Doctoral Thesis

Squamous Cell Cancer of the Head and Neck – a 10 year

follow up

Prospective factors and treatment options for patients suffering a

squamous cell cancer of the head and neck

submitted by

Martin Christoph Lanzer

Date of birth: 18.04.1984

to obtain the medical degree

Doctor of medical science (Dr. sci. med.)

conducted at the

Department of otorhinolaryngolgoy, division of general

othorhinolaryngology, head and neck surgery

Medical University Graz

under supervision of

OA Dr. Sabine Reinisch and Prof. Dr. Heinz Stammberger

i

Sworn Declaration

I declare by word of honor, that I’ve written and conducted the present doctoral thesis unaided

and autonomously; there were no other quotes and citations used than the marked and fully

reproduced quotes and citations

Eidesstattliche Erklärung

Ich erkläre ehrenwörtlich, dass ich die vorliegende Arbeit selbstständig und ohne fremde Hilfe

verfasst habe, andere als die angegebenen Quellen nicht verwendet habe und die den benutzten

Quellen wörtlich oder inhaltlich entnommenen Stellen als solche kenntlich gemacht habe.

Place, Date Signature

ii

Dedicated to my parents for their lifelong support, that finally brought me to this point.

A very special and cordially thank to Sabine Reinisch, MD as well as Prof. Heinz Stammberger, MD

for their guidance throughout this doctoral thesis.

iii

Zusammenfassung

Trotz leicht rückläufiger Zahlen in der Krebsstatistik, stellen Tumore im Bereich des Kopfes und

des Halses nach wie vor ein wachsendes Problem in der Bevölkerung dar. Die steigende Zahl an

neu auftretenden Tumoren bei zum Teil immer jünger werdenden Patienten und das Aufkommen

von neuen – zum Teil – aggressiven Therapieoptionen führt zu mehreren herausfordernden

Entscheidungen. Bei der Frage, welche Therapie für den Patienten die beste Lösung darstellt

fließen viele Einflussfaktoren gleichzeitig ein. Auch ist zu berücksichtigen dass der Patient

Therapieangebote nicht akzeptiert oder andere Einflussfaktoren wie zum Beispiel der allgemeine

Zustand des Patienten die gewählte Therapie nicht zulässt. Wie kommt man zur richtigen

Therapiewahl? Was sind die Faktoren die den Medizinern die Anhaltspunkte geben, welcher

Tumor aggressiver therapiert werden soll und bei welchem Tumor die adjuvante Therapie dem

Patienten einen entscheidenden Vorteil – oder doch nur eine zusätzlich Belastung - bringen kann.

Der initiale Gedanke, der die Forschung vorantreibt, ist im Endeffekt immer die Optimierung von

bestehenden Systemen und Therapien. Dies war auch in erster Linie unsere Fragestellung: durch

die Aufarbeitung unserer Therapieentscheidungen bei Patienten mit Kopf-, Halstumoren wollten

wir einerseits unsere Ergebnisse darstellen und überprüfen, und uns – insbesondere - mit der

angloamerikanischen Literatur vergleichen, um konsequenterweise Therapieschemata zu

optimieren und Überlebensraten bei gleichzeitiger Senkung der Morbidität des Menschen zu

steigern. Bei allem Enthusiasmus und Engagement, die zur Bekämpfung des Tumorleidens

aufgebracht werden, sollte nicht außer Acht gelassen werden, was der Patient für eine

Lebensqualität unter der Therapie hat: können wir dem Patienten wirklich helfen - und ist es nicht

nur der Stolz der behandelnden Ärzte - alles zu versuchen um schlussendlich die dem Patienten

noch verbliebenen Tage so ertragbar als möglich zu gestalten.

Zusammenfassend konnten wir mehrere entscheidende Faktoren des Überlebens erkennen:

1)Einerseits sind es vor allem die chirurgisch Fertigkeiten, die überlebensnotwendig sind.

Prognosen von Tumoren, die nicht in sano reseziert werden konnten, sind deutlich schlechter.

Dies kann auch durch eine adjuvante Therapie (in erster Linie Strahlentherapie) nicht kompensiert

werden. 2)Weiters zeigte sich, dass das Verhältnis der exzidierten Lymphknoten zu den

metastatisch befallenen Lymphknoten in Zukunft eine entscheidende Rolle spielen kann. Je mehr

Lymphknoten in den abfließenden Lymphbahnen nicht befallen sind, umso eher die

Wahrscheinlichkeit dass diese Lymphknoten – im Sinne von Wächterlymphknoten – die Aussaat

von Tumorzellen verhindern konnten.

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3)Wir konnten demonstrieren, dass bei Tumoren der Mundhöhle sowie des Oropharynx bei

bekannt hoher Wahrscheinlichkeit von kreuzenden, mittellinienübergreifenden

Lymphabflusswegen eine bilaterale Hals-Dissektion nicht zwingend indiziert ist. Mit Ausnahme

von Tumoren größer als 4cm, Infiltration von mehr als 4mm, mittellinienüberschreitende

Tumoren, Lymphgefäßeinbrüche sowie mehrfacher ipsilateraler Lymphknotenbefall stellen

bilaterale Hals-Dissektionen ein „Over Treatment“ dar. 4)Radikale Hals-Dissektionen führen - bei

deutlicher Zunahme der Patientenmorbidität – nicht zu höheren Überlebensraten. Vielmehr zeigt

sich die Kombination von selektiven Dissektionen mit adjuvanter Strahlen(-Chemo)therapie als

effektive und zugleich patientenschonende Therapie zur lokoregionären Tumorfreiheit. 5)Wir

konnten die schon in der Literatur beschriebenen negativen Prognosefaktoren bestätigen:

Hypopharynxtumoren, Größe des Tumors sowie Lymphknotenbefall – insbesondere mehrerer

Lymphknotenlevel. Auch die histologischen Faktoren wie perineurale Invasion,

Lymphgefäßeinbrüche, Blutgefäßeinbruch, Lymphknotenkonglomerate sowie - sehr bedeutend -

Kapseldurchbruch der Lymphknoten konnten wir als prädiktive Faktoren demaskieren.

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Abstract

Head and neck cancer is a serious and still growing problem around the world. The increasing

incidence of newly diagnosed cancer with the decreasing age of the patients diagnosed, in

combination with newly – partly aggressive – therapeutic options, leads to many challenging and

unsolved problems. Especially the decision regarding the treatment plan is of outstanding

importance. Factors of influence, such as ambition or rejection of the patient as far as for example

surgical procedures or radiotherapy are concerned, common physical state of the patient –

thinking of the kidney malfunction or blood count, and possibilities as well as limits of

chemotherapeutical agents must be considered. What is the pathway for the best treatment

plan? What are the factors building the evidence on which more aggressive treatment options

are chosen, and how to weigh, whether adjuvant therapy might be a benefit or just an additional

burden for the patient?

Initially, scientific research in medicine is based either upon the striving for optimization or

progress to develop new treatment options, or to improve existing treatment modalities. By

analyzing our own treatment decisions we have made for the last 10 years in patients with

squamous cell carcinoma of the head and neck, we wanted to evaluate our results and outcomes

of our patients and particularly compare the disease free and overall survival of our patients with

the outcome of patients described in the Anglo-American literature. The aim of this study was to

optimize our treatment modalities, prolong patients survival and - probably most important –

reduce patients morbidity.

In our results, we were able to conclude various determining variables for survival:

1)It is of outstanding importance, that surgical skills are at highest level to assure negative

resection margin whenever possible. Patients not being operated in sano have by far a worse

prognosis – even if adjuvant therapies (radiotherapy, chemotherapy or both) are applied.

2)Relationship between excised positive lymph nodes and total number of excised lymph nodes

during a neck dissection might play a very important role in future decisions whether adjuvant

therapy should be applied or not. The more lymph nodes are not affected with metastatic tumor

cells, the better it is for the prognosis. This might be similar to sentinel lymph nodes in other

tumor entities. 3)In tumors of the oropharyngeal region and the oral cavity, a bilateral neck

dissection is not mandatory in every case, despite the high probability of crossing lymph drainage

to the other side. With the exception of tumors bigger than 4cm, infiltration deeper than 4mm,

tumor crossing the midline and multiple ipsilateral metastatic lymph nodes, a bilateral neck

dissection is not indicated. 4) Radical neck dissection, including excision of the

sternocleidomastoid muscle, the jugular vein and the submandibular gland do not lead to better

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prognosis, despite the high patient morbidity related to this procedure. Instead, combination of

selective neck procedures with adjuvant radiotherapy or radio-chemotherapy are effective and

tolerated treatment options. Although side effects are known, quality of life is not diminished

dramatically.

5) Analog to the literature, we could confirm the negative prognostic factors for overall survival

and disease free survival: localization of the tumor in the hypopharyngeal region, size of the

tumor and lymph node status – especially if more than one lymph node level is affected.

Furthermore the histological factors such as perineural invasion, lymph vessel invasion, blood

vessel invasion, conglomerate lymph node and capsule penetration could be unmasked as

predictive factors for survival.

