Little is known of the impact of case reports and case series on the initiation of prospective preclinical or clinical research that are eventually substantiated by controlled clinical trials.50
To obtain the various approvals necessary to initiate a clinical trial there must be preliminary evidence on which to base the hypothesis that a treatment may be efficacious. Case reports and small uncontrolled case series are frequently this first line of evidence51
but they are not often cited as the primary supporting evidence justifying a subsequent trial.
Observations from the historical use of a compound have proven useful in the identification of some modern drugs. Arsenic has been used as a therapeutic agent for more than 2,400 years.52
In the 15th
century, William Withering who discovered digitalis was a strong proponent of arsenic-based therapies. Arsenic trioxide was recorded in the Compendium of Materia Medica by Li Shi-Zhen (1518–1593).53
Pharmacology texts of the 1880s describe the use of arsenical pastes for cancers of the skin and breast.54
In the 18th
century, Thomas Fowler compounded a potassium bicarbonate-based solution of arsenic trioxide (As2
) that would bear his name. Fowler’s solution was used empirically to treat a variety of diseases into the early 20th
In 1878, a report from Boston City Hospital described the effect of Fowler’s solution on the reduction of white cell counts in two normal people and one patient with “leucocythemia”.56,57
Arsenic compounds were administered as antileukaemic agents until they were replaced by radiation therapy.57
The hematological use of arsenic experienced a resurgence in popularity in the 1930s when its efficacy was reported in patients with chronic myelogenous leukaemia (CML).57
In the early 1990’s, reports from China described the induction of clinical and hematological responses by arsenic trioxide in patients with de novo and relapsed acute promyelocytic leukaemia (APL).58–60
The results of these observational studies were then confirmed in randomized clinical trials in the U.S.61,62
Consequently, arsenic trioxide (TrisenoxTM
) was approved for the treatment of relapsed or refractory APL by the U.S. Food and Drug Administration in September 2000.
Another example of the potential benefits, but also the pitfall of using case reports of unconventional approaches to justify the initiation of prospective cancer clinical trials is the PC-SPES story. PC-SPES is a proprietary formulation that was marketed as a dietary supplement by Botanic Lab (Brea, CA) from 1996 through 2002.63
PC-SPES apparently came to the attention of cancer researchers through reports of use by prostate cancer patients.64
Several articles published between 1999 and 2003 described the results of observational studies and clinical trials conducted before adulteration with warfarin, indomethacin and diethystilbesterol was identified in several PC-SPES lots.65
These findings led the National Center for Complementary and Alternative Medicine in 2002 to place a hold on ongoing studies of PC-SPES and a moratorium on further research with the compound.66
After several years, two recent reports indicate the reemergence of research with mixtures of the extracts of the herbs from the PC-SPES formula, hopefully, without the adulterants.67,68
Since many herbal medicines have undergone little or no research, often there is little objective information about the potential risks and benefits of their use. Despite the popular notion of herbs as safe, a variety of adverse events associated with their use alone or in combination with conventional anticancer therapy has been reported including occurrence of severe bone marrow depression. Oncologists and medical practitioners should be aware of the adverse effects associated with these herbs, and be sure to obtain a thorough history of the use of such compounds from their patients.
It is generally not possible to ascertain from a published case report whether or not a patient’s tumour regression was the result of the herbal medicine. Spontaneous remissions have been reported to occur for a variety of malignancies.69
However, given the history of the serendipitous finding of useful therapeutics, well documented cases of cancer regressions with an herbal medicine warrant some consideration for the initiation of prospective research.
The NCI Best Case Series (BCS) program is a process of evaluating case report information from health care practitioners that involves the same rigorous scientific methods used to evaluate treatment responses with conventional medicine.70
The program is an opportunity for CAM practitioners to share their well documented cancer cases with the goal of assessing whether sufficient evidence is available for NCI-initiated prospective research.
When surveyed, a majority of both CAM practitioners treating cancer patients and cancer researchers interested in CAM expressed a willingness to participate in collaborative research.70,71
The same surveys identified a lack of awareness of appropriate funding resources as a major obstacle to such research. OCCAM has developed funding opportunity announcements (FOAs) to support research in areas with little or no research evidence for particular interventions. One of the FOAs (PA-09-168) encourages research of approaches for which case report information may be the primary, or only available supporting information.72
Some of the barriers to performing research on herbal therapies include the availability and development of herbal products for research studies. There are also significant difficulties in developing herbal placebos. Crude herbs have bulk, colour, aroma and taste that are difficult to mimic with therapeutically inert ingredients. Another barrier is the estimation of the effect of a single component (e.g., a component herb or diet), or the interaction between two or more components present in an intervention.73
In conclusion, this review identified published cases of cancer patients treated with herbs and that reportedly experienced significant clinical benefit or toxicity. Many of the herbs with positive outcomes apparently have not yet been explored with prospective clinical research. Useful therapeutics have been identified via observations of patients treated with what were once considered unconventional approaches. We propose that the research community should endeavor to conduct prospective research when credible evidence is available suggesting potential benefit to cancer patients from herbal or other unconventional approaches.