gms | German Medical Science

82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e. V.

Deutsche Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e. V.

01.06. - 05.06.2011, Freiburg

Combination MTD and metronomic chemotherapy – a better way to organ preservation and remission in advanced HNSCC?

Meeting Abstract

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German Society of Oto-Rhino-Laryngology, Head and Neck Surgery. 82nd Annual Meeting of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery. Freiburg, 01.-05.06.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11hno08

DOI: 10.3205/11hno08, URN: urn:nbn:de:0183-11hno088

Veröffentlicht: 3. August 2011

© 2011 Schedler et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen ( Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.



Treatment of advanced HNSCC still lacks a gold standard. Variable MTD (maximal tolerated dose) regimens have been in use for UICC stage III and IV HNSCC since 1985, and finding the right regimen may get confusing. Cisplatin (CDDP) based regimens are well established as well in induction (neoadjuvant) CT as in concurrent RCT. Initially superior response rates published for PF (Cisplatin/ 5-FU), even though effective didn't stand controlled randomized trials and the test of time. The addition of Taxanes (PT) generated improved, but not consistent results and in part significant toxicities. The triplet combination of TPF brought reproducible high and lasting response rates, but unfortunately also increased acute and latent toxicity including fatal outcomes, especially in Docetaxel based regimens.The acute toxicities in actuary trials with induction TPF, followed by RCT required reduction to TP (Docetaxel, Cisplatin) for ethic reasons. In the meantime significant late toxicities, again including toxic deaths and severe tissue damage compromising the organ preservation effect were reported from different study groups all over the world.

Metronomic CT (met-CT) is a relatively new approach to treat advanced cancer, not by primary toxicity to malignant tumors, but by interfering with signal pathways and senescence of cancer cells, largely by antiangiogenetic effects. In the meantime a host of literature regarding this approach has been accumulated and constantly expanded, even though the majority of medical community has not taken notice of the new appoach.

Our intent was to find out, why a metronomized CBV-Kelsen regimen (Cisplatin, Bleomycin, Vindesine ) used at University Hospital Homburg/Saar from 1987 to 1996 produced consistent high response rates without significant toxicities (C.Heib 1995). We perpetuated its use in the years 1996 up to now with similar results experienced at Homburg. This regimen, available in 2 versions (CBV I, CBV II) represents a combination of an MTD and metronomic regime, CBV I: MTD Cisplatin (110mg/m²) d1, Vindesine (3mg/m², 5mg max total dose) d15, metronomic Bleomycin 15mg i.m. d2,3,5,7,9,11,13. In CBV II ("split course") Cisplatin 50 mg/m² d1, Vindesine 3mg/m² d1, Bleomycin 15mg d2,4,6,8,10 followed by 2–5 day pause, then repeat as above and finish with 100mg/m² MTX with or without Folinic acid rescue, depending on patients status and blood count. Thus CBV I counts for 14 and Split course regime for a total of 20 days metronomic application.

Our results represent the Ramstein Experience 1996–2009: N=138 Pat., cycles: N=386 (CBV I=289, CBV II=97), the Homburg 1987–1996 data are so far not accessible yet. Typical side effects are nonfebrile, reversible Neutropenia WHO grade II/III effectively treated by CSF up to 2002 (Sargramostin), from 2003 G-CSF (Lenograstim,Filgrastim)

Platinsalt induced anemia effectively treated by early administration of Erythropoetin alpha (Erypo®) or Darbepoetin (Aranesp®). Platinsalt induced hyperemesis treated by combination 5-HT3 blockers/Dexamethason warrants good tolerance even in high dose CDDP (110mg/m²) like in CBV regimen.

Rare side effects are: reversible renal failure w/o dialysis (N=3), reversible, febrile neutropenia( N=1), reversible pneumotoxicity (reduced CO-transferfactor, N=5), reversible neurotoxicity (intestinal atonia N=7), palsy of peronaeus nerve (PPN, N=17) non reversible PPN (N=2), skin toxicity (Bleomycin) in part reversible (N=16). No toxic deaths (TD N=0).

Possible reduction of pulmonary toxicity by:

1. metronomic i.m. application, 2. closing cycle with Vinca alcaloid, 3. strict radiologic momitoring, 4. consequent dispensing of oral enzyme therapy (eg Phlogenzym® 2-2-2/d) during total treatment period?

Organ preservation: Salvage operations (N=14): laryngectomies N=4 (3xR0, preservation rate13/17=76%), enoral resection N=3 (2xR0), neck dissection N=7 (4xR0). Combined MTD-metronomic CT possible, even in immunologic compromised patients after organ transplantation and under immunosuppressants (eg. Azathioprin, Cyclosporin).

