Management of Lymph Node Metastases Jochen A. Werner, Marburg, Germany

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

p53 Werner JA et al. (1997) Cancer Immunol. Immunother. 44: Gottschlich S et al. (2000) Oncology 59: Gottschlich S et al. (2001) Anticancer Res. 20: Ki-S 11, Ki-67 Kuropkat C et al. (1999) Virchows Arch. 435: CYFRA 21-1 Kuropkat C et al. (2002) Oncology 63: Matrixmetalloproteinasen und deren Inhibitoren Werner JA et al. (2002) Clin. Exp. Metastas. 19: Kuropkat C et al. (2002) Anticancer Res. 22: Mandic R et al. (2002) Anticancer Res. 22: Dünne AA et al. (2003) Anticancer Res. 23: (im Druck) EGF-Rezeptor Mandic R et al. (2001) Anticancer Res. 21: Aneuploidie Görögh T et al. (1997) J Cancer Res Clin Oncol. 123: Cyclin D-1, c-erbB-2 Kuropkat C et al. (2002) Auris Nasus Larynx 29: LOX Rost T et al. (2003) Anticancer Res. 23: Prognostic markers Aneuploidie, ANG, bcl2, bFGF, BFGF, Cathepsin D, CD34(+), CD4/CD8, c-erbB-1, c- erbB-2, chromosomal heterozygosity, collagen VII, COX-2, c-Src, CD117, Cyclin D1, Cyclin D3, Cyclooxygenase-2, CYFRA 21-1, cytochrome P4501A1 polymorphisms, E48 antigen, E-cadherin, EGF-R, eIF4E, fragile histidine triad gene, frequent 3p allele loss, GAGE-3/4/ 5/6/8, galectin-1, galectin-3, glutathione S-transferase P1-1/M1/T1, GM-CF, GRADING, HSP27, HSP70, immuno- suppressive acid protein, Infiltrationstiefe, ING1, ING3, INK4a-ARF, Kapselruptur, Ki-67, Ki-S11, Laminin-gamma 2, LOX, LOXL2, Ly6-D, Lymphangiosis, M-CSF, MMPs, MTI/II, Muc-1 Gen, N-Acetylneura- minsäure, p16, p16INK4A, p21, p53, PAI-1, PCNA, PLK, PLK, PTEN/MMAC1, RAGE Gen, Rb, sICAM-1, SPF, sVCAM-1, TGF- alpha, TGF-beta, Thomsen-Friedenreich antigen, thymidine phosphorylase,Tie-2 receptor, TIMPs, TP53, type IV collagen, urokinase receptor, cyclin A, UTKA, VEGF, 11q13 amplification, 3q overrepresentation - Perinodal Spread ? - Matrixmetalloproteinases ?

Meta-Analysis of the Prognostic Significance of Perinodal Spread in HNSCC Patients Dünne AA, Müller HH, Eisele DE, Kessel K, Moll P, Werner JA Eur. J. Cancer (in press) Study methodology allowed enrollment of only 9 studies of 115 published papers Excluded studies lacked regarding primary tumor location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data Results: Perinodal spread is a doubling risk factor that reduces the 5- year-survival by univariate analysis Conclusion: Creation of international standards for assessment of micro- or macroscopic perinodal spread is important. This challenge should be approached by carefully designed multi-centre studies

Meta-Analysis on the Significance of Matrix Metalloproteinases for Nodal Disease in Head and Neck Squamous Cell Carcinoma S. Wiegand, A.A. Dünne, H.H. Müller, R. Mandic, P. Barth, R.K. Davis, J.A. Werner Cancer 104: (2005) Problem: Heterogenity of data collection, immuno-histochemical staining and statistical methods 14 studies with 710 patients for 5 different MMPs (MMP-1, -2, -3, -9, -14) could be included into Meta-Analysis Results: MMP-2, -3, -14 were found to possibly play a role in the metastatic behaviour of HNSCC tumors Conclusion: As a first step, standardization of immuno-histochemical staining procedures and evaluation protocols is required. These are the prerequisites to achieve comparable results for further evaluation.

