Intratumoral mistletoe (Viscum album L) therapy in patients with unresectable pancreas carcinoma: A retrospective analysis

Integrative Cancer Therapies

Volumn 13, Issue 4, 2014, Pages 332-340

  Schad, Friedemann ^a,b   Atxner, Jan ^b   Buchwald, Dirk ^a   Happe, Antje ^b   Popp, Stephan ^b   Kröz, Matthias ^a,b   Matthes, Harald ^a,b  

^a Hospital Gemeinschaftskrankenhaus Havelhoehe   (Germany)

^b Havelhoehe Research Institute   (Germany)

Author keywords

endoscopic ultrasound; intratumoral; mistletoe therapy; pancreatic cancer; Viscum album

Indexed keywords

CISPLATIN; ERLOTINIB; FLUOROURACIL; GEMCITABINE; METOCLOPRAMIDE; MITOXANTRONE; OXALIPLATIN; PACLITAXEL; PIRITRAMIDE; VISCUM ALBUM EXTRACT; ABNOBA VISCUM; ANTINEOPLASTIC AGENT; DEOXYCYTIDINE; PLANT EXTRACT; PLATINUM COMPLEX;

ADULT; ADVANCED CANCER; AGED; BILE DUCT BYPASS; BONE METASTASIS; CANCER COMBINATION CHEMOTHERAPY; CANCER PALLIATIVE THERAPY; CANCER RADIOTHERAPY; CANCER RECURRENCE; CANCER STAGING; CANCER SURGERY; CANCER SURVIVAL; DRUG DOSE INCREASE; DRUG FEVER; DRUG INDUCED HEADACHE; DRUG MONITORING; DRUG SAFETY; ENDOSCOPIC ECHOGRAPHY; FEMALE; FOLLOW UP; GASTROENTEROSTOMY; HUMAN; MAJOR CLINICAL STUDY; MALE; MONOTHERAPY; MULTIMODALITY CANCER THERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; OVERALL SURVIVAL; PAIN; PANCREAS CARCINOMA; PANCREATICODUODENECTOMY; PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; PRIORITY JOURNAL; QUALITY OF LIFE; RETROSPECTIVE STUDY; REVIEW; SKIN IRRITATION; VISCUM ALBUM; ADVERSE EFFECTS; ANALOGS AND DERIVATIVES; CARCINOMA; CHEMICALLY INDUCED; ENDOSCOPIC ULTRASONOGRAPHY; FEVER; INTERVENTIONAL ULTRASONOGRAPHY; INTRALESIONAL DRUG ADMINISTRATION; MIDDLE AGED; PALLIATIVE THERAPY; PANCREATIC NEOPLASMS; PATHOLOGY; PHYTOTHERAPY; SURVIVAL RATE; VERY ELDERLY;

ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CARCINOMA; CISPLATIN; DEOXYCYTIDINE; ENDOSONOGRAPHY; ERLOTINIB HYDROCHLORIDE; FEMALE; FEVER; FLUOROURACIL; HUMANS; INJECTIONS, INTRALESIONAL; MALE; MIDDLE AGED; MITOXANTRONE; NEOPLASM STAGING; ORGANOPLATINUM COMPOUNDS; PACLITAXEL; PALLIATIVE CARE; PANCREATIC NEOPLASMS; PHYTOTHERAPY; PLANT EXTRACTS; RETROSPECTIVE STUDIES; SURVIVAL RATE; ULTRASONOGRAPHY, INTERVENTIONAL; VISCUM ALBUM;

EID: 84901806299     PISSN: 15347354     EISSN: 1552695X     Source Type: Journal    
DOI: 10.1177/1534735413513637     Document Type: Review

References (89)