Case report of a 67 year old male (H.P.), hypopharyngeal cancer, doublet UICC IV stage , FD 1/2004, status after liver transplantation 1997 for liver CI and HCC, incarceration of ICC on a length of 7 cm by metastatic growth, infiltra- tion of thyroid cartilage (T4, N3). Histology: moderately keratinizing SCC, G2. Ongoing immunosuppressive medication, not to be discontinued. Planned therapy: 2 cycles of CBV, follwed by RT 70Gy and 1–2 cycles adjuvant CBV. CR after 2x CBV. Pat. received a 7 weeks long (!) dental sanation elsewhere. Presented again with local regrowth (palpable neck mass) and otalgia. He received a 3. cycle CBV and got started on RT 2 weeks after completion of CT. The last cycle of CBV was administered 6 weeks after completion of RT. During normal fractionated RT (7 weeks, 72 Gy), CDDP, 50 mg total dose, weeks 2,3,4,5 were administered. Therapy was tolerated remarkably well, except for grade 3, reversible, Bleomycin induced skin toxicity. Pat. desease free alive 88 mths after first diagnosis (5/2011).

CBV in combined MTD-metronomic approach is a well tolerated, effective and low cost, alternative CT regimen. The long "exposure" time of advanced tumors to therapeutic agents seems to be crucial for the superior results of this approach. The 1987–1996 Homburg experience still awaits retrospective evaluation, while our actuary data claim randomized prospective multicentered trials, certainly not to be funded by the industry, and therefore most likely never being implemented. Still, metronomic and combined MTD-met CT could be the future in the treatment of advanced HNSCC.


Browder T, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878-86.
Dietz A, Keilholz U, Flentje M. Organerhalt bei Larynx-Hypopharynx-Karzinomen Was ist das? Der Onkologe. 13(2):118-128. DOI: 10.1007/s00761-006-1153-0 Externer Link
Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 1971;285: 1182-6.
Fontana, A. et al. Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res. 2009;15:4954-62.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncol. 2001;2:733-40.
Gatenby RA, Silva AS, Gillies RJ, Frieden BR. Adaptive therapy. Cancer Res. 2009;69:4894-903.
Ghiringhelli F, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol. 2004;34:336-44.
Ghiringhelli F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56:641-8.
Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972;136:261-76.
Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105:1045-7.
Heib CE. Analyse der Behandlungsergebnisse und Nebenwirkungen einer Induktionschemotherapie in Kombination mit hochdosierter Strahlentherapie bei Tumoren der UICC Stadien III-IV im Kopf-und Halsbereich. Inauguraldissertation an der Universität des Saarlandes.1995.
Hida K, Hida Y, Shindoh M. Understanding tumor endothelial cell abnormalities to develop ideal anti-angiogenic therapies. Cancer Sci. 2008;99:459-66.
Kelsen DP, Bains M, Hilaris B, Chapman R, McCormack P, Alexander J, Hopfan S, Martini N. Combination chemotherapy of esophageal carcinoma using cisplatin, vindesine, and bleomycin. Cancer. 1982;49:1174-7.
Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423-36.
Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays. 1991;13:31-6.
Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039-49.
Kesari S, et al. Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults. Neuro Oncol. 2007;9:354-63.
Knecht R. Strahlen-, Chemo- und Targettherapie von Kopf-Hals-Karzinomen – Neue Entwicklungen. HNO. 2009;57(5):436-45. DOI: 10.1007/s00106-009-1909 Externer Link
Kovács AF, Eberlein K, Smolarz A, Weidauer S, Rohde S. Organerhaltende Therapie bei inoperablen Patienten mit primären Mundhöhlen- und Oropharynxkarzinomen Möglichkeiten und Grenzen. Oral and Maxillofacial Surgery. 2006;10(3):168-77. DOI: 10.1007/s10006-006-0684-2 Externer Link
Krzyzanowska MK, et al. A phase II trial of continuous low-dose oral cyclophosphamide and celecoxib in patients with renal cell carcinoma. Cancer Chemother Pharmacol. 2007;60:135-41.
Laquente B, Vinals F, Germa JR. Metronomic chemotherapy: an antiangiogenic scheduling. Clin Transl Oncol. 2007;9:93-8.
Loeffler M, Kruger JA, Reisfeld RA. Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase. Cancer Res. 2005;65: 5027-30.
Lord R, et al. Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol. 2007;177:2136-40.
Lutsiak ME, et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862-8.
Pasquier E, Andre N, Braguer D. Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: implications for cancer treatment. Curr Cancer Drug Targets. 2007;7: 566-81.
Sarmiento R, Gasparini G. Antiangiogenic metronomic chemotherapy. Onkologie. 2008;31:161-2.
Schedler M, Lind A, Schätzle W, Stauder G. Adjuvant therapy with hydrolytic enzymes in oncology - a hopeful effort to avoid bleomycinum induced pneumotoxicity? J Cancer Res and Clin Oncol. 1990;116(Suppl., Part I), Abst. B5.206.02 WM 52 (1-05-3)
Simon C, Plinkert PK. Multimodale Therapiestrategien bei der Behandlung von Kopf- und Halskarzinomen. HNO. 2008;56(6):575-84. DOI: 10.1007/s00106-008-1718-x Externer Link
Steinbild S, et al. Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients-results of a phase II study. Onkologie. 2007;30:629-35.
Sterba J, et al. Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: single-center pilot study. Onkologie. 2006;29:308-13.
Sterba J, Pavelka Z, Slampa P. Concomitant radiotherapy and metronomic temozolomide in pediatric high-risk brain tumors. Neoplasma. 2002;49:117-20.
Vogt T, et al. Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer. 2003;98:2251-6.
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59-73.