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1 Introduction ................................................................................................................................... 11

1.1 Definition ............................................................................................................................. 11

1.2 Epidemiology ........................................................................................................................ 11

1.2.1 Global incidence .............................................................................................................. 11

1.2.2 Global mortality ............................................................................................................... 13

1.3 Classification of squamous cell carcinoma .......................................................................... 15

1.3.1 Primary tumor ................................................................................................................. 15

1.3.2 Lymph node ..................................................................................................................... 18

1.3.3 TNM-Staging .................................................................................................................... 19

1.4 Classification of neck lymph nodes ...................................................................................... 21

1.5 Classification of neck dissection .......................................................................................... 22

1.6 Risk factors for squamous cell carcinoma ............................................................................ 24

1.6.1 Alcohol ............................................................................................................................. 24

1.6.2 Tobacco ............................................................................................................................ 25

1.6.3 Human Papilloma Virus (HPV) ......................................................................................... 25

1.6.4 Diet and Nutrition ............................................................................................................ 26

1.6.5 Proteomics and genomics................................................................................................ 26

2 Material and Methods ................................................................................................................... 27

2.1 Methods ............................................................................................................................... 27

2.2 Measured endpoints ............................................................................................................ 27

2.2.1 Recurrence free survival .................................................................................................. 27

2.2.2 Disease free survival ........................................................................................................ 27

2.2.3 Overall survival ................................................................................................................ 28

2.3 Database .............................................................................................................................. 28

2.4 Statistical analyses ............................................................................................................... 33

2.5 Neck Dissection .................................................................................................................... 34

2.6 Treatment plan .................................................................................................................... 34

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2.6.1 Radiotherapy ................................................................................................................... 34

2.6.2 Chemotherapy ................................................................................................................. 35

3 Results ........................................................................................................................................... 38

3.1 Patients ................................................................................................................................ 38

3.2 Distribution of localizations and sub-localizations .............................................................. 38

3.3 Distribution of gender, classification, lymph node status and grading ............................... 40

3.4 Time of follow-up ................................................................................................................. 40

3.5 Overall survival ..................................................................................................................... 42

3.6 Tumor localization ............................................................................................................... 44

3.6.1 Disease free survival depending on tumor localization................................................... 44

3.6.2 Overall survival depending on tumor localization ........................................................... 44

3.6.3 Does the tongue carcinoma represent a special entity within the oral cavity? .............. 45

3.6.4 Tumor localization and further outcome ........................................................................ 46

3.7 Tumor classification ............................................................................................................. 47

3.7.1 Disease free survival considering tumor classification .................................................... 47

3.7.2 Overall survival considering tumor classification ............................................................ 48

3.8 Lymph nodes ........................................................................................................................ 50

3.8.1 Lymph node status .......................................................................................................... 50

3.8.2 Number of positive lymph nodes .................................................................................... 53

3.8.3 Number of positive and overall lymph nodes excised .................................................... 55

3.8.4 Lymph node ratio as a predictive factor for disease free and overall survival ................ 57

3.9 Tumor stage ......................................................................................................................... 60

3.10 Tumor grade ......................................................................................................................... 60

3.11 Histological aspects: ............................................................................................................. 62

3.11.1 Association of histological aspect and localization of recurrence: ............................. 64

3.12 Neck dissection: ................................................................................................................... 65

3.12.1 Correlation between extent of neck dissection and outcome: ................................... 66

3.12.2 Impact of radical neck dissection: ............................................................................... 69

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3.12.3 Does type of neck dissection effect locoregional recurrence free survival? .............. 72

3.12.4 Benefit of elective bilateral neck dissection in patients with a clinical negative

contralateral neck: ........................................................................................................................ 75

3.13 Effect of excision of non-lymphatic structures on disease free and overall survival: ......... 77

3.14 Resection margin: ................................................................................................................ 77

3.14.1 Disease free survival considering resection margin: ................................................... 77

3.14.2 Overall Survival considering Resection Margin: .......................................................... 79

3.14.3 Influence of postoperative therapy in patients with resection margins R0, R1 or R2 on

disease free survival: ..................................................................................................................... 80

3.14.4 Influence of postoperative therapy in patients with resection margin R0, R1, or R2 on

overall survival: .............................................................................................................................. 83

3.15 Adjuvant therapy: ................................................................................................................ 86

3.15.1 Radiotherapy: .............................................................................................................. 86

3.15.2 Chemotherapy: ............................................................................................................ 87

3.16 Impact and importance of adjuvant therapy: ...................................................................... 88

3.16.1 Impact of adjuvant therapy considering tumor classification: ................................... 88

3.16.2 Impact of adjuvant therapy considering Lymph Node Status: .................................... 92

3.17 Adjuvant therapy in early stage tumors (stage I and stage II) ............................................. 96

3.18 Adjuvant therapy in advanced tumors (stage III and stage IV): ........................................... 97

3.19 Multivariate data analysis: ................................................................................................. 100

3.19.1 Recurrence free survival:........................................................................................... 100

3.19.2 Disease free survival: ................................................................................................. 101

3.19.3 Overall survival: ......................................................................................................... 102

3.20 Recurrence: ........................................................................................................................ 103

3.21 Cause of death: .................................................................................................................. 107

4 Discussion: ................................................................................................................................... 109

4.1 Tumor Stage: ...................................................................................................................... 109

4.2 Tumor Grade: ..................................................................................................................... 109

4.3 Histological aspects: ........................................................................................................... 110

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4.4 Tumor Localization: ............................................................................................................ 111

4.4.1 Hypopharynx: ................................................................................................................ 111

4.4.2 Tongue Cancer: .............................................................................................................. 112

4.5 Lymph Node Status: ........................................................................................................... 112

4.6 Lymph Node Ratio: ............................................................................................................. 112

4.7 Resection Margin: .............................................................................................................. 113

4.8 Neck Dissection: ................................................................................................................. 114

4.8.1 Preserving non lymphatic tissue: ................................................................................... 114

4.8.2 Preserving lymphatic tissue: .......................................................................................... 114

4.8.3 Clinical Node Negative Neck – is there a need of elective contralateral Neck Dissection?

....................................................................................................................................... 116

4.9 Adjuvant therapy in advanced disease: ............................................................................. 117

References ........................................................................................................................................... 120

Tables .................................................................................................................................................. 130

Figures ................................................................................................................................................. 133

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1 Introduction:

1.1 Definition(1): Head and neck squamousa cell carcinomab arises from the oral, pharyngeal, or laryngeal mucosa and

resembles the squamous cells that comprise most of the upper layers. Squamous cells are found in

the tissue that forms the surface of the skin, the lining of hollow organs of the body, and the

passages of the respiratory and digestive tracts.

According to the 9th volume of the World Health Organization Classification of Tumors(2), squamous

cell carcinoma can histologically be divided into six (for hypopharynx, larynx and trachea) and seven

(for oropharynx and oral cavity) subgroups: verrucous carcinoma, basaloid squamous cell carcinoma,

papillary squamous cell carcinoma, spindle cell carcinoma, acantholitic squamous cell carcinoma,

adenosquamous carcinoma, and for oral cavity and oropharyngeal cancer also carcinoma

cuniculatum.

1.2 Epidemiology: Head and neck cancer is a serious and still growing problem around the world. Oral and pharyngeal

cancer, grouped together, is the sixth most common cancer worldwide(3). More than 90 % of cancer

in this tumor sites are squamous cell carcinomas.

1.2.1 Global incidence(4):

According to the International Agency for Research on Cancer, there is a wide geographical variation

in the incidence of this cancer. Countries with high incidence rates are found in parts of both eastern

and western Europe (e.g. Spain, France, Luxembourg, Hungary, Slovakia, and Romania), parts of

south America (e.g. Brazil and Uruguay) as well as the Caribbean region, parts of South and Southeast

Asia, especially India, Chinese Taipei, Bhutan, Taiwan, Sri Lanka, and in the Pacific region (e.g. Papua

New Guinea).

a Squamous (from Latin squamosus, from squama a scale): consisting of one or more layers of flat platelike cells

b Carcinoma, pl. carcinomas or carcinomata: an invasive malignant tumor derived from epithelial tissue that

tends to metastasize to other areas of the body

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Figure 1) Worldwide incidence for lip, oral cavity, pharyngeal and laryngeal cancer according to GLOBOCAN (2008)

In 2008, age-standardized incidence ratio for Europe was led by Hungary 27,1 deaths per 100,000,

followed by Luxembourg and Slovakia with 15,8 and 15,4 deaths per 100,000, respectively.

Table 1) Ranking of age-standardized incidence rate of lip, oral cavity, oropharyngeal and laryngeal cancer in Europe according to GLOBOCAN (2008)

HEAD AND NECK CANCER: BOTH SEXES – INCIDENCE, ALL AGES

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1.2.2 Global mortality(4):

Similar to world-wide incidence of head and neck cancer, the same countries have to be named in

highest mortality rates: Papua New Guinea, Bhutan, Hungary, Bangladesh, Sri Lanka, Chinese Taipei,

and India with age-standardized mortality rates of 16.58, 15.32, 14.53, 13.51, 12.77, 11.52 and 11.39,

respectively.

