Controversies surrounding complementary and alternative medicine in
cancer
Stéphane Lejeune1, Michael Baum2, Nicole Heine1, Vinjar Fonnebo3
1European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium
2UniversityCollegeLondon and, The PortlandHospital, London, United Kingdom
3National ResearchCenter on Complementary and Alternative Medicine, Faculty of Medicine, University of Tromso, Tromso, Norway
SUMMARY
The material for this article summarizes the main issues discussed at an education session held by the EuropeanSchool of Oncology/ European Organisation for Research and Treatment of Cancer Education Session “Controversies around Complementary and Alternative Medicine in cancer”, which took place on 23–24 February 2006 at the EORTC Headquarters in Brussels. The meeting was established because the use of complementary and alternative medicine (CAM) by cancer patients is reported to be on the increase. CAM is reported to be widely used by cancer patients although accurate prevalence data are lacking. The reasons why cancer patients are using CAM are not fully understood. The paucity of good clinical data represents a problem when evaluating the efficacy and the safety profile of CAM. Clinical research in CAM is challenging and complex but none of the difficulties are unique to the CAM field. Communication and dialogue between patients and doctors about CAM needs to improve. Although the body of evidence is limited, the clinician should inform the patient regarding the efficacy and safety of using a particular CAM. So far, the quality of data derived from clinical trials, when available, is generally poor. The patient should be made aware of the risks caused by the uncertainties related to the use of untested or insufficiently tested, CAM.Oncologists are facing the challenge to give an objective and responsible answer to this type of demand. Cancer organizations play an important role in distributing the information to oncologists.Doctors need objective and independent information on CAM interventions, especially on safety,side effects and possible interactions with conventional medicine, as well as a critical appraisal of evidence of efficacy. These gaps in our knowledge shouldn’t be left empty and therefore open for exploitation for misinformation or the promotion of quackery. In total, 80 participants from 21 countries attended this session and the controversial issues concerning complementary and alternative medicine in cancer were discussed.
INTRODUCTION
The complementary and alternative medicine (CAM) field covers a complex and heterogeneous array of methods involving diagnosis and therapy that are not part of standard medical treatment (as described by evidence-based clinical practice guidelines, consensus statements or common medical practice) and are either used alternatively (instead of) or complementary (in addition) to a standard cancer treatment. CAM represents a variety of interventions ranging from chemically well defined molecules or other substances and mixtures from plant or animal origin to non-material methods like body therapy, spiritual healing or psychosocial procedures.
These methods are used by patients and practiced by some physicians. Despite their social recognition, the practice of CAM is not taught in medical schools in Europe (with only a few exceptions)and is not generally integrated into mainstream health care. The reasons for this are many, one of the most important being the lack of evidence regarding efficacy and safety. A number of clinical trials on CAM in cancer are reported in the literature. During 1966 to2005, 105 published phase III trials were identified in a systematic review;1however, the quality of these trials was not assessed by this systematic review. It is not the scope of our present report, but we shall give a restrictive series of examples of randomized controlled trials. Two large studies on mistletoe extract have been performed. Steuer-Vogt et al. conducted a randomised multicenter trial of a standardized mistletoe extract used as an adjuvant therapy for patient with resected head and neck cancer.2The European Organisation for Research and Treatment in Cancer conducted a randomized and controlled adjuvant trial to compare Iscador (mistletoe extract) withrecombinant IFN-2b or recombinant IFN- to a control group after surgical removal or curative resection of lymph-node metastasis.3Those two studies reported no benefit in terms of disease-free interval, disease-specific survival, and quality of life when using mistletoe extract as adjuvant treatment for two different cancers. The effect of soy phytoestrogens on hot flashes in postmenopausal women breast cancer were investigated by a randomized placebo-controlled double-blind trial.4Both groups experienced a reduction of hot flashes episodes but without significant differences and a strong placebo effect was therefore suspected. Shen J and colleagues have investigated the effectiveness of electroacupuncture in controlling chemotherapy-induced emesis in a randomized controlled trial.5The authors concluded that the adjunct of electroacupuncture was more effective than standard antiemetic treatment alone but the observed effects had limited duration. The efficacy of the adjunction of shark cartilage was evaluated in a randomized placebo-controlled double-blind clinical trial in patients with advanced breast or colorectal carcinoma.6Patients were selected randomly for receiving shark cartilage product or a placebo in addition of standard cares. No differences were reported in term of overall survival and quality of life of patients receiving the shark cartilage or the placebo.
