High-Dose Viscum album Extract Treatment in the Prevention of Recurrent Bladder Cancer: A Retrospective Case Series
Introduction: Viscum album extract (European mistletoe), containing immuno-active compounds with dose-dependent cytotoxic activity, is being used as an adjuvant cancer treatment in Europe. Few studies have yet been done with high-dose, fever-inducing Viscum album treatment.
There are an estimated 386,000 new cases of bladder cancer reported globally each year, with 150,000 deaths.1 Approximately 70% of patients with bladder cancer present with nonmuscle-invasive cancer, with recurrence in 50% to 70% of cases and progression to muscle-invasive cancer in 10% to 20% of cases.2 Active and passive tobacco exposure is the main risk factor for bladder cancer, followed by occupational exposure to benzene derivatives and arylamines.3
Radical cystectomy with neoadjuvant chemotherapy is the standard therapy for muscle-invasive bladder cancer.3 Treatment of nonmuscle-invasive bladder cancer, which includes pathology Stages Ta, T1, and Tis, is transurethral resection. Intravesical bacillus Calmette-Guérin immunotherapy is used to reduce recurrence and progression risk in these patients.4 Intravesical treatment with mitomycin C has also been shown to reduce tumor recurrences and is used in the immediate postoperative period after resection of nonmuscle-invasive cancer.5 Cystectomy should be considered for patients at high risk of recurrence and is indicated when intravesical bacillus Calmette-Guérin immunotherapy fails.5
Whole plant extract of Viscum album (European mistletoe) contains a variety of immunoactive compounds with dose-dependent cytotoxic activity and is used as adjuvant cancer therapy in Europe.6,7 The immunoactive compounds include mistletoe lectins, viscotoxins, and other low-molecular-weight proteins, including VisalbCBA (Viscum album chitin-binding agglutinin), oligosaccharides and polysaccharides, flavonoids, and triterpene acids. The whole plant extract and several of its compounds on their own are cytotoxic, and mistletoe lectins in particular have strong apoptosis-inducing effects. The antitumor activity of mistletoe lectins, including a prophylactic effect, has also been linked to their immunostimulatory effect, including in vitro and in vivo activation of monocytes/macrophages, granulocytes, natural killer cells, T cells, dendritic cells, and the induction of a variety of cytokines.6,8,9-11 Furthermore, Viscum album extracts appear to interfere with tumoral angiogenesis.6 A recent trial showed survival benefit in patients with advanced pancreatic cancer who were receiving Viscum album extracts,12,13 and durable tumor regression has been documented in case reports.14
Most studies to date have tested the effects of low doses of Viscum album extract.6,7 However, more recently, clinicians have explored the use of high doses of the extract in light of its strongly dose-dependent cytotoxic activity6,7 and with the aim of increasing the immunostimulatory and fever-inducing effect of this treatment at initial doses.8 Careful patient monitoring with high-dose treatment is important. Manufacturers recommend starting with the lowest strength, titrating upward until a mild fever and/or local inflammatory reaction occurs. Anaphylactic reactions to Viscum album extracts have been reported but are rare.15 High-dose fever-inducing Viscum album extract treatment had a tumor-reducing effect in patients with advanced hepatocellular carcinoma.16 Fever or hyperthermia has direct cytotoxic effects in human beings, activates antitumor immune mechanisms, and results in improved drug delivery to tumor sites through vasodilatation.17
However, to our knowledge, no studies have yet been done to explore the effect of high-dose, fever-inducing Viscum album extract treatment on bladder cancer recurrence. Therefore we did a retrospective analysis of the case notes of a series of patients with bladder cancer undergoing treatment with subcutaneous injections of high-dose Viscum album (Salicis, grown on willow trees) extract at one hospital outpatient clinic, to explore the effect of high-dose treatment on tumor recurrence.
