Cancer and Society
Quackery Mistletoe: for cancer or just for Christmas?
Brian Gadsby/Science Photo Library
See Online for appendix
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One of the epidemiologist Ben Goldacre’s tests to alert suspicions of scientific quackery is a strong, inexplicable geographic variability, based on the reasoning that what works, spreads. Highly localised practices do not have the hallmarks of effective (or validated) therapies. So it is for extracts of European mistletoe (Viscum album L.), which represent one of the most prescribed alternative anticancer drugs in a variety of countries in Europe, particularly those who speak German, while being almost unknown in others, such as the USA. In fact, mistletoe use is very widespread, with 465 000 prescriptions paid by German health insurance in 2002, and the plant’s medicinal properties are relatively well studied as a result. Use of mistletoe as an anticancer agent started with Austrian-born Rudolf Steiner in 1916, creator of an esoteric philosophy called anthroposophy. In a belief descended from the medieval tradition of the “doctrine of signatures” (in which herbs were thought to cure body parts they resembled), Steiner thought the semiparasitic lifestyle of the mistletoe plant might provide a possible antidote to parasitic cancers living off human tissues.
The aims of mistletoe therapy include stimulation of the immune system, amelioration of symptoms of chemotherapy and radiotherapy, and improved quality of life; therapy is recommended alongside conventional medicine, although some advocates also suggest beneficial effects on survival and even direct antitumour activities. Specific medicinal properties are attributed to certain biologically active molecule classes found in mistletoe preparations, including mistletoe lectins, viscotoxins, flavonoids, and membrane lipids. Of these, the lectins have been attributed a primary therapeutic role, and have been suggested to function through inducing apoptosis, as well as stimulating proliferation of immune compartments including neutrophils and natural killer cells. There is no clear mechanistic explanation as to why non-specific immune activation should enhance antitumour defences, yet increased neutrophil counts are held in several studies to be a satisfactory and successful endpoint. And critics hold that this reactogenicity, which probably plays a part in a range of side-effects that include fevers, allergic reactions, and even sarcoidosis and kidney failure, makes the use of mistletoe worse than ineffective. Today mistletoe is commercially produced according to different schools of thought. Some preparations including Lektinol and Cefalektin emphasise the therapeutic lectin component and are administered at fixed doses, two or three times per week by subcutaneous injection. Conversely, in preparations based on the anthroposophical tradition, a range of active ingredients are assumed to work together, and injection regimens are administered using escalating
doses to reach an adequate potency. These include the most common therapeutic, Iscador, as well as Isorel and Helixor. As mistletoe grows on a variety of host trees, including oak, spruce, elm, and poplar, the host species along with time of harvest, extraction method, and commercial producer of the medicine all represent factors that will affect the chemical constituents of the final product. With regard to the effects of whole plant extracts and constituent parts on cells in the laboratory, a large number of in-vitro studies have produced evidence suggestive of cell-killing and immunostimulatory properties, particularly with the lectin and viscotoxin components. Yet others have criticised the optimism associated with such studies, citing contradictory pro-proliferation effects reported in some studies, and noting the highly limited supply of plant-derived chemotherapeutics (with exceptions including paclitaxel, derived from the bark of yew trees). As a result of their relative popularity, mistletoe-based therapies have been repeatedly tested in clinical trials for efficacy, yet many of these have been hampered by methodological failures. Previous reviews of these trials have used varied methods of inclusion and reached different conclusions. In 2008, a Cochrane review attempted a comprehensive appraisal of the scientific literature. The reviewers were unable to find evidence to support clinical efficacy of any cancer therapeutic outcomes. 21 of 43 studies assessed met the inclusion criteria, with many studies reported to have major weaknesses that reduced the reliability of the findings. These included failures to randomise, small sample sizes, and the presence of large numbers of patients who were excluded from analysis or
www.thelancet.com/oncology Vol 14 December 2013
Cancer and Society
otherwise not assessed. Given that most trials were presumably started with the best of intentions, it is deeply unfortunate that so many should fail the most basic standards of adequate scientific design. What can explain the popularity of an apparently ineffectual therapy such as mistletoe? With the leviathan drug development industry so slow to produce new treatments against many cancers, frustrations are often voiced by both doctor and patient. We rationalise often ineffectual therapies by citing the extensive heterogeneity of cancer, leading to the difficulties of targeting appropriate therapies
to stratified cohorts. This might be confusing to patients, so it should be unsurprising that simpler and more natural-sounding alternative therapies that offer to cure or manage symptoms hold such popular appeal, even if they have failed to pass clinical trials. But although mistletoe has been used since before the advent of modern chemotherapy, and is considered a natural alternative, it is certainly not without its own toxicities. Patients must be educated sufficiently to make an informed choice, and if they are choosing alternative therapies, we must do more to understand their reasoning.