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

Sentinel Node in Head and Neck Cancer

Intermediate Results => Extirpation of only one SN (SN1) is not representative! Werner et al.: Br J Cancer 87: (2002) Werner et al.: Head Neck 26: (2004) => Lymphatic mapping with detection of SN 1-3 confirms concept of SND with removal of the main metastatic level. => Shall three tracer accumulating lymph nodes be extirpated regularly or is it a question of further limiting selective ND (e.g. SND II-III or IIA-III)?

Systematic review and diagnostic meta-analysis of published literature regarding until December Total of 301 patients with oral cavity primary tumors and 46 patients with oropharyngeal primary tumors from 19 articles were included for the meta-analysis. V. Paleri et al.: Sentinel node biopsy in squamous cell cancer of the oral cavity and oral pharynx: a diagnostic meta-analysis. Head Neck Sep;27(9):

Sentinel Node - Critical discussion Quality of injection and thus experience of the examiner plays an important role for the exactness of this technique Complex architecture and distribution of lymph vessels in the head and neck lead to a high risk of possible pitfalls B-mode sonography plus FNA (van d. Brekel) has the same specificity and sensitivity, depending on the examiner, however, IT IS NON-INVASIVE

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

1906 – 2006

Neck dissection 100 years experience ! Standardized indications ?

ND in N+ and N0 Neck RND, N + Neck MRND,SND Wait and see, N 0 Neck SND,MRND (RND) RT (N1, >N1?)

?

More than ten years later ?

Extent of surgical intervention in case of N0 neck in head and neck cancer patients – an analysis of data collection of 39 hospitals Dünne A.A., Folz B.J., Kuropkat C., Werner J.A. Eur. Arch. Otorhinolaryngol. 261: (2004) Standardized questionnaire: 52 year-old male patient, moderately differentiated squamous cell carcinoma (G2), no lymphangiosis carcinomatosa, N0 neck according to imaging Results: There is no unique treatment concept of the surgical neck treatment in Germany. Conclusion: Necessity to develop stage-associated treatment concepts of the cervical lymphatic drainage.

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

Presence of malignant tumor cells in persistent neck disease after radiotherapy The presence of viable cancer cells in radiated neck nodes is a novel prognostic marker for disease-specific survival in patients treated for SCCs of the pharynx with advanced neck disease Simon C. et al. (2005) Eur Arch Otorhinolaryngol 22 [Epub ahead of print] Neck dissection for patients with N2 or greater neck disease after CRT is necessary to eradicate residual disease. The complication rate of SND after CRT with hyperfractionated radiotherapy is low. SNDs are technically feasible when performed within the "window" between the acute and chronic CRT injury (4-12 weeks). Stenson KM et al. (2000) Arch Otolaryngol Head Neck Surg 126:

Hyperfractionated Accelerated Radiation Therapy (HART) with Mitomycin C / 5-FU versus Cisplatin / 5-FU in locally advanced HNSCC Prof. Dr. V.G. Budach, Charite, Berlin, Germany Translational research project: Presence of malignant tumor cells in persistent neck disease after radiotherapy

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

Future Strategies - Translymphatic Chemotherapy - Magnetic drug-targeting

Future Strategies - Translymphatic Chemotherapy - Magnetic drug-targeting

A phase III placebo-controlled study in advanced head and neck cancer using intratumoural cisplatin/epinephrine gel Br. J. Cancer 87: (2002) Werner J.A., Kehrl W., Pluzanska A., Arndt O., Lavery KM, Glaholm J., Dietz A., Dykhoff G., Maune S., Stewart M.E., Orenberg E.K., Leavitt R.D. Intratumoral injection of cisplatin/epinephrine gel: 14/57 patients (25%) tumor volume reduction (16% complete, 9% partial regression), vs. 3% regression under placebo control (p=0.007) Side effect: Volume reduction of neighbouring lymph nodes Question: Possibility of drug targeting utilizing CDDP conjugated block copolymer tracking systems for translymphatic treatment of draining lymph nodes

Block copolymer carrier systems for translymphatic chemotherapy of lymph node metastases Dünne A.A., *Börner H.G., Schlaad H., Kukula H., Werner J.A., Antonietti M. (submitted) Most effective application of high cargo-load CDDP tracking system (48 wt.% CDDP) curing 90% of animals. Systems containing 1 or 10 wt.% of CDDP were less effective but still cured 50% of the animals. Systems contained mg/kg per body weight CDDP compared to 1ml/kg per body weight as usually used for curative intravenous administration Side effect: No severe systemic and local side effects during therapy and follow- up phase, but mild adverse effects in all animals (therapy groups): local hair loss after 7-12 days accompanied by mild, local inflammation after days Next step: Design of PEO-b-polypeptides with advanced functions, such as programmed carrier degradation or specific liberation of reporter molecules after delivery of the drug load.