Table 2) Ranking of age-standardized mortality rate for lip, oral cavity, pharyngeal and laryngeal cancer worldwide according to GLOBOCAN (2008)

Figure 2) Worldwide incidence for lip, oral cavity, pharyngeal and laryngeal cancer according to GLOBOCAN (2008)

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Countries with the highest age-standardized mortality rate (ASR) in Europe are Hungary, Slovakia,

Romania and Republic of Moldova, with ASR 14,5, 10,1, 9,3 and 8,9, respectively per 100,000 people.

Luxembourg, suffering a high ASR in incidence (15,8 per 100,000) is not in the front line in age-

standardized mortality rate with only 4,0 per 100,000 people.

Austria has an age-standardized incidence rate of 8,9 per 100,000 and an age-standardized mortality

rate of 4,1 per 100,000.

Table 3) Ranking of age-standardized mortality rate of lip, oral cavity, oropharyngeal and laryngeal cancer in Europe according to GLOBOCAN (2008)

According to the World Health Organization (WHO), the number of patients dying because of lip, oral

cavity or pharyngeal tumor is rising in Austria and Germany, while it is declining in countries like

Australia, Canada, United Kingdom and United States of America.

In Austria, crude rate of death because of a tumor in this region is 8,69 per 100,000 for male and 2,85

per 100,000 for female(5). In 2008, 483 males and 150 females died because of lip, oral cavity,

pharyngeal or laryngeal tumor.

Of outstanding importance is the fact that German speaking countries (Austria, Germany, and

Switzerland) with an age standardized incidence rate of 8,5 – 10,4 per 100,000 people have a lower

incidence rate than the United States of America. Nevertheless, in age standardized mortality rate,

German speaking countries with 3,2 - 4,1 per 100,000 people had a significant higher mortality rate

compared to America with only 2,2 per 100,000 people.

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Figure 3) Mortality crude rate from lip, oral cavity and pharynx in Australia, Austria, Canada, Germany, United Kingdom and United States of America(5)

1.3 Classification of squamous cell carcinoma:

1.3.1 Primary tumor:

Formerly, the classification of tumors into T stages has always been more arbitrary than defined.

There has always been a close inverse relationship between classifications of tumors into T stages

and overall survival; the bigger the tumor, the higher the T stage and the worse the prognosis.

In the sixth edition of the TNM-Staging System of the International Union against Cancer (UICC) and

the American Joint committee on Cancer (AJCC) a uniform descriptor for size for the above head and

neck sites was introduced. Furthermore category T4 was further subcategorized into T4a and T4b;

subcategory a, for tumors being resectable, subcategory b for tumors infiltrating or involving vital

structures and thus not being suitable for surgical resection.

The latest edition of the TNM-Staging System subdivides the localization into 3 groups: oral cavity

and lip, pharyngeal region and larynx.

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1.3.1.1 Primary tumor of the oral cavity and lip(6):

In classification of primary tumor, it is customary to use the variables “X” if primary tumor is

unknown, “0” if there is no evidence of primary tumor, and “is” in case of a carcinoma in situ. This

classification is used in any site of head and neck carcinoma.

In oral cavity and lip carcinomas, T1 is a tumor smaller than 2cm in diameter. Between 2cm and 4cm

in greatest dimension it is considered T2, and if tumor mass is bigger than 4cm, it is classified as T3. If

tumor invades structures like cortical bone, muscles or nerves but is still resectable, it is considered

T4a, if primary tumor is not resectable, patient is classified with a T4b tumor.

Table 4) Staging system of the oral cavity and lip cancers, according to the sixth-edition of the TNM-Staging System of the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)

1.3.1.2 Primary tumor of the pharyngeal region:

Compared to oral cavity and lip cancer, classification of pharyngeal regions is similar, except

nasopharyngeal cancer. In nasopharyngeal cancer, tumors confined to the nasopharynx are classified

as T1. If extend of primary tumor includes soft tissue, it is upstaged to T2 - T2a if parapharyngeal

structures are not involved, T2b if parapharyngeal structures are involved.

In case of bone structure involvement and/or paranasal sinus involvement staging of primary tumor

is T3. A T4 stage is a tumor with intracranial extension, involvement to the infratemporal fossa or

hypopharynx, as well as masticator space, orbit or involvement of cranial nerves. In nasopharyngeal

cancer there is no subdivision of T4.

In oropharyngeal and hypopharyngeal cancer, tumor classification until T3 is comparable with cancer

of oral cavity as described above. In oropharynx, T4a equals invasion of larynx, hard palate or

mandible as well as invasion of muscle of tongue or medial pterygoid. In T4b, lateral pterygoid

muscle or pterygoid plate are involved. Further involvement of lateral nasopharynx, skull base or

tumor encasing carotid artery puts patient into a T4b classification.

T4a in hypopharyngeal cancer is classified in case of invasion of thyroid/cricoid cartilage, hyoid bone,

thyroid gland, esophagus or central compartment of soft tissue. If tumor invades prevertebral fascia,

encases carotid artery, or involves mediastinal structures it is classified as T4b.

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According to the sixth-edition of TNM staging system of the UICC and AJCC T4b tumors are tumors

that are not resectable.

Table 5) Staging system of pharyngeal cancers, according to the sixth-edition of the TNM-Staging System of the UICC and AJCC, *parapharyngeal extension denotes posterolateral infiltration beyond the pharyngobasilar fascia

1.3.1.3 Primary tumor of the larynx:

For classification of the larynx, the region is subdivided into supraglottis, glottis, and subglottis. For

all laryngeal regions T1 conforms a tumor limited to one subsite, with normal vocal cord mobility. To

simplify T2 and T3 for the different sub-regions, T2 tumors show impaired vocal cord mobility,

whereas T3 tumors are tumors with vocal cord fixation (detailed classification see table below). T4a

equals invasion of cricoid or thyroid cartilage and/or invasion of tissues beyond the larynx and T4b

equals invasion of prevertebral space, encased carotid artery, or invasion of mediastinal structures.

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Table 6) Staging system of laryngeal cancers, according to the sixth-edition of the TNM-Staging System of the UICC and AJCC

1.3.2 Lymph node:

The sixth-edition of TNM-Staging System of the UICC and the AJCC defines the classification of lymph

node staging similarly to that of the T-stage. The N stage is also subdivided into two subgroups: all

head and neck sites except nasopharynx and the nasopharyngeal cancer.

1.3.2.1 Lymph node staging for all head and neck sites except nasopharynx:

Points of interest in lymph node classification are size (i.e. 3cm and 6cm) and bilateral lymph node

metastasis. If there is no pathological lymph node, patients are classified as N0. If only one lymph

node is positive, classification is either N1 for lymph nodes smaller than 3cm in diameter, N2 if lymph

node is between 3 – 6cm, and N3 if lymph node is bigger than 6cm.

Within N2 classification, there are three subgroups: N2a, N2b and N2c. If only one lymph node (3-

6cm in diameter) is positive, it is considered N2a, if there are more ipsilateral positive lymph nodes of

any size smaller than 6cm, it is considered N2b. Contralateral or bilateral lymph node metastasis is

considered to be N2c.

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Table 7) Staging system for lymph nodes of all head and neck sites except nasopharynx, according to the sixth-edition of the TNM-Staging System of the UICC and AJCC

1.3.2.2 Lymph node staging for nasopharyngeal tumors:

Different to lymph node status of other regions, margin between N1 and N3 for nasopharyngeal

tumors is 6cm in diameter. Extension to the supraclavicular fossa automatically puts the patient into

a N3 status. Bilateral lymph node metastasis is considered a N2 status.

Table 8) Staging system for lymph nodes of nasopharyngeal tumor, according to the sixth-edition of the TNM-Staging System of the UICC and AJCC, *midline nodes are considered to be ipsilateral nodes

1.3.3 TNM-Staging(7)

With three variables (TNM) offering a high possibility of different variation, a stage grouping was

necessary. Stage grouping, currently proposed by the American Head and Neck Society is as follows:

20

Table 9) Tumor staging of squamous cell carcinomas in oral cavity, oropharynx, hypopharynx and larynx

Table 10) Tumor staging of nasopharyngeal tumors

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1.4 Classification of neck lymph nodes: Classification of neck regions was made according to the American Head and Neck society(8,9):

Level I includes the submental and submandibular nodes. It is divided into Level IA - the submental

nodes - between the medial margins of the anterior bellies of the digastric muscles, and Level IB –

the submandibular nodes – which are lateral to level IA and anterior to the vertical plane, defined by

the posterior edge of the submandibular gland. Previously, the stylohyoid muscle was defined as the

posterior border of level IB. The dissection plane typically used to separate Level IB and Level IIA is

along the fascia overlying the posterior aspect of the submandibular gland.