1. Heinemann V, Wilkowski R. Behandlung des fortgeschrittenen und metastasierten Pankreaskarzinoms. Dtsch Arztebl. 2005 ; 102: 2720-2725
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 ; 60: 277-300
3. Beger HG, Rau B, Gansauge F, et al. Pancreatic cancer: low survival rates. Dtsch Arztebl Int. 2008 ; 105: 255-262
4. Coleman MP, Gatta G, Verdecchia A, et al. EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann Oncol. 2003 ; 14: 128-149
5. Burris H, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 ; 15: 2403-2413
6. Van Laethem JL, Verslype C, Iovanna JL, et al. New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel. Ann Oncol. 2012 ; 23: 570-576
7. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 ; 25: 1960-1966
8. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 ; 364: 1817-1825
9. Tempero MA, Berlin J, Ducreux M, et al. Pancreatic cancer treatment and research: an international expert panel discussion. Ann Oncol. 2011 ; 22: 1500-1506
10. Seufferlein T, Bachet JB, Van Cutsem E, Rougier P. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 ; 23: 33-40
11. Choi M, Kim R, Saif MW. What options are available for refractory pancreatic cancer?. JOP. 2012 ; 13: 163-165
12. Tokh M, Bathini V, Saif MW. First-line treatment of metastatic pancreatic cancer. JOP. 2012 ; 13: 159-162
13. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011 ; 378 (9791). 607-620
14. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010 ; 362: 1605-1617
15. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 ; 324: 1457-1461
16. Moriai T, Makino TT, Ishii K. Intratumoral treatment of pancreatic cancer with mitomycin-C adsorbed to activated carbon particles: a clinical trial on 15 cases. Anticancer Res. 1989 ; 9: 1799
17. Hecht JR, Farrell JJ, Senzer N, et al. EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study. Gastrointest Endosc. 2012 ; 75: 332-338
18. Lee I, Lee YH. The effect of various therapeutic solutions including colloidal chromic 32P via an intratumoral injection on the tumor physiological parameters of AsPC-1 human pancreatic tumor xenografts in nude mice. Clin Cancer Res. 1999 ; 5: 3139s - 3142s
19. Smith JP, Stock E, Orenberg EK, et al. Intratumoral chemotherapy with a sustained-release drug delivery system inhibits growth of human pancreatic cancer xenografts. Anticancer Drugs. 1995 ; 6: 717-726
20. Otsuji E, Yamaguchi T, Yamaoka N, et al. Intratumoral administration of neocarzinostatin conjugated to monoclonal antibody A7 in a model of pancreatic cancer. J Surg Oncol. 1993 ; 53: 215-219
21. Otsuji E, Yamaguchi T, Tsuruta H, et al. The effect of intravenous and intra-tumoural chemotherapy using a monoclonal antibody: drug conjugate in a xenograft model of pancreatic cancer. Eur J Surg Oncol. 1995 ; 21: 61-65
22. Carrió M, Visa J, Cascante A, Estivill X, Fillat C. Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P450 2B1 in a pancreatic tumor model: combination with the HSVtk/GCV system. J Gene Med. 2002 ; 4: 141-149
23. Cascalló M, Calbó J, Capellà G, et al. Enhancement of gemcitabine-induced apoptosis by restoration of p53 function in human pancreatic tumors. Oncology. 2005 ; 68: 179-189
24. Löhr M, Bago ZT, Bergmeister H, et al. Cell therapy using microencapsulated 293 cells transfected with a gene construct expressing CYP2B1, an ifosfamide converting enzyme, instilled intra-Arterially in patients with advanced-stage pancreatic carcinoma: a phase I/II study. J Mol Med. 1999 ; 77: 393-398
25. Kanyama H, Tomita N, Yamano T, et al. Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy. Cancer Res. 2001 ; 61: 14-18
