Folie 1

1
Management of Lymph Node Metastases
Jochen A. Werner, Marburg, Germany
2

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

3

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

4

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

5
Prognostic markers
  p53 Werner JA et al. (1997) Cancer Immunol.
Immunother. 44 112-116 Gottschlich S et al.
(2000) Oncology 59 31-35 Gottschlich S et al.
(2001) Anticancer Res. 20 2613-2616   Ki-S 11,
Ki-67 Kuropkat C et al. (1999) Virchows Arch.
435 590-595   CYFRA 21-1   Kuropkat C et al.
(2002) Oncology 63 280-285   Matrixmetalloprotein
asen und deren Inhibitoren Werner JA et al.
(2002) Clin. Exp. Metastas. 19 275-282 Kuropkat
C et al. (2002) Anticancer Res. 22
2221-2227 Mandic R et al. (2002) Anticancer Res.
22 3281-3284 Dünne AA et al. (2003) Anticancer
Res. 23 (im Druck) EGF-Rezeptor Mandic R et al.
(2001) Anticancer Res. 21 3413-3418 Aneuploidie
Görögh T et al. (1997) J Cancer Res Clin Oncol.
123 39-44 Cyclin D-1, c-erbB-2 Kuropkat C et
al. (2002) Auris Nasus Larynx 29
165-74 LOX Rost T et al. (2003) Anticancer Res.
23 1565-1575
 
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 ?

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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
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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
94-100 (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.
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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

9
Sentinel Node in Head and Neck Cancer
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Intermediate Results
gt Extirpation of only one SN (SN1) is not
representative!
gt Lymphatic mapping with detection of SN 1-3
confirms concept of SND with removal of the main
metastatic level.
gt 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)?
Werner et al. Br J Cancer 87 711-715
(2002) Werner et al. Head Neck 26 603-611 (2004)
11
V. Paleri et al. Sentinel node biopsy in
squamous cell cancer of the oral cavity and oral
pharynx a diagnostic meta-analysis.Head Neck.
2005 Sep27(9)739-47.
Systematic review and diagnostic meta-analysis of
published literature regarding until December
2003. 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.
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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
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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

14
1906 2006
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Neck dissection
100 years experience !
Standardized indications ?
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ND in N and N0 Neck
N Neck
RND,
MRND,
SND
RT (N1, gtN1?)

N 0 Neck
Wait and see,
SND,
MRND
(RND)
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?
19
?
More than ten years later
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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. 261 295-303 (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.
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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

23
Presence of malignant tumor cells in persistent
neck disease after radiotherapy
Stenson KM et al. (2000) Arch Otolaryngol Head
Neck Surg 126950-956
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).
Simon C. et al. (2005) Eur Arch Otorhinolaryngol
22 Epub ahead of print
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
24
Translational research project
Presence of malignant tumor cells in persistent
neck disease after radiotherapy
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
25

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

26
Future Strategies

• Translymphatic Chemotherapy
• Magnetic drug-targeting

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Future Strategies

• Translymphatic Chemotherapy
• Magnetic drug-targeting

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A phase III placebo-controlled study in advanced
head and neck cancer using intratumoural
cisplatin/epinephrine gel
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.
Br. J. Cancer 87 938-944 (2002)
Intratumoral injection of cisplatin/epinephrine
gel 14/57 patients (25) tumor volume reduction
(16 complete, 9 partial regression), vs. 3
regression under placebo control (p0.007)
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
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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 0.25-0.003 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 10-14 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.
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Future Strategies

• Translymphatic Chemotherapy
• Magnetic drug-targeting

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BMBF BIO-DISC Guided local and regional
pharmacotherapy utilizing an external magnetic
field and shock waves (FKZ 0313674)
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
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5th International Symposium on Advances in Head
and Neck Cancer - Basic and Clinical Research
January 17-20, 2007 Marburg
34

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

35

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

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Session 13 Detection of Lymph Node Metastases
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• Magnet Resonance Imaging
• Computed Tomography
• B-Mode-Sonography FNA
• Positron Emission Tomography

38
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
241627-1634
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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 207123-130
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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
41
No study compares
The most experienced MRI-radiologist
with
The most experienced CT-radiologist
with
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
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Advantage of B-mode sonography
Surgeon himself is able to performe the
examination of the neck as dynamic approach.
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Diagnostic Imaging Future Concept ?
Radioimmunodetection and Immuno-PET
G A van Dongen, Amsterdam
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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.
48
Individual
Concepts for Neck dissection in Head and Neck
Cancer
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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
125403-408
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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
gt Lymphatic mapping is a tool, not a magic
51
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 1007-1016 (2004)
17 Patients, UICC IV Oropharynx, prim.
radiochemotherapy (60-70.6 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
gt Need for multi-centre results