Level II holds the upper internal jugular nodes. Level II is from the posterior aspect of the

submandibulary gland to the posterior border of the sternocleidomastoid muscle and above the level

of the bottom of the body of the hyoid bone. The middle jugular nodes are in level III, between the

two anatomical landmarks - the body of the hyoid bone superiorly and the bottom of the cricoid arch

inferiorly. Lower to level III is level IV – the lower jugular nodes – between the level of the bottom of

the cricoid arch and the level of the clavicle. The boundaries of Level III and Level IV anteriorly was

previously the lateral aspect of the sternohyoid muscle, and changed now to the medial border of

the common carotid artery, so that positive lymph nodes can be allocated by radiologist, since

sternohyoid muscle is not a landmark easily to discern. Nevertheless, intraoperative, surgeons can

choose the lateral aspect of the sternohyoid muscle as the anterior border.

Table 11) Borders of neck lymph node regions(10)

Posteriorly, the posterior edge of the sternocleidomastoid muscle is the borderline of Level II-IV to

Level V, the so called posterior triangle nodes. Level V is divided into Level VA and Level VB by the

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bottom level of the cricoid arch. Lymph nodes above this level are considered Level VA, lymph nodes

below are considered Level VB. Level V is limited posteriorly by the medial aspect of the trapezius

muscle.

The upper visceral nodes – Level VI – lies between the carotid arteries, from the level of the bottom

of the body of the hyoid bone to the level of the top of the manubrium.

Level VII is below the level of the top of the manubrium but above the innominate vein – the superior

mediastinal nodes. Lateral margins of Level VII are the carotid arteries.

Retropharyngeal nodes are medial to the carotid arteries and behind the pharyngeal tube, from the

skull base to the level of the hyoid bone, and supraclavicular nodes are at or caudal to the level of the

clavicle and lateral to the carotid arteries.

Figure 4) Anatomical subsites of the head and neck region(11)

1.5 Classification of neck dissection: In 1991 the American Academy of Otolaryngology-Head and Neck Surgery in conjunction with the

Education committee of the American Society for Head and Neck Surgery, developed a classification

system of neck dissection. The concept based on the radical neck dissection as the fundamental

procedure with which every other neck dissection has to be compared. In the modified radical neck

dissection, at least one or more non-lymphatic structures have to be spared. In the selective neck

dissection, at least one or more lymphatic levels are spared:

They concluded the radical neck dissection and the modified radical neck dissection together, as

comprehensive neck dissection, since no lymphatic tissue is spared. Both include the complete

23

removal of all the lymph node levels I-V. In the radical neck dissection additional resection of the

spinal accessory nerve, the internal jugular vein and the sternocleidomastoid muscle is conducted.

The Academy divides the modified radical neck dissection into 3 groups: Type 1 is a radical neck

dissection, only the spinal accessory nerve is preserved; in Type 2 next to the spinal accessory nerve,

also the internal jugular vein is preserved. Type 3 is a radical neck dissection with preservation of all

non-lymphatic structures (spinal accessory nerve, internal jugular vein and sternocleidomastoid

muscle).

As explained, the selective neck dissection equates any type of lymphadenectomy that spares at least

one or more lymphatic levels. The Academy sub-classifies the selective neck dissection into 4 groups:

supraomohyoid neck dissection, posterolateral neck dissection, lateral neck dissection and anterior

neck dissection.

Supraomohyoid neck dissection refers to the removal of lymph neck node levels I-III. Inferior

boundary of this procedure is the omohyoid muscle. In the posterolateral neck dissection, lymph

neck node levels II-V and the suboccipital and retroauricular nodes are removed. In the lateral neck

dissection the lymph nodes along the jugular vein are removed – levels II-IV. The anterior neck

dissection refers to the removal of the anterior compartment of the neck in lymph node level VI.

Even more aggressive than the radical neck dissection is the extended neck dissection: this operation

includes not only the radical neck dissection with the removal of lymph neck node levels I-V with all

the non-lymphatic structures spinal accessory nerve, internal jugular vein and sternocleidomastoid

muscle but in addition removal of other lymph node groups and/or non-lymphatic structures for

example such as the carotid artery, the hypoglossal or vagal nerve or the anterior lymph neck nodes.

In 2000 Ferlito et al confounded neck dissections and came up with a modified terminology of

classification similar to the terminology offered by the American Association of Head and Neck

Surgery. In addition to the former terminology, he added suprahyoid neck dissection as dissection of

levels I and II, extended supraomohyoid neck dissection as the removal of levels I-IV, and the

anterolateral neck dissection in which neck lymph node levels II-IV and VI are removed:

24

Table 12) Classification and terminology of neck dissection(12)

In 2008, the Acadamy made once again changes in the terminology(9). Their latest recommendation

is to specifically address every level excised in a selective neck dissection as the level excised plus the

non-lymphatic tissue removed, for example: selective neck dissection (II,III,IV,IJV,SCM) as the

removal of levels II to IV with the additional removal of the internal jugular vein and the

sternocleidomastoid muscle.

1.6 Risk factors for squamous cell carcinoma: Risk factors for development of squamous cell carcinoma are multiple - especially alcohol and

tobacco, as well as betel quid, fruits, certain diets, and lately, HPV are considered as etiologic factors.

1.6.1 Alcohol:

It is well accepted throughout the literature that alcohol, aside from smoking, is an independent risk

factor for head and neck cancers(3). Hashibe et al(13) demonstrated that the odds ratio to develop a

squamous cell carcinoma in the head and neck region was 2,04 if someone drank more than three

drinks per day versus no alcohol consumption. It seems that it is not the type of alcohol used, but

more important the total amount of alcohol consumption throughout the lifetime(14).

25

1.6.2 Tobacco:

All forms of tobacco are carcinogenic, and recently, evidence for smokeless tobacco causing oral and

pharyngeal cancer has been evaluated and confirmed(15). Gandini et al(16) conducted a systematic

meta-analysis of observational studies on cigarette smoking and cancer from 1961 until 2003. The

relative risk (RR) in this meta-analysis was 6,98 (95% CI: 3,14-5,52) for current smokers. RR for

smokers to develop a larynx or oral cavity cancer was 3,43 (95% CI 2,37 – 4,94) times higher.

Cigarette smokers who were never drinkers had an increased risk of pharyngeal and laryngeal cancer

(13)

1.6.3 Human Papilloma Virus (HPV):

HPV are a very heterogeneous group of viruses. Less than 100 variants of any HPV type have been

detected by DNA sequence analysis, with each type defined as having more than 10% dissimilarity in

the combined nucleotide sequences of E6 and E7 genes(17,18). Most (>90%) HPV-associated head

and neck squamous cell cancers are caused by one virus type, HPV 16, the same type that leads to

HPV-associated anogenital cancers(19).

1.6.3.1 Epidemiology of HPV:

In a Danish study by Lajer et al(20) investigating and reviewing on the role of human papilloma virus

in head and neck cancer, he demonstrated that the incidence and prevalence of HPV associated

cancer is difficult to evaluate. Range of patients with a positive HPV status was from 0% up to 93%

(33 studies included). In the USA, about 40-80% of oropharyngeal cancers are caused by HPV,

whereas in Europe the proportion varies from around 90% in Sweden to less than 20% in

communities with the highest rates of tobacco use(19). However, while tobacco abusus as an

etiologic factor for head and neck cancer is declining, the role of HPV in oral and oropharyngeal

cancer is increasing, especially in younger ages(19,21).

1.6.3.2 Biology of HPV:

HPV-associated head and neck cancer arises most commonly in the oropharyngeal region, especially

in the lingual and palatinal tonsils(22). Target points of virus DNA are the oncoproteins E6 and E7

leading to a dysregulated expression. Protein E6 induces degradation of p53 through ubiquitin-

mediated proteolysis, leading to substantial loss of p53 activity. E7 protein binds and inactivates the

retinoblastoma tumor suppressor gene product pRB, leading to cell-cycle disruption, proliferation,

and malignant transformation(23,24).

1.6.3.3 Unsolved importance of HPV:

Despite the recognized importance of HPV in oropharyngeal cancer, the epidemiology of oral HPV

infection is not well understood. Shanti Marur et al(19) disclosed the unknown aspects of oral HPV

infection:

Does HPV infection cause cancer at other head and neck subsites than the oropharyngeal

region?

26

How common is prevalent and persistent oral HPV infection in general population

What is the natural history of oral HPV cancer? Which factors affect oral HPV persistence and

progression, and what is the median time from oral HPV infection to cancer?

Why are men more likely to be affected by oral HPV infection, and why is the incidence in

oral HPV infection increasing in men, while this is not seen in women?

Is there an association of P16 immunohistochemistry and HPV 16 status?

Why do we see a better overall survival in HPV-positive cancer; should there be a different

treatment for those being HPV-negative?

Do precancerous oropharyngeal lesions exist, and would testing for persistent oral HPV

infection be a useful screening method?

What impact do HPV vaccines have on oral HPV infection?