We reviewed the case notes of all patients with bladder cancer being treated at the outpatient clinic of the Alexander von Humboldt Klinik, Bad Steben, Germany. This hospital is a specialty center for high-dose Viscum album extract treatment.22 Inclusion criteria were patients with confirmed, resectable (nonmuscle-invasive or muscle-invasive), urothelial bladder cancer who had undergone treatment with at least three injections of high-dose Viscum album (Salicis) extract between January 2006 and December 2012. We excluded patients who had had a cystectomy or those with advanced, inoperable bladder cancer. We reviewed patient data until December 31, 2013. Patients were contacted to verify their personal details, and we acquired written informed consent. We conducted brief interviews, which included exploration and documentation of patients' experiences during treatment with high-dose Viscum album extract treatment. Formal ethics approval was not required to carry out this case series. All patients were sent copies of our final analysis.
We calculated recurrence and progression risk in these patients using the European Organisation for Research and Treatment of Cancer (EORTC) risk tables.23 In cases where patients had not responded to intravesical bacillus Calmette-Guérin immunotherapy, defined as recurrence of a high-grade tumor at 3 months after treatment, or recurrence after intravesical bacillus Calmette-Guérin immunotherapy, we used the progression risk of more than 25% after 5 years as reported by Davis et al.24
We assessed the pattern of bladder cancer recurrence in included cases and categorized patients into 1 of 4 groups: likely beneficial effect, possible beneficial effect, unlikely beneficial effect, and not possible to assess. We considered high-dose Viscum album extract to have a likely beneficial effect when recurrence and progression risk was close to 100% and there was no more than 1 tumor recurrence after treatment. We considered there to be a possible beneficial effect when patients had no further recurrences 1 month after the start of treatment, tumor-free follow-up more than 30 months after treatment, and recurrence risk at time of treatment initiation between 62% and 78% (based on an EORTC score). We considered treatment to have an unlikely beneficial effect when patients had more than 1 recurrence after treatment. Patients with other circumstances explaining tumor nonrecurrence—for example, patients already tumor-free after another treatment or when tumor-free follow-up was less than 30 months—were categorized as not possible to assess.
For all included patients in this analysis, the treatment used was Iscucin Salicis (Wala Heilmittel GmbH, Bad Boll, Germany), an aqueous extract of Viscum album (European mistletoe) grown on willow trees (Salicis). Preparation involves extraction from freeze-dried whole plant with isotonic solution over 14 days without fermentation or heating, in accordance with methods reported in the German Homeopathic Pharmacopoeia (Rule 38).25 One ampoule (1 mL) of a 1:20 concentration (5%, Strength H) contains 50 mg of the "mother extract" (including approximately 5.9 mg/mL of lectin, a key active ingredient)26; concentration 1:400 (0.25%, Strength G) contains 2.5 mg; concentration 1:8000 (0.0125%, Strength F) contains 0.125 mg; and concentration 1:160,000 (0.000625%, Strength E) contains 0.00625 mg. Strengths F, G, and H fulfilled our criteria for high dose. Iscucin Salicis is licensed for the German market by the German Federal Institute for Drugs and Medical Devices.
For included patients in this series, the schedules of Viscum album extract treatment were individualized but followed general principles. All injections were given as 1-mL aqueous solutions subcutaneously in the lower aspect of the abdomen or upper part of the thigh. An initial dose of Iscucin Salicis at the highest strength, H (except Strength F in Case 2), was given in the outpatient clinic to observe reaction. Patients who responded with high fever and inflammatory reactions at the injection site received further injections, usually once weekly for 3 to 8 weeks. If no or little reaction occurred, injections were continued daily over 3 to 4 days to achieve the required inflammatory reaction. In patients with little or no reaction even after daily administration, Strength H was followed by weekly or twice-weekly injections of Iscucin Salicis Potency series II (a set containing Strengths D, E, F, and G) given in the order of 2×G, 2×F, 3×E, and 3×D and repeated over several months. One patient (Case 8) also received other types of Viscum album extract preparations.
Because the Alexander von Humboldt Klinik does not provide specialized urology services, all patients were followed up simultaneously by a private-practicing urologist or at a urology center.
We identified eight patients who met our inclusion criteria: seven with nonmuscle invasive bladder cancer (pTa and pT1) and one with muscle-invasive bladder cancer (pT2a) who had refused cystectomy. Three cases are reported here in detail.