26. Löhr M, Müller P, Karle P, et al. Targeted chemotherapy by intratumour injection of encapsulated cells engineered to produce CYP2B1, an ifosfamide activating cytochrome P450. Gene Ther. 1998 ; 5: 1070-1078
27. Schmidt T, Ziske C, Märten A, et al. Intratumoral immunization with tumor RNA-pulsed dendritic cells confers antitumor immunity in a C57BL/6 pancreatic murine tumor model. Cancer Res. 2003 ; 63: 8962-8967
28. Udagawa M, Kudo-Saito C, Hasegawa G, et al. Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation. Clin Canc Res. 2006 ; 12: 7465-7475
29. Bauer C, Bauernfeind F, Sterzik A, et al. Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model. Gut. 2007 ; 56: 1275-1282
30. Linghu E, Matthes K, Mino-Kenudson M, Brugge WR. Feasibility of endoscopic ultrasound-guided OncoGel (ReGel/paclitaxel) injection into the pancreas in pigs. Endoscopy. 2005 ; 37: 1140-1142
31. Matthes K, Mino-Kenudson M, Sahani DV, et al. EUS-guided injection of paclitaxel (OncoGel) provides therapeutic drug concentrations in the porcine pancreas (with video). Gastrointest Endosc. 2007 ; 65: 448-453
32. Lewis JJ, Kowalski TE. Endoscopic ultrasound and fine needle aspiration in pancreatic cancer. Cancer J. 2012 ; 18: 523-529
33. DeNittis AS, Stambaugh MD, Lang P. Complete remission of nonresectable pancreatic cancer after infusional colloidal phosphorus-32 brachytherapy, external beam radiation therapy, and 5-fluorouracil: a preliminary report. Am J Clin Oncol. 1999 ; 22: 355-360
34. Chang KJ, Nguyen PT, Thompson JA, et al. Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma. Cancer. 2000 ; 88: 1325-1335
35. Hecht JR, Bedford R, Abbruzzese JL, et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res. 2003 ; 9: 555-561
36. Sangro B, Mazzolini G, Ruiz J, et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol. 2004 ; 22: 1389-1397
37. Klapman JB, Chang KJ. Endoscopic ultrasound-guided fine-needle injection. Gastrointest Endosc Clin N Am. 2005 ; 15: 169-177
38. Matthes H, Buchwald D, Kröz M, Schad F. Integrative Therapiemöglichkeiten des inoperablen Pankreaskarzinoms-eine Übersicht. Deutsche Zeitschrift für Onkologie. 2008 ; 40: 106-110
39. Schad F, Axtner J, Happe A, et al. Network Oncology (NO): a clinical cancer register for health services research and the evaluation of integrative therapeutic interventions in anthroposophic medicine. Forsch Komplementmed. 2013 ; 20: 353-360
40. Riphaus A, Wehrmann T, Weber B, et al. S3-guidelines "Sedierung in der gastrointestinalen Endoskopie" 2008 (AWMF-Register-Nr. 021/014). Z Gastroenterol. 2008 ; 46: 1298-1330
41. Melzer J, Iten F, Hostanska K, Saller R. Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. Forsch Komplementmed. 2009 ; 16: 217-226
42. Horneber M, Bueschel G, Dennert G, et al. How many cancer patients use complementary and alternative medicine: a systematic review and metaanalysis. Integr Cancer Ther. 2012 ; 11: 187-203
43. Kienle GS, Kiene H. Review article: influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients. A systematic review of controlled clinical studies. Integr Cancer Ther. 2010 ; 9: 142-157
44. Khil LY, Kim W, Lyu S, et al. Mechanisms involved in Korean mistletoe lectin-induced apoptosis of cancer cells. World J Gastroenterol. 2007 2811 ; 13:
45. Seifert G, Jesse P, Laengler A, et al. Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro. Cancer Lett. 2008 ; 264: 218-228
46. Kovacs E. Investigation of the proliferation, apoptosis/necrosis, and cell cycle phases in several human multiple myeloma cell lines: comparison of Viscum album QuFrF extract with vincristine in an in vitro model. ScientificWorldJournal. 2010 ; 10: 311-320