1.6.4 Diet and Nutrition:

Diet and nutrition are also risk factors for head and neck squamous cell carcinoma. Although the

individually micronutrients that might be responsible for the development of malignant cells have

not been formally identified, vegetables and fruits that protect against oral cancer and precancer are

rich in ß-carotene, vitamin C, and vitamin E, with antioxidant properties(25). Furthermore,

epidemiologic studies from northern China, parts of Africa and Iran could demonstrate the

association of nutritional zinc deficiency, associated with restricted diet and exposure to carcinogenic

N-nitrosamines and the etiology of esophageal cancer(26).

1.6.5 Proteomics and genomics:

Aside known etiologic factors, such as alcohol, tobacco et cetera, investigation on circumstances,

leading more easily to the development of head and neck cancer are debated throughout the

literature. Especially proteomics and genomics will play a more important role in the future,

especially for diagnostic reasons(27).

27

2 Material and Methods:

2.1 Methods: We analyzed in a retrospective study all neck dissections of patients being operated during the years

1999 until 2009.

Selection Criteria: Histologically confirmed squamous cell carcinoma of the oral cavity, nasopharynx,

oropharynx, hypopharynx and larynx. All patients were operated during the years 1999 until 2009. All

patients were treated with surgical resection of the primary tumor and neck dissection of the neck

lymphatics. Furthermore, patients were consequently observed or treated with radiotherapy,

chemotherapy, or combined radiochemotherapy.

Exclusion Criteria: Other histological diagnosis than squamous cell carcinoma. Localization of a

squamous cell carcinoma other than oral cavity, nasopharynx, oropharynx, hypopharynx or larynx.

Patients undergoing therapy after metastasis from a former squamous cell carcinoma. Patients

having metastasis before undergoing neck dissection. Patients not being operated at the

otorhinolaryngological department of the Medical University Hospital Graz. Patients receiving

palliative treatment initially.

A total of 293 patients, with a histological proven squamous cell carcinoma of the oral cavity,

oropharnyx, nasopharynx, hypopharnyx or larynx were included into the study for further statistical

evaluation.

Patient data were obtained by searching patient records, pathological findings, operation protocols

as well as data extraction out of the datasystem medocs, which was installed in our facility in 2001.

Furthermore CT scans were looked at, as well as patients that were lost to follow up were contacted,

or if contact failed, tumor register and death register were looked at to check whether patient was

still alive.

2.2 Measured endpoints:

2.2.1 Recurrence free survival:

Recurrence free survival was the period of time between date of operation of the primary tumor and

date of occurrence of first recurrence at any location (local recurrence, locoregional neck recurrence,

distant metastis). If the patient died prior to the end of the study, or prior to getting a recurrence

he/she was censored from further follow-up. If the patient died due to on behalf of tumor relapse,

presenting himself at final stage, he therefore was considered as patient with recurrence and later on

as patient dying of disease.

2.2.2 Disease free survival:

Disease free survival was the period of time between date of operation of the primary tumor and

date of occurrence of first recurrence at any location (local recurrence, locoregional neck recurrence,

28

distant metastis), occurrence of second primary, or death. If patient was lost to follow up prior to

death or end of study he therefore was excluded at last time of appearance at our hospital.

2.2.3 Overall survival:

Overall survival was the period of time between date of operation of the primary tumor and date of

death for any reason. If patient was lost to follow up prior to death or end of study he therefore was

excluded at last time of appearance at our hospital.

2.3 Database: For collection of patient data, a database using MS Access as platform was created.

First layer consisted of basic patient information: name, age, gender, and further notes if

necessary:

Figure 5) First layer of database with basic information

29

Second layer was intended for preoperative information of the cancer: localization,

classification, lymph node status, distant metastasis, grading, and histological additional

information, such as perineural invasion. Furthermore, information on preoperative therapy

was filled out on this layer:

Figure 6) Second layer of database with tumor specific information

30

Third layer held information of the surgical treatment of the primary tumor: time of

operation, type of operation, resection margin, and whether neck dissection was conducted

within 30 days of primary surgery:

Figure 7) Third layer of database with information on tumor excision

31

Fourth layer contained all information on the conducted neck dissection: time and type of

neck dissection, side of neck dissection, number of excised lymph nodes, number of positive

lymph nodes, surgeon who made the neck dissection. Furthermore precise information on

lymph node levels excised, as well as information on non-lymphatic tissue such as accessoric

nerve, jugular vein, submandibular gland, sternocleidomastoidal, and omohyoidal muscle.

Figure 8) Fourth layer of database, holding information on neck dissection

32

Fifth layer held information of postoperative chemotherapy and radiotherapy, type of

chemotherapy used, information on recurrence (time of recurrence as well as localization of

recurrence), information on death (time and cause of death), as well as information on the

last patient data entry for follow-up time.

Figure 9) Fifth layer of database holding information of adjuvant therapy, recurrence and death

33

The sixth layer contained information on possible second primary tumors: was there a pre- or

postoperative second malignancy.

Figure 10) Sixth layer of database holding additional information

2.4 Statistical analyses: For statistical analyses SPSS 17 software was used. Initially, patient data was analyzed descriptively,

looking for frequency of occurrences and distribution of occurrences. Based on this distribution,

diverse groups were formed and analyzed for comparability using the chi-square test. Adjacent

groups were compared for outcome.

Points of interest were overall survival (OS), disease free survival (DFS) and recurrence free survival

(RFS). Factors influencing those points of interest were compared using log-rank test and Kaplan-

Meier survival curve, as well as chi-square test to evaluate difference between two groups.

34

2.5 Neck Dissection: Nomenclature of neck dissections used for our patients(9):

Radical neck dissection: Regio I-V, no preservation of non-lymphatic tissue (jugular vein,

m.sternocleidomastoideus, accessoric nerve)

Modified radical neck dissection: Regio I-V, preservation of at least one non-lymphatic tissue

Posterolateral neck dissection: Regio II-V, regardless of non-lymphatic tissue

Lateral selective neck dissection: Regio II-IV, regardless of non-lymphatic tissue

Supraomohyoidal neck dissection: Regio I-III, regardless of non-lymphatic tissue

Suprahyoidal neck dissection: Regio I-II, regardless of non-lymphatic tissue

2.6 Treatment plan: Patients were diagnosed by clinical examination, ultrasound, CT or MRI scan, and histological

evaluation (HE-Stain). In specific situations (i.e. carcinoma of unknown primary, uncertain metastatic

disease) Positron Emission Tomography was conducted for aggregation of further information.

Treatment plan was drawn by an interdisciplinary team including oncologists, radiooncologists,

pathologists and otorhinolaryngologists. Radiotherapy applied was 60Gy for R0 and 66Gy – 70Gy for

R1 and R2, daily dose depending on the patients physical condition between 1,8Gy and 2,0Gy.

Concomitant adjuvant chemotherapy used was either cisplatin or carboplatin/5FU. One patient

received concomitant adjuvant immunotherapy with Erbitux.

2.6.1 Radiotherapy:

Radiotherapy plays a very important role in the treatment of head and neck malignancies. In head

and neck tumors, radiooncologists are confronted with the tumor on the one side, but with a lot of

normal tissue that is of vital importance in near proximity: spinal cord, auditory and optic apparatus,

salivary glands, mandible and vocal cords. Therefore exact targeting of the tumor mass, while at the

same time sparing normal tissue, is a main factor for treatment outcome and quality of life.

For this reason, conventional radiotherapy, although offering a homogenous dose distribution by

lateral beams to encompass the known primary and the lymphatic structures, becomes more and

more inadequate since normal structures in the proximity receive high dose of radiation(28). In head

and neck cancer, especially salivary gland function is at risk during radiotherapy, causing chronic

xerostomia with associated adverse impact on taste, swallowing, dentition, speech and therefore

quality of life; hence, this is one of the most common rationales for intensity modulated radiation

therapy (IMRT). Furthermore, the capacity of IMRT to limit dose to normal tissue structures may also

allow dose escalation and differential dose painting, thereby accomplishing “in field tumor

boosting”(29).

35

2.6.1.1 What is IMRT?

In intensity-modulated radiation therapy, a specific technique of linear accelerator-based radiation

therapy is used, whereby beams are modulated in such a manner to produce highly conformal dose

distributions:

IMRT delivery techniques with linear accelerator can be divided into two classes: techniques with

fixed gantry, “step and shoot” and “sliding window”, and rotational techniques, called “intensity

modulated arc therapy” and “volumetric modulated arc therapy”. In contrast, in conventional head

and neck radiotherapy, static fields are shaped by blocks and modulated by simple beam wedges or

tissue compensators(30). In IMRT variable dose intensities can be delivered through the segment of

each treatment field, thereby maximizing conformality of the ultimate dose distribution(28).

2.6.1.2 Advantage of IMRT:

Advantages of IMRT are most obvious if critical structures are invaginated or completely surrounded

by the tumor mass, building a concavity in its surface. In this type of geometric situation, IMRT can be

used to shape the isodose lines around the critical structures – which was not possible with normal

three dimensional techniques. A target that has regions on its surface that are concave should be a

common condition for the usage of IMRT(31). Staffurth et al reviewed that inverse-planned IMRT

maintains parotid saliva production and reduces acute and late xerostomia during radiotherapy for

locally advanced head and neck cancers(32).

