Ensayos clínicos

1. Filling in The Gaps
Recent clinical investigations into Viscum Album

2. Disclosure
• I am an owner and director in a for-profit facility that provides
mistletoe treatments to patients
• I have been provided an honorarium for this presentation, but
organizers have had no input on the content
• I have no relevant disclosures

3. Speaker Background
• Clinic Director for Marsden Centre for Excellence in Integrative
Medicine
• Residency Director for postgraduate residency in Integrative Oncology
• Chair of Principles of Care Task Force Oncology Association of
Naturopathic Physicians
• Conduct research into the use of intravenous Viscum album in cancer
patients

4. Goals
• Understand the Gaps in the clinical science for Viscum album therapy
• Understand recent (past 5 years) investigations in the use of viscum in
cancer
• Understand the level of evidence for various clinical indications of
viscum album in order to both apply viscum album appropriately in
cancer patients and speak accurately about the state of knowledge
• Learn about novel applications and further questions to be answered
surrounding viscum therapy

5. What We Know…And What Is Still
To Be Learned

6. Common Misconceptions About Viscum Album
• The assertion that there is little to no evidence supporting VA use in
cancer is patently false
• Continued propagation of irrelevant data about mistletoe
toxicology/pharmacology leads to recommendations against its
integrative use in patients undergoing conventional care

7. Examples of Specific Misconceptions
• Physician desk reference along with other databases cite the
following concerns regarding mistletoe:
• Viscum album is potentially hepatotoxic
• Viscum album may affect cytochrome P series enzymes

8. Toxicity of VA Herb
• VA & American Mistletoe have a long history of safe use in traditional medicine
• While toxicity has been observed with ingestion of these plants it is usually higher
doses
• Symptoms include:
• Nausea, vomiting, diarrhea, hypertension followed by shock
• A case review of 14 patients with American mistletoe leaf or berry ingestions
failed to show any symptoms of toxicity.
• Based on that series, ingestion of 1-3 mistletoe berries or 1-2 leaves is unlikely to
produce serious toxicity
• Of the accidental (pediatric) or intentional exposure of raw plant mistletoe in the
past 25 years there were no deaths and 97% were asymptomatic
• 2 cases of deaths due to mistletoe preparation in past 25 years were due to
chronic ingestion of tea preparations

9. Viscum & Cytochrome Interaction

10. Systematic Research Reviews

11. S – 15.10.08
Cochrane Review on Mistletoe Therapy 2010

12. Cochrane Review Results
Outcome N Results
Survival 13 6/13 insufficient
Tumor Response 7 2/7 insufficient
QOL/ 16 14/16 significant but inconclusive
due to study quality
• 80 studies were found but
58 were excluded due to
lack of prospective design
and/or randomization
• 21 studies were reviewed
• Overall total of 3484
randomized patients
• 5 different VA preps were
studied
Of the 7/13 studies that did not show a positive result on
survival:
• 4/7 had a statistically non-significant trend towards better
survival
• 0 trials showed a negative trend

13. Viscum Survival: Gynecological Cancers

14. Gynecological Review Results
• This systematic review looked at 19 RCT and 16 non-RCTs and 11
single arm cohorts with a total number of participants of 2,420;
6,399; and 1130 respectively
• Survival:
• 9 RCT and 13 non-RCTs reported on survival
• 12 reported a statistically significant benefit
• None reported a negative impact
• QOL:
• 15 RCT and 9 non-RCT reported on QOL
• 21 reported statistically positive results

15. Viscum and QOL: Review Article

16. QOL Review Results
• Systematic review of 26 RCTs and 10 non-RCTs
• 22 trials reported a benefit
• 3 indicated no difference
• 1 did not report a result

17. Challenges of Performing Research With VA
• Research in the area of VA as in other cancer areas is difficult due to
the nature of the intervention and its application in the context of
integrative care
• Some consistent critiques of historical VA research include:
• Substantial trial heterogeneity: of intervention, patients characteristics,
clinical diagnosis, measured outcomes, design and potential positive and
negative biases.
• Blinding not done in any of the trials because of rapidly unblinding of both
clinical staff and patients

18. Challenges of Performing Research With VA Cont’d
• Additional challenges in VA research:
• Systematic differences in care for patients apart from what is being studied in the
intervention group beyond the intervention itself
• Co-interventions are often sought
• In areas where patients have ready access to viscum there can be contamination of control
groups
• Attrition Biases
• VA research often has significant issues related to patient recruitment
• Willingness to participate in VA trials is low for both referring providers and patients
• This leads to long recruitment periods and inevitable alterations/deviations in study protocol
• Many recently published trials began before updates to GCP IHP guidelines
• systemic internal quality control such as monitoring and auditing were rare

19. Summary Known and Unknown Effects of Viscum
Known
• The preponderance of the
accumulated data is that viscum
has a positive impact on cancer in
the areas of:
• Improved QOL
• Reduced Side Effects of Conventional
Cancer Care
• While some argue that these
effects are scientifically proven
there are still arguments that the
quality of studies were poor
Unclear
• Some data exists that viscum improves
overall survival
• Most of the positive data is in retrospective
studies
• Prospective randomized trials are sparse
and have more variable conclusions
• Which clinical situations show survival
advantage
• Are there clinical situations where viscum
is not effective at improving QOL?
• While some data exists that viscum
increase treatment response
• Data is inconsistent
• Studies that show effects are small and
involve more invasive ways of delivery

20. Recent Clinical Investigations
Filling in the Gaps

21. Recent Clinical Investigations
• These are some interesting clinical investigations completed over the
past 5 years
• They Fall into 3 categories:
1. Quality trials looking at validating safe use and impacts on QOL/side effects
of conventional care
2. Quality trials looking at cancer specific mortality impacts
3. Novel Applications – Higher dose, Intravenous, Intravesicular, Intrapleural

22. QOL and Viscum a Qualitative Analysis

23. QOL Exploratory Study - Design
• A prospective, cohort-study comprised 25 patients with different
types of cancer.
• EORTC QLQ-C30 Version 3.0 tracking through 3 months of treatment
• If patients agreed they were interviewed and their responses
recorded verbatim and analyzed
• Interviews focused on the following themes:
• (a) how the patients became aware of their disease, (b) how they opted for
MT, (c) what they expected from MT, (d) their attitude toward CAM, (e) how
the diagnosis of cancer affected their life, (f) whether they suspected
particular cause of their disease, and (g) whether they used a personal coping
strategy.

24. Results - EORTC

25. Exploratory Results – Qualitative Analysis
• Decision to undertake mistletoe therapy
• Family members and provider choice
• Patient expectations of mistletoe therapy
• Strengthen immune system, to fight cancer and strengthen healing
• Disease meaning
• Most participants felt their disease had a specific meaning for them, but this did not
affect their treatment choices
• Participants observations of mistletoe therapy effect
• Less depression and better emotional stability
• Feeling stronger and with more energy
• Participants reported a sense of autonomy and the ability to make a
personal contribution to their disease

26. QOL and Advanced Pancreatic Cancer

27. Pancreatic Cancer QOL - Design
• Prospective RCT n = 220
• 110 patients received mistletoe therapy averaging 61 injections over
the treatment period
• 110 patients in control group
• Patients were asked to fill out EORTC QOL version 3 questionnaire

28. Pancreatic Cancer QOL -
Results

30. Phase I Study (NCCAM, NIH, USA)
S – 25.9.07
Indication: Advanced solid tumours (stage IV)
(Pancreas, colorectal, lung and breast cancer)
Objectives: Impact of HELIXOR A on pharmacokinetics,
pharmacodynamics and safety of Gemcitabine (Gemzar®)
Study design: Open, monocentric, prospective
Patient numbers: 44 patients (20 f, 24 m), 29 - 81 years old
Previous
cancer therapy: No previous therapy (n=11)
Chemotherapy and/or radiotherapy (n=33)
Mansky, P. et al.: Manuscript in preparation

31. Phase I: Study Results

32. Phase I Study Results Cont’d
• Trend to increase ANC (P = 0.06) on first 3 weeks of VA treatment
• Significant increase in ANC (P = 0.03) after 6 weeks of VA treatment
• MTD of Gemcitabine was 1380 mg/m2 (higher than normal)
• There were no episodes of febrile neutropenia
• Treatment response was consistent with published response of
Gemcitabine

33. Viscum & Survival: Pancreatic Cancer

34. Study Design
• phase III, open-label, randomized, group-sequential study
• adults aged 18 or greater with locally advanced or metastatic cancer
of the pancreas (stage III/IV)
• with any history of previous therapies but not eligible for
antineoplastic therapies anymore;
• no other anti- neoplastic therapies planned during the study except 5-
fluorouracil (FU)/leucovorin for symptom alleviation.