47. Harmsma M, Ummelen M, Dignef W, Tusenius KJ, Ramaekers FC. Effects of mistletoe (Viscum album L.) extracts Iscador on cell cycle and survival of tumor cells. Arzneimittelforschung. 2011 ; 56: 474-482
48. Choi SH, Lyu SY, Park WB. Mistletoe lectin induces apoptosis and telomerase inhibition in human A253 cancer cells through dephosphorylation of Akt. Arch Pharm Res. 2004 ; 27: 68-76
49. Bar-Sela G. White-berry mistletoe (Viscum album L.) as complementary treatment in cancer: does it help?. Eur J Integr Med. 2011 ; 3: e55 - e62
50. Zänker K, Matthes H, Bock PR, Hanisch J. A Specific mistletoe preparation (Iscador-Qu®) in colorectal cancer (CRC) patients: more than just supportive care?. J Cancer Sci Ther. 2012 ; 4: 264-270
51. Delebinski C, Jaeger S, Kemnitz-Hassanin K, et al. A new development of triterpene acid-containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia. Cell Prolif. 2012 ; 45: 176-187
52. Maier G, Fiebig HH. Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs. 2002 ; 13: 373-379
53. Pryme IF, Bardocz S, Pusztai A, Ewen SWB. Suppression of growth of tumour cell lines in vitro and tumours in vivo by mistletoe lectins. Histol Histopathol. 2006 ; 21: 285-299
54. Elluru SR, van Huyen JPD, Delignat S, et al. Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer. 2008 ; 8: 161
55. Lyu SY, Park WB. Mistletoe lectin modulates intestinal epithelial cell-derived cytokines and B cell IgA secretion. Arch Pharm Res. 2009 ; 32: 443-451
56. Pryme IF, Tilrem P. Oral mistletoe lectins: a case for their use in cancer therapy. Cancer Ther. 2007 ; 5: 287-300
57. Hajtó T, Fodor K, Perjési P, Németh P. Difficulties and perspectives of immunomodulatory therapy with mistletoe lectins and standardized mistletoe extracts in evidence-based medicine [article ID 298972]. Evid Based Complement Alternat Med. 2011 2011 ;:
58. Engdal S, Nilsen OG. Inhibition of P-glycoprotein in Caco-2 cells: effects of herbal remedies frequently used by cancer patients. Xenobiotica. 2008 ; 38: 559-573
59. Rostock M, Huber R, Greiner T, et al. Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Res. 2005 ; 25 (3B). 1969-1975
60. Matthes H, Schad F, Schenk G. Viscum album in the therapy of primary inoperable hepatocellular carcinoma (HCC). Gastroenterol. 2004 ; 126: A101 - A102
61. Schad F, Matthes B, Matthes H. Intraläsionale Viscumtherapie bei Hepatozellulärem Karzinom. Der Merkurstab. 1999 ; 52: 120-22
62. Stumpf C, Ramirez-Martinez S, Becher A, Stein GM, Büssing A, Schietzel M. Intratumorale Mistelapplikation bei stenosierendem Rezidiv eines Cardia-Carcinoms. Erfahrungsheilkunde. 1997 ; 46: 509-513
63. Matthes H. Intraläsionale Mistelinjektionen in Lebermetastasen bei kolorektalem Karzinom und in das primäre hepatozelluläre Karzinom (HCC). Der Merkurstab. 1997 ; 50: 41
64. Schad F, Kröz M. Intraläsionale und kombinierte subkutan-intravenöse Misteltherapie bei einem Patient mit Kolonkarzinom. Der Merkurstab. 1999 ; 52: 399-406
65. Scheffler A, Mast H, Fischer S, Metelmann H Grundlagen der Misteltherapie. Scheer R Becker H Berg PA, ed. Stuttgart, Germany: Hippokrates Verlag ; 1996: 453-464.
66. Orange M, Fonseca M, Lace A, von Laue HB, Geider S. Durable tumour responses following primary high dose induction with mistletoe extracts: two case reports. Eur J Integr Med. 2010 ; 2: 63-69
67. Nabrotzki M, Scheffler A Die Misteltherapie in der Tumortherapie. Scheer R, ed. Essen, Germany: KVC Verlag ; 2001: 453-464.