Inverse planning is another advantage of IMRT over traditional 3D conformal radiotherapy. Instead of

the planner, trying a variety of configurations of beams, wedges and beamweights until a suitable

match is found to the dose prescription (forward planning) the reverse is attempted and dose-

volume constraints and/or dose limits are specified. For both, planned target volumes and avoidance

structures dose limitations can be set, for example: “not more than x% of the y structure may receive

dose zGy or more”. Adjacent, the specification drives the optimization and the computer code will do

the best to satisfy the constraint(33).

Nevertheless, improvements of the dose distribution with IMRT are often accomplished at the

expense of dose homogeneity within the target, and high-dose regions sometimes spill over to

surrounding critical structures(31).

2.6.2 Chemotherapy:

Chemotherapeutics used in our patients were cisplatin, carboplatin in combination with 5-

fluorouracil and the epidermal growth factor inhibitor cetuximab. Since cetuximab was not

commonly used at our facility by the end of the study in 2009, only one patient received cetuximab.

Knowing the high potency of platinum-based chemotherapeutics in head and neck cancer compared

to other chemotherapeutic agents(34), either cisplatin or carboplatin represented the treatment of

choice at our department. Introducing carboplatin in clinical daily routine in 1992 as a platinum-

based analogue with a distinctly different toxicity profile favorable to toxicity profile of cisplatin,

carboplatin has become a commonly preferred agent over cisplatin in different solid tumors. In head

and neck cancer, however, cisplatin appears to be superior to carboplatin as far as therapeutic

36

effectiveness is concerned(35). Therefore, if patient’s health condition admitted the usage of

cisplatin, it was our treatment of choice. Likewise, Go et al(36) reviewed the effectiveness of

Cisplatin/5FU versus Carboplatin/5FU, once again demonstrating the high effectiveness of Cisplatin

along with the strong neurotoxic and especially nephrotoxic effects. Chemotherapeutic dose applied

in the literature are most often 3 circles of 100mg/m2 cisplatin or 3 circles of 400mg/m2

carboplatin(37) together with 5FU. For cisplatin as monochemotherapy, either low-dose weekly at 30

to 40 mg/m2 or every 3 weeks at doses of 75 to 100mg/m2 are described in the literature(38).

In our department, cisplatin was used as concurrent radiochemotherapy after resection of the

primary tumor. Dose of cisplatin applied was 100mg/m2 on the 1st, 22nd and 43rd day of radiotherapy.

This traditional cyclical approach of delivery of concurrent cisplatin has not been compared directly

with schedules that utilize smaller doses more frequently. Although studies exist on the effect of

“non-standard” schedules, comparisons between those two treatment options are missing(39).

Therefore we applied 3 circles of 100mg/m2 cisplatin.

2.6.2.1 Cisplatin(40):

Cisplatin is the first introduced platinum-based chemotherapeutic drug. Like all platinum-based

drugs, it interacts in vivo with the DNA, causing crosslinking within the DNA-strand and hence

triggers apoptosis.

Most common side effects(41) are: nephrotoxicity, neurotoxicity, nausea and vomiting, ototoxicity,

and electrolyte disturbance.

2.6.2.2 Carboplatin(42):

Carboplatin is also a platinum-based chemotherapeutic. Introduced in the 1980’s it has gained

popularity in clinical treatment since side-effects, compared to cisplatin, are reduced.

Especially the elimination of nephrotoxic side effects, and more easily controlled nausea and

vomiting is a main advantage over cisplatin. Disadvantages are the myelosuppressive effect(43) on

the one side, and the, less potency compared to cisplatin. Therefore, carboplatin is used together

with 5-Fluorouracil.

2.6.2.3 5-Fluorouracil(44):

5-Fluorouracil (5FU) is a pyrimidine analogue, which operates by a noncompetitive inhibition of

thymidylate synthase.

Main side effects include myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity.

Furthermore it also causes both acute central nervous system (CNS) damages and progressively

worsening delayed degeneration of the CNS.

37

2.6.2.4 Cetuximab(45):

Cetuximab (marketed under the name Erbitux®), is a chimeric (mouse/human) monoclonal antibody,

an epidermal growth factor inhibitor.

Cetuximab is indicated for the treatment of patients with squamous cell carcinoma of the head and

neck in combination with platinum-based chemotherapy for first line treatment of recurrent and/or

metastatic disease and in combination with radiation therapy for locally advanced disease.

Known side effects are severe infusion reactions that can even lead to anaphylactic shock and cardiac

arrest. Other common side effects include especially acne-like rash, photosensitivity,

hypomagnesemia due to magnesium wasting, and less commonly, pulmonary and cardiac toxicity.

38

3 Results:

3.1 Patients: In the years 1999 until 2009 a total of 502 neck dissections on 475 patients were conducted:

475 patients underwent any form of neck dissection at the department of otorhinolaryngology of the

Medical University of Graz. 360 patients had a histological proven squamous cell carcinoma. Most

other findings than squamous cell carcinoma was adenocarcinoma, lymphadenitis and sarcoma. 15

patients were diagnosed with malignant melanoma and 20 patients had a carcinoma of the parotid

gland.

Out of the remaining 360 patients, 17 patients had a primary in a different location than the oral

cavity, oropharynx, nasopharynx, laryngopharynx or larynx. 18 patients suffered a distant metastasis

before undergoing neck dissection.

Furthermore, 32 patients were excluded because diagnosis of cancer was either before 1999,

treatment plan was palliative initially, patient underwent neck dissection twice or patient was not

operated at the department of otorhinolaryngology department of the Medical University of Graz.

A total of 293 patients met all inclusion/exclusion criteria.

Figure 11) Distribution of patients who were neck dissected and included into the study during the years 1999-2009

3.2 Distribution of localizations and sub-localizations: Most patients had a squamous cell carcinoma of the oropharynx (94 patients) followed by oral cavity

(74), laryngopharynx (49) and larynx (44). There were 26 patients with an carcinoma of unknown

primary (CUP) and 6 patients had a nasopharyngeal squamous cell carcinoma. In oral cavity cancer,

39

most primaries were in the tongue and floor of the mouth, 40 and 26 respectively. If primary was in

the oropharyngeal region, most patients suffered a tumor of the tonsils (67 patients).

Figure 12) Distribution of sublocalizations: floor of the mouth 26, tongue 40, cheek mucosa 2, lip 6, soft palate 6, root of tongue 19, lateral pharyngeal wall 2, tonsils 67, nasopharynx 6, sinus piriformis 38, postcricoidal region 1, epiglottis 7, lateral laryngopharyngeal wall 1, supraglottic 15, glottis 27, transglottic 2, unknown primary 26

40

3.3 Distribution of gender, classification, lymph node status and grading: Mean age of patients at diagnosis was 64 years. Distribution of gender was 243 male versus 50

female patients. Most patients had a tumor classification of pT2 (86 patients), followed by 68 pT3

and 65 pT1 tumors. 48 patients had a pT4 and as mentioned, 26 had a CUP. As far as lymph node

status is concerned, most patients had a pN2 status (135 patients), followed by pN0 (109) and 38

patients with a pN1 status. 11 patients suffered a pN3 disease.

Most tumors were poorly (151 patients) and moderately (127) differentiated. Only 10 patients were

well differentiated and 5 patients had an anaplastic cancer. Therefore tumor grade was grouped into

high differentiated (well-differentiated and moderately-differentiated) and low differentiated

(poorly-differentiated and undifferentiated) for statistical analysis.

Table 13) Distribution of cancer staging in patients

3.4 Time of follow-up: Median time of follow-up was 34 months. Range of observation was 0 – 128 months (5% - 95%

percentiles; range of observation was 5 - 104 months). As expected, there is no normal dispersion,

therefore median is used in statistical analysis.

41

Figure 13) Time of follow up in months

Figure 14) Test of normality

42

Table 14) Test of normality proving there is no normal dispersion

3.5 Overall survival: Median survival of 293 patients was 108 months. Overall median survival in men was 101 months;

overall median survival in women was 108 months. There was no statistical significance between

overall survival between men and women.

Table 15) Statistic for survival of male, female and overall survival

43

Figure 15) 5 year overall survival

Figure 16) 5 year overall survival considering gender

44

3.6 Tumor localization

3.6.1 Disease free survival depending on tumor localization

Considering tumor localization for disease free survival, there was no statistical significance showing

a particular tumor region as being more likely to undergo a recurrence. Although the nasopharynx

seems to have a better disease free survival, considering the low number of patients (6 patients with

a nasopharyngeal cancer) the result was not statistically significant (Log Rank = 0,342)

3.6.2 Overall survival depending on tumor localization

Tumor localization did not have a statistical significant impact on overall survival according to the

Log-Rank test (Log-Rank = 0,095).