A 59-year-old woman presented in February 2006 with 2 months of right-sided, colicky abdominal pain. Her medical history highlighted the removal of a uterine myoma and right-knee arthrosis with prosthetic replacement. She was a smoker (20 cigarettes per day since early adulthood). A urothelial carcinoma of the right renal pelvis, Stage pT3G1, was diagnosed by computed tomographic (CT) scan and renal biopsy. Nephroureterectomy was performed in February 2006. During cystoscopy in April 2006, 4 superficial bladder tumors were removed. (Upper urinary tract urothelial cancer has a 20% to 50% risk of recurrence, as does bladder cancer.2) She received 6 rounds of intravesical bacillus Calmette-Guérin immunotherapy (BCG Medac, Hamburg, Germany) at weekly intervals beginning in May 2006. Two new tumors—1 was high-grade (World Health Organization Grade 3)—were removed in November 2006. Cystectomy was not recommended to her (although 2013 European guidelines recommend cystectomy for failure to respond to bacillus Calmette-Guérin immunotherapy5). In November 2006, the patient was treated with high-dose Viscum album extract treatment, which was provided as follows:
There was no further recurrence of bladder cancer tumors after the initiation of Viscum album extract treatment at follow-up with annual cystoscopy/ureteroendoscopy and CT scan in 2007, and with magnetic resonance imaging in 2009 and 2012. This patient took early retirement in 2008 unrelated to her medical condition, feels well today, and remains socially active. She has reduced smoking to 7 or 8 cigarettes a day.
The patient told us: "The mistletoe treatment was intense, like I imagine chemotherapy [would be] but without nausea and vomiting. Shortly after starting mistletoe treatment I began feeling better and felt my strength return. Without the regular encouragement by Dr W, I would not have been able to tolerate the fever reactions. I think mistletoe stopped my tumors from returning."
A 62-year-old woman presented with hematuria and received a diagnosis of superficial bladder cancer in 1991 (pathology records were missing). Her medical history was remarkable for longstanding essential hypertension and for hysterectomy for treatment of multiple uterine myomas at age 40 years. She smoked 7 to 10 cigarettes per day.
In 1997 and 2001, she had bladder cancer recurrences, Stage pTaG2 (data obtained from medical records; pathology reports were missing). After 2 further recurrences in May and June 2005, Stage pTaG1 and pTis, respectively, she received intravesical instillation of mitomycin C and a single course of bacillus Calmette-Guérin immunotherapy consisting of 6 intravesical treatments. Intravesical bacillus Calmette-Guérin immunotherapy was not continued because it induced cystitis. In June 2008, she had a multifocal pTaG2 and pTisG3 recurrence, causing right ureteral ostium stenosis with hydronephrosis, which was alleviated by placement of a ureteral stent. In July 2008, clear cell adenocarcinoma of the left kidney, a cancer of different cellular origin than urothelial cancer, was diagnosed (pT1aG2L0M0), and a partial nephrectomy was performed. In August 2008, a multifocal bladder tumor (Stage pTisG3) was found. Cystectomy was recommended, but the patient declined treatment.
She looked for additional treatment options and began Viscum album extract treatment in November 2008. Strength F rather than Strength H was selected because she appeared too fragile to tolerate a high fever. The treatment schedule was as follows:
No further recurrence was observed at annual cystoscopy assessments. Her quality of life, however, was affected by frequent bladder infections with dysuria, probably because of the ureteral stent. Antibiotic treatments provided limited, temporary relief. Dysuria stopped with placement of a new stent in November 2013 (1 month before study completion). Because of the last transurethral resection she has incontinence, as she is unaware when her bladder is full.
The patient told us: "Since the mistletoe treatment I no longer live in fear of the cancer returning. However, I have been in constant discomfort and pain because of my urinary [tract] infections."