35. Study Results

36. Study Results cont’d

38. Adjuvant VA In Osteosarcoma
• Study Design:
• Patients with post surgically locally relapsed, metastatic free,
histologically confirmed osteosarcoma
• Patients were treated 12 months with either:
• Subcutaneous VA 3 times weekly (self-injection) using standard dose
escalation/reduction based on injection site response, or
• Oral etoposide standard adjuvant schedule
• Total patients 20 – viscum 9, etoposide 11

39. Adjuvant VA In Osteosarcoma: Results
• Conclusions of trial
• VA seemed to prolong time DFS in
osteosarcoma cases (whereas
etoposide seemed not to)
• VA was well tolerated with only
minimal reversible side effects

40. IV Therapy & Fever Induction

41. IV and Fever Therapy - Design
• Retrospective study at 2
institutions
• 59 patients received IV viscum at
these institutions during the
study period
• No exclusions
• Side effects and temperatures
were examined
• Peak core temperature was
examined in 90% of treatments

42. IV Therapy Fever - Results

43. Viscum and Pleural Effusion

44. Mistletoe Pleural Effusion – Design
• Single arm multicenter controlled trial
• No control group
• patients were drained and had intrapleural installation of viscum
preparation
• Patients retreated after re-emergence of pleural effusion (3-7 days)
• Response Criteria:
• CR – No return of effusion with in 4 weeks
• PR – Incomplete resolution of fluid but asymptomatic with no need for
further pleurodesis
• NR – further treatment required within 4 week

45. Mistletoe Effusions – Results
• Summary
• 49 CR
• 11 PR
• 2 NR

46. Intravenous Viscum Phase I Trial

47. Intravenous Viscum Phase 1 - Design
• Prospective, dose-escalating, phase I GCP study without control group
• Classical phase I 3 + 3 dose escalation scheme was followed
• Dose groups were 200, 400, 700, 1200 and 2000 mg
• If the maximum dose was tolerable three more patients should be
treated weekly for 9 weeks in order to evaluate intermediate term
safety
• N = 21 patients advanced cancer not receiving concurrent
chemotherapy

48. IV Viscum Phase 1 – Results cont’d

49. IV Viscum Phase 1 –
Results cont’d
• One patient had a febrile reaction and
unexpected rise in ALT/AST which
resolved and did not recur on further
treatment
• Some patients experienced either
improvements in tumor markers
• One patient with progressive disease
demonstrated on CT scan experienced
stable disease for 6 months and only
mild progression after 9 months

50. Viscum and Intravesicular Administration

51. Intravesicular Mistletoe - Design
• Single group dose escalation study patients with non-muscle invasive
bladder cancer
• Treated with weekly instillations of mistletoe extract for 6 weeks post
TURB (with marker tumor left to observe effect)
• 3+3 design
• 45-675 mg of mistletoe extract
• N = 37
• Residual disease and recurrence was recorded

52. Intravesicular Mistletoe - Results
• At week 12 ~70% of patients had no evidence of marker tumor at
week 12
• Many patients did not complete the trial but of the 19 who did 14
had no recurrence at 1 year
• No serious adverse events were reported

53. So what gaps have been filled in the past 5 years
• Mistletoe is a safe therapy with decades of established use in patients
• There is a large body of evidence supporting its use to improve cancer
patient’s QOL and to reduce side effects of conventional care
including higher quality, prospective randomized trials
• There is growing evidence to support mistletoe improving overall
survival, but we are not clear on the magnitude of effect in most
clinical situations
• Emerging data in high dose, locally administer mistletoe like
intravenous, intrapleural and intravesicular therapy shows potential
for disease response modification

54. Future Directions…More Questions=More Gaps
• Systematic evaluations of intra-tumoral applications
• Systematic evaluations looking at IV vs. SC vs combined regimens in
cancer patients
• Evaluations of non-aqueous extracts of viscum in cancer patients
• Methanolic extracts

55. Questions?