Clearly a demand for effective, nontoxic, palliative medicines is there in adjunct to conventional cancer therapies. Anticancer use of mistletoe might have unscientific origins. The stark geographical distribution of its use might suggest it persists for sociological rather than medicinal reasons. But its persistence and popularity suggest that we have important lessons to learn from mistletoe about what patients want and need.
through with, and recovers from this drastic preventive surgery. Through a series of straight-tocamera interviews combined with real-life filming with close family members, her husband, doctor, and Caitlin herself, the series of short 5–10 min episodes relay her story in a frank, succinct way. In the first couple of episodes Caitlin talks about why she has decided to have the surgery and mentions the startling statistics that she has been given: a 50% chance of breast cancer by age 50 years compared with a 2% chance in women of the same age without the mutation, and a 56–87% chance by age 70 compared with a 7% chance in other women. Some women in the same situation choose to wait until their risks increase later in life before they undergo this surgery, but for Caitlin, losing family members to the disease had cemented the decision in her mind; the loss of her breasts was worth removing the fear of waiting for her fate, which was “outweighing everything else”. Despite natural concerns about missing her breasts,
the pain of the procedure, and how her husband would react to her new body, the support that she received from those closest to her obviously helped, as she remains upbeat and positive about her decision throughout the series. Caitlin documented her process in part because she wanted to inform young women about having a double mastectomy for preventive reasons after she found herself wanting more information when she was researching the topic initially. She has also found the documentary procedure to be a great distraction, helping her to put a positive spin on something that could have generated many negative emotions. On the whole the documentary is a very optimistic, honest look at the outcome of a young women’s path following a positive test for the BRCA1 mutation. Caitlin’s warmth and humour and the lovely relationship between her and her husband make easy watching of a difficult journey. Other less considered issues perhaps, such as medical financing, body image worries, and postsurgical muscle strengthening are also touched upon,
Alex de Giorgio, *Justin Stebbing Imperial College, London [email protected]
Web Screw You Cancer In May, 2013, actress Angelina Jolie spoke out about her decision to undergo a preventive double mastectomy after discovering that she had the BRCA1 mutation. Although the prevalence of this hereditary mutation in the general population is low, testing positive massively increases the chances of developing breast and ovarian cancer. For women who have a family history of these cancers, Jolie’s decision to have a prophylactic mastectomy, and to talk openly about why, not only gave exposure to BRCA1 testing, but also to having this surgical procedure as a preventive measure. Caitlin Brodnick—a comedian living in New York, NY, USA—was one of these women living under the shadow of a family history of breast cancer. Her concerns were confirmed 3 years ago when she discovered she was positive for the BRCA1 mutation. As a result, earlier this year aged only 28 she made the brave decision to have surgery to remove both of her breasts. Screw You Cancer—an online docuseries in association with Glamour magazine—follows Caitlin on her journey as she prepares for, goes
www.thelancet.com/oncology Vol 14 December 2013
Screw You Cancer Season 1, 8 episodes. http://video.glamour.com/ series/screw-you-cancer Condé Nast, 2013 For Angelina Jolie’s NY Times article on her mastectomy see http://www.nytimes. com/2013/05/14/opinion/mymedical-choice.html
1265
Quackery Mistletoe: for cancer or just for Christmas?
Brian Gadsby/Science Photo Library
See Online for appendix
1264
One of the epidemiologist Ben Goldacre’s tests to alert suspicions of scientific quackery is a strong, inexplicable geographic variability, based on the reasoning that what works, spreads. Highly localised practices do not have the hallmarks of effective (or validated) therapies. So it is for extracts of European mistletoe (Viscum album L.), which represent one of the most prescribed alternative anticancer drugs in a variety of countries in Europe, particularly those who speak German, while being almost unknown in others, such as the USA. In fact, mistletoe use is very widespread, with 465 000 prescriptions paid by German health insurance in 2002, and the plant’s medicinal properties are relatively well studied as a result. Use of mistletoe as an anticancer agent started with Austrian-born Rudolf Steiner in 1916, creator of an esoteric philosophy called anthroposophy. In a belief descended from the medieval tradition of the “doctrine of signatures” (in which herbs were thought to cure body parts they resembled), Steiner thought the semiparasitic lifestyle of the mistletoe plant might provide a possible antidote to parasitic cancers living off human tissues.
The aims of mistletoe therapy include stimulation of the immune system, amelioration of symptoms of chemotherapy and radiotherapy, and improved quality of life; therapy is recommended alongside conventional medicine, although some advocates also suggest beneficial effects on survival and even direct antitumour activities. Specific medicinal properties are attributed to certain biologically active molecule classes found in mistletoe preparations, including mistletoe lectins, viscotoxins, flavonoids, and membrane lipids. Of these, the lectins have been attributed a primary therapeutic role, and have been suggested to function through inducing apoptosis, as well as stimulating proliferation of immune compartments including neutrophils and natural killer cells. There is no clear mechanistic explanation as to why non-specific immune activation should enhance antitumour defences, yet increased neutrophil counts are held in several studies to be a satisfactory and successful endpoint. And critics hold that this reactogenicity, which probably plays a part in a range of side-effects that include fevers, allergic reactions, and even sarcoidosis and kidney failure, makes the use of mistletoe worse than ineffective. Today mistletoe is commercially produced according to different schools of thought. Some preparations including Lektinol and Cefalektin emphasise the therapeutic lectin component and are administered at fixed doses, two or three times per week by subcutaneous injection. Conversely, in preparations based on the anthroposophical tradition, a range of active ingredients are assumed to work together, and injection regimens are administered using escalating
doses to reach an adequate potency. These include the most common therapeutic, Iscador, as well as Isorel and Helixor. As mistletoe grows on a variety of host trees, including oak, spruce, elm, and poplar, the host species along with time of harvest, extraction method, and commercial producer of the medicine all represent factors that will affect the chemical constituents of the final product. With regard to the effects of whole plant extracts and constituent parts on cells in the laboratory, a large number of in-vitro studies have produced evidence suggestive of cell-killing and immunostimulatory properties, particularly with the lectin and viscotoxin components. Yet others have criticised the optimism associated with such studies, citing contradictory pro-proliferation effects reported in some studies, and noting the highly limited supply of plant-derived chemotherapeutics (with exceptions including paclitaxel, derived from the bark of yew trees). As a result of their relative popularity, mistletoe-based therapies have been repeatedly tested in clinical trials for efficacy, yet many of these have been hampered by methodological failures. Previous reviews of these trials have used varied methods of inclusion and reached different conclusions. In 2008, a Cochrane review attempted a comprehensive appraisal of the scientific literature. The reviewers were unable to find evidence to support clinical efficacy of any cancer therapeutic outcomes. 21 of 43 studies assessed met the inclusion criteria, with many studies reported to have major weaknesses that reduced the reliability of the findings. These included failures to randomise, small sample sizes, and the presence of large numbers of patients who were excluded from analysis or
www.thelancet.com/oncology Vol 14 December 2013
Cancer and Society
otherwise not assessed. Given that most trials were presumably started with the best of intentions, it is deeply unfortunate that so many should fail the most basic standards of adequate scientific design. What can explain the popularity of an apparently ineffectual therapy such as mistletoe? With the leviathan drug development industry so slow to produce new treatments against many cancers, frustrations are often voiced by both doctor and patient. We rationalise often ineffectual therapies by citing the extensive heterogeneity of cancer, leading to the difficulties of targeting appropriate therapies
to stratified cohorts. This might be confusing to patients, so it should be unsurprising that simpler and more natural-sounding alternative therapies that offer to cure or manage symptoms hold such popular appeal, even if they have failed to pass clinical trials. But although mistletoe has been used since before the advent of modern chemotherapy, and is considered a natural alternative, it is certainly not without its own toxicities. Patients must be educated sufficiently to make an informed choice, and if they are choosing alternative therapies, we must do more to understand their reasoning.