After hematuria developed in a 64-year-old woman, a high-grade, muscle-invasive urothelial bladder cancer (Stage pT2aG3) was diagnosed in May 2007. The tumor was resected transurethrally. No local tissue infiltration and no metastases were found after a CT scan and bone scintigraphy. The patient had worked for 15 years in a polyvinyl chloride factory, a known risk factor for liver cancer, but not bladder cancer. She had never smoked. Her medical history was unremarkable. She was offered a cystectomy but felt overwhelmed by the cancer diagnosis and refused any invasive procedures.
She contacted different physicians for alternative treatment options and began Viscum album extract treatment in May 2007. She received no mitomycin C instillations, no chemotherapy, and no radiotherapy. Viscum album extract treatment was provided as follows:
In September 2008, 16 months after the initial diagnosis, she had recurrence (Stages pTaG2 and pTisG3 tumors), for which she underwent transurethral resection. Treatment with Viscum album extract was continued as mentioned earlier, but she also received intravesical bacillus Calmette-Guérin immunotherapy in November 2008 (Month 12), which caused gross hematuria. Intravesical bacillus Calmette-Guérin immunotherapy was restarted in April 2009, again causing gross hematuria, and she received 1 instillation every 3 months until the end of 2012. The patient meticulously kept urologist appointments, initially with quarterly (and since 2010 approximately once every 6 months) cystoscopies and abdominal ultrasound examinations. She has been tumor-free for more than 5 years' follow-up.
The patient told us: "When I had the initial mistletoe injections it felt like my abdomen was cooking and as if it was an anthill. Today I feel even better and stronger than before my bladder cancer diagnosis."
Tables 1a and 1b highlight the number of tumor recurrences and the outcomes for each patient. Reported tumors were removed by transurethral resection in all cases. Figure 1 shows a timeline of tumor recurrences and treatment for each patient.
Among the 8 patients, 28 episodes of recurrence were observed from diagnosis until December 2013 (median = 3.5 recurrences per patient; range = 1-6 per patient). After intravesical bacillus Calmette-Guérin immunotherapy or mitomycin C therapy (received by 7 patients), 12 episodes of recurrence occurred over 694 months of follow-up (median = 1.5 recurrences per patient; range = 0-4 recurrences; 5-year cumulative incidence = 1.0). Following initiation of treatment with high-dose Viscum album extract, 5 recurrences occurred over 523 months of follow-up (median = 0 recurrences per patient; range = 0-3 recurrences; 5-year cumulative incidence = 0.55). These outcomes were not comparable, however, because the interventions overlapped considerably. Among the 4 patients who received intravesical bacillus Calmette-Guérin immunotherapy, 2 patients had further recurrences but stopped having recurrences once Viscum album extract treatment was initiated (see Figure 1, Patients 1 and 2). The tumor-free follow-up from initiation of Viscum album extract treatment until December 31, 2013 was 421 patient months (median = 48.5 tumor-free months per patient; range = 32-86 tumor-free months). Final cystoscopy controls (all negative for recurrences) were performed between November 2013 and April 2014 for all patients except Case 5, in which the last cystoscopy occurred in November 2011. (For this patient, tumor-free follow-up was counted only until November 2011.) None of the patients was identified with cancer progression.
The outcomes for each patient are described by category of effect.
Possible Beneficial Effect
Unlikely or Uncertain Beneficial Effect
In summary, an effect from Viscum album extract treatment appeared to be a possibility in five patients (Cases 1, 2, 3, 6, and 8), could not be assessed in two cases (Cases 5 and 7), and was unlikely in one patient (Case 4).
Most patients experienced fever up to 40º C and local redness at the injection site (less than 5 cm in diameter in all cases) as part of the intended immune reaction. One patient had nausea and headache after using a particular additional Viscum album extract preparation, from a birch tree (Case 8). No patient needed to stop treatment because of side effects.