Future Strategies - Translymphatic Chemotherapy - Magnetic drug-targeting

BMBF BIO-DISC: Guided local and regional pharmacotherapy utilizing an external magnetic field and shock waves (FKZ ) External magnetic field concentrates ferrofluide particles in lymph nodes, followed by application of extern shock waves to unhinge the chemo- therapeutic agent from its linkage, which results in an increase of local effectiveness Question: Mechanism of magnetic drug-targeting in lymph node metastases

5th International Symposium on Advances in Head and Neck Cancer - Basic and Clinical Research January 17-20, 2007 Marburg

1.Incidence 2.Nodal Factors Affecting Prognosis 3.„N“ Staging (AJCC-UICC-2002) 4.Diagnostic Imaging 5.Management of the N+-neck 6.Management of the N0-neck 7.Adjuvant Therapy 8.The Post Chemo/R.T. neck 9.Future Strategies

Magnet Resonance Imaging Computed Tomography B-Mode-Sonography + FNA Positron Emission Tomography

Session 13 Detection of Lymph Node Metastases

Magnet Resonance Imaging Computed Tomography B-Mode-Sonography + FNA Positron Emission Tomography

Discrimination of metastatic cervical lymph nodes with MRI imaging in patients with head and neck cancer MRI imaging is most useful in discriminating metastatic nodes. Sumi M et al. (2003) AJNR Am J Neuroradiol 24:

Comparison of CT and MR imaging in staging of neck metastases Computed tomography performed better than magnet resonance imaging for all interpretative criteria. Curtin HD (1998) Radiology 207:

B-Mode-Sonography B-mode sonography of the neck is superior to palpation, computed tomography and MRI Its application is useful in differential diagnosis, surgical planning, and the postoperative care of the neck. Iro H et al. (2000) Kopf-Hals-Sonographie. Springer, Berlin

The most experienced MRI-radiologist No study compares: The most experienced CT-radiologist The most experienced ultrasound specialist The discussion on the best diagnostic tool for small lymph node metastases will remain in the well known scientific fog with

Advantage of B-mode sonography Surgeon himself is able to performe the examination of the neck as dynamic approach.

Diagnostic Imaging: Future Concept ? Radioimmunodetection and Immuno-PET G A van Dongen, Amsterdam

Risk profile Controversy concerning the optimized management of the neck must be aimed a subgroup definition of high risk patients by virtue of individual risk profils in order to reduce the rate of unnecessary surgical or radiotherapeutical interventions. For this purpose, histological and/or molecular markers must be detected which allow high risk patients to be identified on the basis of the primary tumor who might then benefit from a surgical or radiotherapeutical procedure.

Concepts for Neck dissection in Head and Neck Cancer Individual

Midline cases – Supraglottic Cancer 11 patients, N0 neck, peritumoral nanocoll-injection, laser resection of the tumor, bilateral SND Werner JA et al. (2005) Acta Otolaryngol 125:

Sentinel node = solution for the clinically N0 neck? Despite unreflected euphoria, this procedure does not solve any of the relevant problems of the clinical N0 neck => Lymphatic mapping is a tool, not a magic

Effectiveness of radiochemotherapy on lymph node metastases in patients with stage IV oropharyngeal cancer Sapundzhiev N.R., Barth P.J., Vacha P., Dünne A.A., Moll R., Engenhart-Cabillic R., Werner J.A. Oral Oncology 40: (2004) 17 Patients, UICC IV Oropharynx, prim. radiochemotherapy ( Gy), 1-4 month later surgical resection of the primary region and neck dissection Local control: 14/17 (82.4%) patients Regional control: 10/17 (58.8%) patients – no residual mets 7/17 Pat. (41.2%) vital residual mets => Need for multi-centre results