Table 16) Log-Rank test for the impact of tumor localization on overall survival

Figure 17) Kaplan-Meier curve illustrating the overall survival considering tumor localization

45

Nevertheless 25 of 49 patients with a hypopharyngeal cancer died of the disease. Considering other

tumor localizations this was a considerably high number. Therefore, hypopharyngeal cancer was

compared with all other tumor localizations, with the result that hypopharyngeal cancer compared

to other tumor localizations had a significant difference in overall survival (Log Rank = 0.003). This

significant difference in survival remained looking at small tumors separately: pT1 and pT2 tumors of

the hypopharyngeal region compared to other tumor sites remained significant (Log Rank = 0,011)

Figure 18) Small hypopharyngeal cancer compared to small cancer of all other tumor localizations combined showing a significant difference in outcome (Log Rank = 0.011)

Table 17) Test of equality of distribution depending on hypopharyngeal cancer or cancer of other localization

3.6.3 Does the tongue carcinoma represent a special entity within the oral cavity?

Comparing patients suffering a carcinoma of the tongue with other localizations of the oral cavity, we

did not find a statistically significant difference in either disease free survival or overall survival.

Although percentage of overall survival was the lowest in patients with a tongue carcinoma (67,5%)

versus other localizations, Log-Rank test was not significant (Log-Rank = 0,280)

46

Table 18) Overall survival depending on localization of oral cavity carcinoma

3.6.4 Tumor localization and further outcome:

Chi-Square test did not show any significant difference in tumor localization and recurrence or

localization of recurrence. There was no tumor localization more likely to develop a local- or lymph

node recurrence or distant metastasis.

Table 19) Distribution of recurrence, localization of recurrence and number of death according to localization

As mentioned, hypopharyngeal cancer had the worst prognosis for overall survival showing a crude

overall survival rate of 51% dying (25 of 49 patients). Compared with other tumor localizations,

hypopharyngeal cancer had a statistically significant higher percentage of people dying (Chi-Square

test = 0,002).

47

Table 20) Comparison of hypopharyngeal cancer and cancer of other tumor sites in recurrence, localization of recurrence and number of deaths

Looking at the distribution of hypopharyngeal cancer and tumor classification compared to other

cancer sites, there was no statistical significance. Hypopharyngeal cancer did not have a worse tumor

classification.

3.7 Tumor classification:

3.7.1 Disease free survival considering tumor classification:

There was a significant difference in disease free survival considering tumor classification. As

expected, pT1 and pT2 had the best outcome for disease free survival. Nearly the same run of the

curves showed pT3 tumors and tumors with an unknown primary. Tumors classified as pT4 had by far

the worst prognosis (50% have a five year disease free survival). Log-Rank test was significant, Log

Rank = 0,001

48

Figure 19) Kaplan Meier curve illustrating disease free survival considering tumor classification

Table 21) Percentage of patients suffering a recurrence considering tumor classification

3.7.2 Overall survival considering tumor classification:

Similar to disease free survival, overall survival depended strongly on tumor classification. Log-Rank

test showed a statistical significance (Log Rank = 0,020). Likewise to disease free survival, 24 of 48

patients with a pT4 classification died. With same percentage of disease free survival and overall

survival of patients with a pT4 classification, this would imply that those patients who suffered a

recurrence, eventually died.

49

Table 22) Percentag of patients dying considering tumor classification

Figure 20) Kaplan Meier curve illustrating overall survival considering tumor classification

50

3.8 Lymph nodes:

3.8.1 Lymph node status:

3.8.1.1 Disease free survival considering lymph node status:

Although 109 patients presented themselves initially with a pathological negative neck after neck

dissection, only 82 (75%) were disease free after follow up. 21 of 38 patients (55%) with pN1, 85 of

135 (63%) with pN2 and 6 of 11 patients (54%) with pN3 remained disease free. Especially pN1 and

pN2 status presented a very similar run of the curve. Median disease free survival for pN1 was 75

month, for pN2 82 month. pN3 had a median disease free survival of 32 month.

Table 23) Statistical analysis of disease free survival depending on lymph node status

51

Figure 21) Kaplan Meier curve illustrating disease free survival considering lymph node status

3.8.1.2 Overall survival considering lymph node status:

Positive lymph node status was always seen as a bad prognostic factor for outcome and overall

survival, reducing survival up to 50%(46). In our patients, positive lymph node status was also a

strong statistically significant factor for poor outcome (Log Rank = 0,001). 25 of 109 (77%) patients

with a negative lymph node status died, while 69 of 184 patients (62%) died with a positive lymph

node status.

Table 24) Percentage of patients being alive at the end of follow up considering positive or negative lymph node status

52

Figure 22) Kaplan-Meier curve demonstrating the high impact of positive lymph node status on overall survival

Looking at the curves for every lymph node status, pN1 and pN2 had – similar to disease free survival

– once again the same run of the curves. Median survival for pN1 was 78 months versus 88 months in

patients with pN2.

Table 25) Statistical analysis of median overall survival considering lymph node status

53

Figure 23) Kaplan Meier curve illustrating overall survival considering lymph node status (Log-Rank = 0,001)

3.8.2 Number of positive lymph nodes:

Similar to lymph node status, number of positive lymph nodes can also be used for prognosis on

disease free survival and overall survival. Considering the difference of staging within the pN2 stage

(pN2a equates to a single positive lymph node smaller than 6 cm on the ipsilateral side and pN2c

equates to one or more positive lymph nodes on the contralateral side) number of positive lymph

nodes might even deliver a more accurate prognosis.

3.8.2.1 Disease free survival considering number of positive lymph nodes:

Percentage of disease free survival for patients with a negative neck was 75%. By chance, the

number of patients with 1 or 2-5 positive lymph nodes and the number of patients suffering a

recurrence, was the same: 28 of 77 suffered a recurrence, and 49 (64%) remained disease free.

Disease free survival of patients with more than 5 lymph nodes was 47%.

Table 26) Percentage of disease free survival depending on number of positive lymph nodes.

54

Run of the Kaplan-Meier curves of disease free survival depending on number of positive lymph

nodes was similar to the curves of lymph node stage. Kaplan-Meier was statistical significant (Log-

Rank = 0,001).

Figure 24) Kaplan-Meier curve illustrating disease free survival considering number of positive lymph nodes

3.8.2.2 Overall survival considering number of positive lymph nodes:

We did not experience such a high impact on overall survival if one lymph node was positive,

compared to a negative neck. Overall survival was 77% vs. 71% for negative neck and one positive

lymph node, respectively. Also median survival of patients with one positive lymph node offered,

with 108 months a very good prognosis.

In patients with 2 – 5 positive lymph nodes, overall survival was 60%, and in those patients with more

than 5 positive lymph nodes, overall survival went down to 47%. Disease free survival and overall

survival in patients with more than 5 positive lymph nodes at presentation was the same, implicating

that every person with a recurrence died on behalf of the disease.

Median survival for 2-5 positive lymph nodes and more than 5 positive lymph nodes was 52 and 47

months, respectively.

55

Table 27) Statistic of overall survival depending on number of positive lymph nodes (Event = death)

Figure 25) Kaplan-Meier curve illustrating overall survival considering number of positive lymph nodes

3.8.3 Number of positive and overall lymph nodes excised:

Range of positive lymph nodes excised was 0 to 40 lymph nodes. In about one third of patients

(37,2%), lymph node status was negative. 77 patients had one positive lymph node; the same

56

number of patients had 2-5 positive lymph nodes. Only 10% of patients suffered a multiple lymph

node metastasis with more than 5 positive lymph nodes at the neck region.

Figure 26) Number of positive lymph nodes excised

Looking at the relationship between lymph node status and number of lymph nodes excised,

bivariate data analysis (Spearman = 0,000) was statistically significant. The lower the lymph node

status was, the fewer lymph nodes were excised.

Looking at the scatter plot, results of Spearman test is graphically illustrated.

57

Figure 27) Scatter plot of lymph node status and number of lymph nodes excised

3.8.4 Lymph node ratio as a predictive factor for disease free and overall survival:

Looking at our data, both, disease free survival and overall survival was statistically significant

depending on lymph node ratio. As suggested cutoff points(47), we used three groups: <7%, 7-13%,

and >13% ratio.

Percentage of disease free survival for groups of <7%, 7-13%, and >13% was 71,0%, 62,8% and 52,6%,

respectively. Median disease free survival was 108, 48, and 47 months.

58

Table 28) Statistical analysis for disease free survival depending on lymph node ratio

Median overall survival in patients with a lymph node ratio below 7% was 109 months. 76,2% were

still alive after follow-up. In patients with a lymph node ratio between 7-13%, median overall survival

was 48 months, and percentage of survival 58,1%. Worst prognosis was seen in patients with a lymph

node ratio higher than 13%. Median overall survival was 39 months; only 47,4% of patients were still

alive at end of follow-up.