Although the findings of these studies do not support the efficacy of CAM for cancer patients, they prove that good quality clinical trials investigating CAM are feasible. The clinical research methodology seems able to offer adapted study designs. This limited sample of clinical trials targeting different CAM methods used for different treatments indications showed that a variety of endpoints can be considered e.g. quality of life in addition of survival or other surrogate endpoints. Notwithstanding this, the number of good quality trials and therefore the availability of clinical evidence is limited compared with the numerous CAM methods used by cancer patients. In addition, Vickers and colleagues reported that most of the phase III trials involvingCAM agents were conducted without appropriate early-phase development such dose-finding study.1
In this article we will use CAMas the generic name for unconventional methods.
In fact, it is difficult to reach a consensus on a definition of CAM and a working compromise has to be adopted.7 For the first time in Europe, major cancer organizations have organized an international education session around CAM in cancer. We report in this paper the main issues discussed during the EuropeanSchool of Oncology/ European Organization for Research and Treatment of Cancer Education session.8
REASONS WHY CANCER PATIENTS ARE USING CAM
The reasons why cancer patients use CAM are not fully understood. Possible explanations include expectation of cure, helping to control their symptoms, and reduction of side effects of cancer treatments. During his presentation, D Razavi highlighted several findings from surveys: the use of CAM is correlated with the patient’s education status and to disease variables such as stage of disease, severity of physical symptoms, previous treatment cycles, and perceiving a high risk of recurrence. Interestingly, the CAM use does not seem to be correlated with a loss of trust in conventional treatments.
What are the patient’s needs when facing the cancer experience?
In his introduction, M Baum outlined three main domains of patient’s needs. First, patients want to get better (this need relates to the role of conventional health care). Second, patients want to feel better (CAM may play a role). Third, patients want to live better (there could be a role for spiritual support). In addition to medical considerations, the patients’ needs for moral and spiritual support should not be underestimated.From the patient’s perspective, S Rozman, physician and patient representative, outlined the powerful and transforming personal experience that having cancer represents. In this situation, individualized care is what patients need above all. In addition, the cancer patient wants to be recognized “as a full person” and not just “a host to a cancer”.
The cancer diagnosis forces the individual to address his or her mortality perhaps for the first time. Patients often search for meaning and support, sometimes as a last resort. The use of CAM can be related to attitudes of coping with the disease and its generated uncertainties. Cancer patients need to feel that they have control over their lives and that they are playing an active role by taking part in the therapeutic decision process.As D. Ravazi highlighted, the reasons for using CAM in cancer might be related not only to emotional distress, but also to mental disorders. The underlying mental disorder should be detected and treated appropriately. For more information see the published studies by Paltielet al. and Risberg and coauthors.9,10
PREVALENCE OF CAM USE IN EUROPE
According to the media and numerous scientific publications, the use of CAM among cancer patients is increasing. A recent systematic review of surveysconcluded that it is almost impossible to give an accurate general picture for Europe: the results show a wide range of prevalence of CAM use with a median of 39 % (9–78 %).11 In addition, wide ranges of prevalence of CAM use are observed between different surveys performed in the same country. According to M Horneber, this heterogeneity may be explained by the various methodologies used by the surveys i.e. CAM definitions, study population, and interview modes. Therefore, the results are not comparable to each other. In addition, quality problems are present e.g. an irrelevant target population, inadequate sample size, the use of an inadequate or inadequately validated questionnaire, orthe use of interviewers untrained in proper communication techniques that avoid influencing or biasing responses. In the future, the methodological quality of the surveys should be improved. Despite the non-availability of accurate prevalence data, the use of CAM in cancer patients is a phenomenon that should not be neglected.12–14Besides the prevalence data, the expenditure data provide us with an additional indication that the use of CAM is not anecdotalbut represents an emerging market.In the US the annual cost of CAM is approximately $47 billion, and in the UK the annual cost is £1.6 billion. In 2003, European countries have spent almost $5 billion on herbal medicines. In 2003, German Health insurance paid $283 million in reimbursement for prescribed herbal CAM. French health insurances report a total of $196 million of which $91 million were reimbursed by them.15
LEGAL SITUATION OF CAM IN EUROPE
The issue of the legal status of CAM is important because it determines who can practice CAM and under which conditions. The problem is that if CAM is not legally recognized and organized, anybody can practice CAM and treat patients without any professional background. This kind of situation poses risks for the patient as they must consult practitioners sometimes ‘clandestinely’ and there is no quality control in place. G Ersdal presented the results of an overview on CAM legal status performed on 29 European countries (EU and EFTA countries and Switzerland).16EU directives regulate herbal products in the European countries, and these directives are being transposed into national legislation. The legal status in Europe is otherwise highly heterogeneous. Specific CAM therapies are regulated in 18 of 29 countries. The supervising body (i.e. health authorities or medical federations) define which type of CAM is considered “responsible professional conduct” when provided by regulated personnel. In 19 of 29 countries (Middle and Southern Europe) only regulated personnel can legally treat patients, while in the remaining 10 countries (Northern Europe) both regulated and non-regulated (i.e. anybody) may treat patients. The challenge is to determine to what degree and in what way patients might be adequately and legally safeguarded.