68. Werthmann PG, Sträter G, Friesland H, Kienle GS. Durable response of cutaneous squamous cell carcinoma following high-dose peri-lesional injections of Viscum album extracts: a case report. Phytomedicine. 2013 ; 20: 324-327
69. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009 ; 50: 122S - 150S
70. Pazdur R. Response rates, survival, and chemotherapy trials. J Natl Cancer Inst. 2000 ; 92: 1552-1553
71. Massucco P, Capussotti L, Magnino A, et al. Pancreatic resections after chemoradiotherapy for locally advanced ductal adenocarcinoma: analysis of perioperative outcome and survival. Ann Surg Oncol. 2006 ; 13: 1201-1208
72. Saller R, Kramer S, Iten F, Melzer J Fortschritte in der Misteltherapie: Aktueller Stand der Forschung und klinischen Anwendung. Scheer R Bauer R Becker H, ed. Essen, Germany: KCV Verlag ; 2005: 367-403.
73. Orange M Mistletoe therapy for cancer patients. Birmingham, England: University of Birmingham ; 2010:
74. Zerbini A, Pilli M, Ferrari C, Missale G. Is there a role for immunotherapy in hepatocellular carcinoma?. Dig Liver Dis. 2006 ; 38: 221-225
75. Zhou G, Levitsky H. Towards curative cancer immunotherapy: overcoming posttherapy tumor escape [article ID 124187]. Clin Dev Immunol. 2012 2012 ;:
76. Engdal S, Steinsbekk A, Klepp O, Nilsen OG. Herbal use among cancer patients during palliative or curative chemotherapy treatment in Norway. Support Care Cancer. 2008 ; 16: 763-769
77. Cassileth BR, Deng G. Complementary and alternative therapies for cancer. Oncologist. 2004 ; 9: 80-89
78. Cassileth BR, Gubili J, Yeung KS. Integrative medicine: complementary therapies and supplements. Nat Rev Urol. 2009 ; 6: 228-233
79. Tascilar M, de Jong FA, Verweij J, Mathijssen RH. Complementary and alternative medicine during cancer treatment: beyond innocence. Oncologist. 2006 ; 11: 732-741
80. Bisht S, Maitra A. Systemic delivery of curcumin: 21st century solutions for an ancient conundrum. Curr Drug Discov Technol. 2009 ; 6: 192-199
81. Mansky P, Wallerstedt DB, Sannes T, et al. NCCAM/NCI phase I study of mistletoe extract and gemcitabine in patients with advanced solid tumors. J Clin Oncol. 2010 2559 ; 28:
82. Kienle GS, Glockmann A, Schink M, Kiene H. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. J Exp Clin Cancer Res. 2009 ; 28: 79
83. Kienle GS, Kiene H. Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res. 2007 ; 12: 103-119
84. Piao BK, Wang YX, Xie GR, et al. Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients: a prospective randomized controlled clinical trial. Anticancer Res. 2004 ; 24: 303-310
85. Eisenbraun J, Scheer R, Kröz M, Schad F, Huber R. Quality of life in breast cancer patients during chemotherapy and concurrent therapy with a mistletoe extract. Phytomedicine. 2010 ; 18: 151-157
86. Horneber M, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology [article CD003297]. Cochrane Database Syst Rev. 2008 ;: 2
87. Matthes H, Friedel WE, Bock PR, Zänker KS. Molecular mistletoe therapy: friend or foe in established anti-tumor protocols? A multicenter, controlled, retrospective pharmaco-epidemiological study in pancreas cancer. Curr Mol Med. 2010 ; 10: 430-439
88. Friedel WE, Matthes H, Bock PR, Zänker KS. Systematic evaluation of the clinical effects of supportive mistletoe treatment within chemo- and/or radiotherapy protocols and long-term mistletoe application in nonmetastatic colorectal carcinoma: multicenter, controlled, observational cohort study. J Soc Integr Oncol. 2009 ; 7: 137-145
89. Tröger W, Galun D, Reif M, Schumann A, Stankovi N, Milievi M. Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer. 2013 ;: