With so many people diagnosed and suffering with this cancer, more therapies, both conventional and nonconventional, are necessary to help wage a better fight against it.

Mistletoe extract as an injectable therapy has proven to be one such therapy that could potentially add another weapon against many cancers, including colorectal.

What Is Mistletoe?

Aside from its romantic appeal during Christmas, this plant is actually one of the most widely studied complementary cancer therapies in cancer. In Europe, mistletoe or Viscum album is among one of the most prescribed drugs for patients with cancer.^[2] It is a semiparasitic plant that grows on several types of trees including pine, oak, maple, apple, and birch.^[2] It has been used for decades for other health conditions like headaches, hypertension, menopausal symptoms, infertility, arthritis, and rheumatism. Mistletoe therapies are sold under different brand names including Iscador, Helixor, Abnoba Viscum, Lektinol, and Iscucin.^[2] Mistletoe is normally given through injection under the skin (subcutaneously), but can also be given by mouth or intravenously (into the vein), and has also been injected directly into the tumour or pleural cavity. Injections in most circumstances are done at a maximum of three times a week, depending on the size of the reaction and the judgment of a trained health-care practitioner.

How Does Work?

For decades, mistletoe or Viscum album preparations have been used in Europe as a cancer therapy. It seems to work in multiple ways in in vitro studies, which include inhibition of tumour-cell proliferation or growth, induction of apoptosis (programmed cell death), and gene signature expression.^[3] Lectins from the extract, in particular, have strong apoptosis-inducing and immune-stimulatory effects, and appear to exert most of the medicinal effects of mistletoe.^[4] These include in vivo and in vitro activation of macrophages, monocytes, granulocytes, natural killer (NK) cells, T cells, and dendritic cells, as well as the induction of a variety of cytokines.^[5] While all the mechanisms of action are still unclear, mistletoe also appears to stimulate production of B-endorphin (the “feel good” hormone),^[6] on top of its cytotoxic or cancer-killing properties. It has also been shown to prevent the growth of new blood vessels needed for tumours to grow, and additionally appears to protect DNA in white blood cells from damage from things like the effects of chemotherapy.^[2]

Side Effects

The safety of mistletoe extracts has been well-documented, and few side effects have been reported but can include redness, soreness and inflammation at the site of the subcutaneous injection, headache, low-grade fever, and chills. While very rare, allergic reactions have also been reported.[7, 8]

What Does the Research Say?

This is not by any means exhaustive, but here are a few scenarios where mistletoe can and has been used in colorectal cancer patients.

Prevention
Viscum album extracts have been used in many different situations and with a wide variety of cancers, especially in Europe. Its use has been reported even in preventing precancerous lesions from turning malignant. One particular case report of a Caucasian man who had undergone hemicolectomy for a stage-IIIC colon cancer highlights this use.^[4] Five years after his diagnosis, an adenomatous colon polyp was found in this patient, and he refused surgical removal. These types of polyps are a cause of most colorectal cancers, where adenomatous polyps with high-grade dysplasia are at the highest risk of becoming cancerous. After two intratumoural injections of Viscum album extract, there was complete regression of this precancerous, high-grade adenomatous colon polyp eight months after the second injection.^[4] Could this just be a coincidence? Perhaps, but while spontaneous disappearance of colon polyps sometimes occurs in patients with familial adenomatous polyposis and spontaneous remission of an invasive colorectal cancer has previously been reported,^[9] the disappearance of colon polyps is otherwise uncommon.^[10] Regardless of the good outcome in this case, surgical removal of colon adenomas is always advisable.