CAM SAFETY
A distinction should be made between the direct risks that can result from the CAM therapy such as noxious interactions,17 toxic or allergic potential, and the indirect risks that could come from the therapist, such as advice to stop or delay conventional cancer therapies. Moreover, CAM, especially herbal products, are not always quality assured according to Good Manufacturing Practices, which assesses the standardization of content and concentration, and the risk of contamination. According to E Ernst, it is difficult to conceive of an herbal medicine that has no potential for interaction.18In addition; many patients regardless of their age and their health status are combining herbs with drugs. The majority of patients are unaware of the risks of using such combinations and do not discuss herbal use with their treating physician. But are these potential interactions serious? E Ernst reminded the audience that potential risks are not always translated into clinically relevant events and that the incidence of such events is not known because of the lack of hard data. There is also a problem of adverse events being underreported, and systematic research or surveillance is missing in the CAM field. It should be noted that due to the diversity of CAM, the potential risks associated with their use are also variable. For further reading please see the studies by Izzoet al., De Smet, Fugh-Berman and colleagues.19–21
CLINICAL RESEARCH ON CAM IN CANCER
The paucity of good clinical research data represents a problem when evaluating the efficacy and the safety profile of CAM. E Ernst described the potential problems related to clinical research in the CAM field. First, the ‘logistical’ problems i.e. the difficulty in finding CAM practitioners who are willing to collaborate in a randomized clinical trial, and finding patients who consent to be part of a trial. The expected effects of the investigated CAM can be of small magnitude and might be delayed with the consequence of considerable increased cost of the study. The lack of adequate research funds is another of the main logistical issues. The methodological problems can be related to the lack of inert placebos, the difficulty of finding adequate comparators, initiating blinded studies, and the problem of quantifying claimed subtle effects. In the absence of good quality preliminary data it is not possible to elaborate robust hypotheses, which perpetuates a vicious cycle. Without a good hypothesis, it is unlikely that any application for funding would be successful and thus no new study generating good quality data will be funded. Although there are numerous problems pertaining to CAM research, none of them are insurmountable in principle and none of them are unique to the CAM field.
V. Fonnebo outlined the differences in research settings between conventional medicine and CAM. The relationship between the patient and the disease is conceptualized differently and it will have an impact on the definition of the research question. Conventional medicine combats the disease-specific causative factors while CAM practitioners intend to support the defensive systems on a broad front, thereby enabling these systems to combat the disease-specific causative factors. In both CAM and conventional medicine an important goal is that patients can regain the homeodynamic ‘optimal’ status. In diagnosing disease conditions, conventional medicine puts most emphasis on ‘objectively’ measurable variables, whereas the CAM emphasis is more equally distributed between objectively measurable and ‘relational’ variables. In the CAM field, the non-specific effects of a treatment are considered as important and have to be taken into account when evaluating a treatment. It is much closer to the patient’s perspective if the outcome measures also include the non-specific effects experienced in his/her evaluation of the treatment. Some CAM might have considerable non-specific effects for certain conditions. The consequence of these different approaches on CAM evaluation would be that the conventional side will conclude that no effect has been documented, while the CAM side will claim that treatment efficacy or effectiveness was not properly investigated.
CAM research should be conceptualized as whole-system research by first evaluating CAM as a system (e.g. complex of theories and methods i.e. acupuncture for pain) and later by evaluating the system components (e.g. diagnostic methods, treatment by needles or moxibustion).Research needs to first focus on understanding the practice as such before documenting safety issues. In addition, the overall research scheme of CAM needs to be different than the one followed by conventional research. In pharmacological research, chemical substances will be screened and further evaluated for safety and efficacy in phase I, II and III trials. Based on the generated evidence, health authorities will act as a gate keeper and will or won’t authorize the substance to be used for clinical practice. In the CAM field, there is no gate keeper, and the starting point is the clinical practice, as CAM is already out there in the community being used by patients.
S Lejeune provided an overview of European research initiatives in the field of CAM in cancer. As a systematic reviewsuggests,22 important national differences exist in terms of the nature of CAM research and in the volume of publications between European countries. Across the countries, the non-systematic review is the most frequent type of publication. Less than 7% of the publications addressed controlled clinical trials. Some countries publish more than others, but what are the factors that account for these differences? Do significant differences in term of national strategies for research in CAM in cancer or regarding the availability of funding exist? For the majority of countries, research strategies were either non-existent or very poorly developed at a national level. Research is carried out most often by free-standing research projects funded by private bodies and charities. The UK seems to be the only European country where research, funding and national strategies are in place. There is no strategy at the European level. Only few initiatives are targeting the cancer field. Research initiatives that aim to review the literature and to critically appraise the evidence are more common than initiatives performing clinical research involving human subjects.