Clearly a demand for effective, nontoxic, palliative medicines is there in adjunct to conventional cancer therapies. Anticancer use of mistletoe might have unscientific origins. The stark geographical distribution of its use might suggest it persists for sociological rather than medicinal reasons. But its persistence and popularity suggest that we have important lessons to learn from mistletoe about what patients want and need.
through with, and recovers from this drastic preventive surgery. Through a series of straight-tocamera interviews combined with real-life filming with close family members, her husband, doctor, and Caitlin herself, the series of short 5–10 min episodes relay her story in a frank, succinct way. In the first couple of episodes Caitlin talks about why she has decided to have the surgery and mentions the startling statistics that she has been given: a 50% chance of breast cancer by age 50 years compared with a 2% chance in women of the same age without the mutation, and a 56–87% chance by age 70 compared with a 7% chance in other women. Some women in the same situation choose to wait until their risks increase later in life before they undergo this surgery, but for Caitlin, losing family members to the disease had cemented the decision in her mind; the loss of her breasts was worth removing the fear of waiting for her fate, which was “outweighing everything else”. Despite natural concerns about missing her breasts,
the pain of the procedure, and how her husband would react to her new body, the support that she received from those closest to her obviously helped, as she remains upbeat and positive about her decision throughout the series. Caitlin documented her process in part because she wanted to inform young women about having a double mastectomy for preventive reasons after she found herself wanting more information when she was researching the topic initially. She has also found the documentary procedure to be a great distraction, helping her to put a positive spin on something that could have generated many negative emotions. On the whole the documentary is a very optimistic, honest look at the outcome of a young women’s path following a positive test for the BRCA1 mutation. Caitlin’s warmth and humour and the lovely relationship between her and her husband make easy watching of a difficult journey. Other less considered issues perhaps, such as medical financing, body image worries, and postsurgical muscle strengthening are also touched upon,
Alex de Giorgio, *Justin Stebbing Imperial College, London [email protected]
Web Screw You Cancer In May, 2013, actress Angelina Jolie spoke out about her decision to undergo a preventive double mastectomy after discovering that she had the BRCA1 mutation. Although the prevalence of this hereditary mutation in the general population is low, testing positive massively increases the chances of developing breast and ovarian cancer. For women who have a family history of these cancers, Jolie’s decision to have a prophylactic mastectomy, and to talk openly about why, not only gave exposure to BRCA1 testing, but also to having this surgical procedure as a preventive measure. Caitlin Brodnick—a comedian living in New York, NY, USA—was one of these women living under the shadow of a family history of breast cancer. Her concerns were confirmed 3 years ago when she discovered she was positive for the BRCA1 mutation. As a result, earlier this year aged only 28 she made the brave decision to have surgery to remove both of her breasts. Screw You Cancer—an online docuseries in association with Glamour magazine—follows Caitlin on her journey as she prepares for, goes
www.thelancet.com/oncology Vol 14 December 2013
Screw You Cancer Season 1, 8 episodes. http://video.glamour.com/ series/screw-you-cancer Condé Nast, 2013 For Angelina Jolie’s NY Times article on her mastectomy see http://www.nytimes. com/2013/05/14/opinion/mymedical-choice.html
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