Immunomodulation
Immunomodulation is important when speaking about cancer in general, but also has an important role in surgery. Cancer can cause immune depression, while surgery (anesthesia, stress response, ischemia/reperfusion, etc) can act further to suppress the immune system.[11, 12] In particular, major surgery suppresses natural killer (NK) cell cytotoxic or cancer-killing activity, which can be harmful for cancer patients as NK cells play an important role in cell-mediated immune responses against tumour cells. In one such study, colorectal cancer patients undergoing tumour resection were randomly assigned to either mistletoe infusion or no additional therapy.^[13] The NK-cell activity of patients treated with mistletoe extract did not change significantly during the study (7.9% lower 24 hours after surgery). For control patients (those without mistletoe), the NK-cell activity decreased significantly after surgery (NK-cell activity 44.4% lower at 24 hours). Perioperative infusion of mistletoe extracts can prevent a suppression of NKcell activity in cancer patients.^[13] The combined immunosuppressive effects of surgery and cancer may increase the risk of postoperative infections and spreading of the cancer.^[14] Applying immunotherapy perioperatively might improve immune system function and increase resistance to cancer itself, in particular in protection against implantation of circulating tumour cells. Its strength is that it appears to have relatively selective toxicity towards cancer cells and not normal cells,^[15] but has immunomodulating effects by, for one, stimulating the cytotoxic activity of the lymphocytes.^[16]

Chemo and Radiation Support
Cancer-related fatigue (CRF) is a disabling symptom that is prevalent from a patient’s diagnosis and treatment through survivorship and to end of life. Defined as an overwhelming persistent exhaustion and decreased capacity for physical and mental work, it is not relieved by rest.^[17] One study examined fatigue levels during first-line chemo- or radiochemotherapy protocols between two groups, one in which patients were supported by mistletoe preparation (Iscador® Qu—181 patients), and the other a control croup (143 patients) who did not receive this supportive-care treatment.^[18] All patients were stage I–III colorectal cancer patients, and patients who were very sick were preferred candidates to get supportive care with ISC® Qu during the postoperative adjuvant chemo- or chemoradiotherapy. Water-soluble, injectable-extract preparation was injected subcutaneously at a total average dosage of 16 mg to 20 mg mistletoe extract per week. At the end of the median treatment period of 8.6 months, 8.8% or 16/181 patients were diagnosed with CRF in the mistletoe group, and 60.1% or 86/143 in the group without supportive mistletoe therapy.^[18] What is encouraging even further is that no toxicities from the treatment were seen.^[18] In CRF, mistletoe extracts with its anti-inflammatory properties seem to offset the nonspecific sustained inflammatory response that seems to prolong and precipitate CRF.^[19] These anti-inflammatory processes provide a scientific and clinical rationale to use mistletoe extracts within chemo- and chemoradiotherapy protocols in colorectal cancer patients by providing supportive treatment that decreases CRF symptoms and improves quality of life.^[20]

In Europe, patients with colorectal carcinoma frequently receive mistletoe extracts to improve quality of life and survival. In one study that highlights this, patients who had been surgically treated for stage I–III CRC and given adjuvant therapy or conventional aftercare were studied.^[20] Endpoints were adjuvant therapy–related adverse reactions (AT-ADRs), symptoms, and disease-free survival (DFS). 804 (429 mistletoe v. 375 control) CRC patients from 26 centres were observed for a median of 58 versus 51 months.^[20] The median mistletoe therapy lasted 52 months. These patients showed fewer AT-ADRs—19% v. 48%—and fewer persisting symptoms. There also appeared to be a survival benefit for mistletoe patients versus controls. Mistletoe was welltolerated, without life-threatening adverse drug reactions, drug interactions, or tumour enhancement.^[20] Recent clinical trials showed that postoperative mistletoe combined with chemotherapy resulted in increased survival of patients with advanced colorectal carcinomas.^[21]

Other Benefits
Improvement of quality of life has been documented through many studies.^[22] Findings regarding the improvement of both the quality of life and emotional status in all patients treated with mistletoe compared to control patients are in agreement in multiple clinical trials.^[23] Studies have also shown benefits in terms of increased survival in advanced cancer and a reduction in cancer recurrence.[14, 23] In addition, as it stimulates production of B-endorphins, an endogenous opioid substance with analgesic effects as well as the power to enhance the mood and appetite,^[6] it is able to help patients with a spectrum of quality-of-life issues. In an era where a cancer cure still seems to elude our society, therapies like mistletoe or Viscum album extracts provide a tool that can be used to help optimize the health of cancer patients. Extensive preclinical data carried over decades and clinical studies have presented mistletoe extracts as one of the most attractive approaches in adjuvant cancer therapy, now also acknowledged by the National Cancer Institute and the National Institute of Health.^[14] It is worth noting that its widespread use in Europe specifically speaks to the efficacy and benefit of this therapy, and one that highlights a potential benefit for patients in Canada as well.