We present retrospective data from a series of eight patients with recurrent bladder cancer who had been treated with high-dose Viscum album extract treatment. Seven patients had nonmuscle-invasive cancers with frequently recurring tumors, one of whom had not responded to intravesical bacillus Calmette-Guérin immunotherapy; therefore, they were a difficult patient group to manage. Patients had either intermediate-risk or high-risk tumors, as defined by European guidelines.5 One patient with muscle-invasive cancer had refused standard therapy, and so tumor recurrence and progression was almost certain. However, our analysis shows substantial and consistent decrease of recurrences in this series of patients. Despite unfavorable prognoses, we observed mainly positive outcomes after Viscum album extract treatment. Recurrences occurred in only three patients, and only one of those patients had three recurrences, and the patients had consistent, long, tumor-free periods subsequent to these recurrences, with no patient progressing. We therefore consider individual variation a less likely explanation, and a beneficial effect of Viscum album extract treatment as a possible explanation.
The analysis was not designed to compare recurrence incidence between intravesical bacillus Calmette-Guérin immunotherapy/mitomycin C treatment and Viscum album extract treatment. It also is not our intent to suggest management of muscle-invasive cancer without cystectomy. High-dose subcutaneous injections with Viscum album (Salicis) extract may, however, have a preventive role in frequent recurrences of bladder cancer.
Few studies exist regarding the effect of Viscum album extract treatment in recurrence of bladder cancer. In one small study, intravesical treatment with lectin-standardized Viscum album extract seemed to have preventive effect at 12-month follow-up, similar to intravesical bacillus Calmette-Guérin immunotherapy-treated historical controls.28 A small, prospective, randomized study in which low-dose, subcutaneous injections of lectin-standardized Viscum album extract were compared with no prophylactic intervention showed no benefit.29 A randomized trial in 60 patients, comparing intravesical Viscum fraxini-2 with intravesical bacillus Calmette-Guérin immunotherapy found a recurrence rate of 73% vs 30%; muscle-invasive bladder cancer developed in 5 patients in each group.30 A Phase 1b/2a dose-escalation study of intravesical treatment with Viscum album extract showed promising results31 and is currently being followed by a Phase 3 study.32 The treatment approach used in the patients in our case series differed from the approaches used in these other studies; the physicians at our clinic used subcutaneous application (more convenient than intravesical) and Viscum album extract grown on the willow tree (Salicis), which was selected on the basis of positive clinical experience.33
A potential mechanism of action for Viscum album extract in preventing recurrence of bladder cancer is its known antitumor and immune-modulating activity and the potential beneficial effect of fever in cancer treatment as described earlier.8,15 We note, however, that Viscum album extract induced fever after the first 2 to 3 doses only and thus may not be considered fever therapy.
A recurring theme reported by patients in this case series was that the initially exhausting fever reaction was followed by a gain in energy and strength. This is consistent with systematic reviews on the beneficial effect on quality of life and cancer-related fatigue of Viscum album extract treatment.6,7 Some patients experienced the treatment as a turning point in their treatment course, after which they felt more confident that they had overcome the cancer.
This report has several limitations. First, it is retrospective, and there are considerable differences among patients in terms of follow-up and treatment. Second, defining patients into certain categories after data mining is subject to researcher bias. Rather than a cohort, we present a series of individual cases, each assessed individually. The strengths of this report are that we provide direct observation from clinical practice, provide a qualitative judgment of each individual patient history, and have not merely provided an analysis of the best cases.
A prospective study is now needed to assess whether high-dose subcutaneous Viscum album (Salicis) extract can be an additional, bladder-sparing preventive option for patients with medium- to high-risk nonmuscle-invasive bladder cancer.
Dr Kienle and Dr Kiene report that their institute has received restricted research funding from the companies Wala and Weleda in the past five years, unrelated to this report.
Dr von Schoen-Angerer is supported by a grant from the Mahle Stiftung, Stuttgart, Germany, for the writing of case series and case reports. The funder had no role at any stage of the analysis or manuscript preparation.
Johannes Wilkens, MD, treated patients with Viscum album extract, provided patient information, and reviewed the manuscript. Tido von Schoen-Angerer, MD, MPH, conceptualized the report, wrote the manuscript, and prepared Figure 1. Gunver S Kienle, MD; Helmut Kiene, MD; Jan Vagedes, MD; and Johannes Wilkens, MD, critically reviewed the manuscript. All authors read and approved the final manuscript.
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011 Mar-Apr;61(2):69-90. DOI: http://dx.doi.org/10.3322/caac.20107.