Table 29) Statistical analysis for overall survival depending on lymph node ratio

59

Figure 28) Disease free survival and overall survival considering lymph node ratio (Log-Rank = 0,000 for both disease free and overall survival)

However, comparing lymph node ratio 7-13% with lymph node ratio higher than 13%, there was no

statistical difference found. Log-Rank for disease free survival was Log-Rank = 0,200, and for overall

survival Log-Rank = 0,180.

60

3.9 Tumor stage Tumor stage was highly significantly correlated with overall survival (Log-Rank = 0,001). Looking at

the 5-year overall survival rate, probability of survival at 5 years was 94%, 83%, 61%, and 56% for

stage I, stage II, stage III, and stage IV, respectively.

Figure 29) Kaplan-Meier curve illustrating 5 year overall survival depending on stage

3.10 Tumor grade: Considering tumor grade for disease free survival and overall survival, differentiation did not have a

statistically significant impact on either of them. On the contrary, run of the curves for disease free

survival and overall survival were nearly the same. Log Rank test for disease free survival and for

overall survival were 0,616 and 0,426, respectively.

61

Figure 30) Kaplan Meier curve illustrating no impact of tumor grade on disease free survival

Figure 31) Kaplan Meier curve illustrating no impact of tumor grade on overall survival (well-differentiated and undifferentiated tumor grades were excluded out of the graphic on behalf of small patient number)

62

3.11 Histological aspects: Five histological aspects were of special interest: lymphangiosis carcinomatosa, haemangiosis

carcinomatosa, capsule penetration, conglomerate tumor, and perineural invasion. All of them were

strong prognostic factors for reduction of disease free survival, and all of them – except

haemangiosis carcinomatosa – were strong prognostic factors for poor overall survival (reason for

border significance of haemangiosis carcinomatosa can be explained by the small number of patients

n=5).

Reduction of median disease free survival was between 2-3 times as fast. In overall survival,

reduction of survival time was reduced up to factor 10. Representative for all 5 histological aspects,

results of conglomerate lymph nodes are demonstrated in the following figures.

Figure 32) Impact of conglomerate lymph nodes on disease free survival

63

Figure 33) Impact of conglomerate lymph nodes on 5 year overall survival

Table 30) Statistical analysis of conglomerate lymph nodes as prognostic factor for overall survival; median disease free survival was reduced from 108 months to 29 months

64

3.11.1 Association of histological aspect and localization of recurrence:

Table 31) Statistical analysis of histological aspects and occurrence and localization of recurrence

65

All five histological factors were significant for poor outcome, disease free survival, and overall

survival. Perineural invasion was a strong prognostic factor for contralateral lymph node recurrence

(Log-Rank = 0,002) and ipsilateral lymph node recurrence (Log-Rank = 0,001). Haemangiosis

carcinomatosa and conglomerate lymph nodes were strong prognostic factors for distant metastasis

(Log-rank = 0,011 and 0,001, respectively). Lymphangiosis carcinomatosa was a statistically

significant factor for ipsilateral lymph node recurrence (Log-Rank = 0,048) and capsule penetration

was a significant factor for distant metastasis (Log-Rank = 0,048). None of those factors had an

impact on local recurrences.

3.12 Neck dissection: According to the classification of neck dissection proposed by the American Head and Neck Society

and the American Academy of Otolaryngology–Head and Neck Surgery in 2001(48)(9,48), 41 patients

were operated with a radical neck dissection, 85 patients received a modified radical neck dissection,

76 a posterolateral neck dissection, 26 patients a supraomohyoidale neck dissection, 24 patients had

an expanded supraomohyoidal neck dissection (additional resection of region 5a or region 4), 14

patients a lateral selective neck dissection; in two patients lateral selective neck dissection was

expanded to region 5a, 3 patients underwent a suprahyoidale neck dissection, and the remaining 24

neck dissection were selective neck dissections. In 66 patients, neck dissection was performed

bilaterally.

In total, 293 patients received 359 neck dissections

Figure 34) Distribution of types of neck dissections performed (according to the recommendations of the American Head and Neck Society 2008)

Considering lymph node status, the higher the lymph node status was, the more aggressive was neck

dissection. In patients with pN2 or pN3, nearly every patient was treated with either radical neck

dissection, modified radical neck dissection, or posterolateral neck dissection.

66

3.12.1 Correlation between extent of neck dissection and outcome:

3.12.1.1 Excision of number of lymph node levels and disease free survival:

Disease free survival in patients with a negative lymph neck node status (pN0) was 77,4%, 73,7% and

72,2% for patients treated with excision of 1-3 levels, 4-5 levels and more than 5 levels, respectively.

In patients with a positive lymph node status, disease free survival was 72.7%, 59.2% and 64,5%,

respectively. Median survival for pN0 patients could not be calculated (more than 50% of patients

survived), in pN+ patients, median survival for excision of 1-3 levels, 4-5 levels and more than 5 levels

was 85 months, 69 months and 85 months. There was no statistical significance between percentage

of disease free survival and median disease free survival time.

3.12.1.2 Excision of number of lymph node levels and overall survival:

Percentage of overall survival in patients with a negative neck node status (pN0) was 84,9%, 68,4%,

and 72,2% for resection of 1-3 levels, 4-5 levels, or more than 5 levels, respectively. In patients with a

positive neck status (pN+) overall survival for those three groups was: 63,6%, 61,3%, and 67,7%.

67

Statistical analysis did not show any significant difference between those groups. The poor median

overall survival time in patients with a pN+ and resection of 1-3 levels might evolve out of a small

number of patients (n =11)

3.12.1.3 Correlation between extent of neck dissection and outcome in patients with a N0

lymph node status:

Kaplan-Meier curve did not show any differences in run of curve as far as disease free survival in pN0

patients was concerned. However, Kaplan-Meier analysis demonstrated a border significance in

patients with a pN0 status treated only with excision of 1-3 lymph node levels (Log-Rank = 0,088)

68

Figure 35) Kaplan-Meier curve, showing no statistically significant difference in disease free or overall survival depending on number of excised lymph node levels in patients with a pN0 status.

3.12.1.4 Correlation between extent of neck dissection and outcome in patients with a

positive lymph node status:

Patients with a positive lymph node status pN+ did not have a significantly different outcome

depending on amount of lymph node levels excised during neck dissection.

69

Figure 36) Kaplan-Meier curve, showing no statistically significant difference in disease free or overall survival depending on number of excised lymph node levels in patients with a pN+ status.

3.12.2 Impact of radical neck dissection:

3.12.2.1 Impact of radical neck dissection on disease free survival and overall survival in

patients with positive neck lymph node status:

Patients with a positive lymph neck node status treated with a radical neck dissection did not benefit

from this procedure. On the contrary, run of curves of patients treated with radical neck dissection,

even though lacking statistical significance, was below run of curves of patients not treated in a

radical manner (Log-Rank = 0,074).

70

Separating the group of patients with a positive lymph node status into groups of patients with one,

2-5, or more than 5 positive lymph nodes, radical neck dissection did not offer a benefit in overall

survival in any of these groups.

Figure 37) Impact of radical neck dissection on overall survival in patients with a positive lymph node status (Log-Rank = 0,74)

Table 32) Log-Rank test on effect of radical neck dissection considering number of positive lymph nodes

3.12.2.2 Impact of radical neck dissection on disease free survival and overall survival in

stage IV disease:

Altogether, in 41 patients a radical neck dissection was performed. Most patients (38 patients) had a

stage IV disease; two patients had a stage III disease and one patient a stage I.

71

There was no statistically significant difference in disease free survival for patients considering type

of neck dissection (radical vs. non radical neck dissection) in stage I and stage III disease – numbers of

patients were very small. Comparing patients in stage IV being operated either with a radical neck

dissection vs. non radical neck dissection, there was a statistically significant difference in disease

free survival (Log-Rank = 0,002). Surprisingly, patients treated with radical neck dissection suffered

more often from a recurrence.

Figure 38) Kaplan-Meier curve illustrating the negative effect of radical neck dissection on disease free survival (Log-Rank = 0,002)

This is even more remarkable looking at the distribution of tumor classification and lymph node

status. Within stage IV patients, distribution of surgical therapy (radical neck dissection vs. other neck

dissection) was even.

Table 33) Distribution of tumor classification and lymph node status within stage IV disease treated with or without radical neck dissection

In overall survival, run of Kaplan-Meier curve in patients receiving radical neck dissection was still

below the curve of patients not undergoing radical therapy, but statistical significance was missing.

72

Nevertheless, striving for radical neck dissection to prevent patients from recurrence is not indicated.

Figure 39) Overall survival of patients with stage IV disease depending on type of neck dissection (Log-Rank = 0,115)

3.12.3 Does type of neck dissection effect locoregional recurrence free survival?

Both, in patients with a negative lymph node status (pN0), and in patients with a positive lymph node

status (pN+), there was no significant difference of the impact of type of neck dissection on

locoregional neck lymph node recurrence free survival. Only 7 patients of 109 patients (6,4%) with a

negative neck at diagnosis developed a locoregional lymph node recurrence during follow up.

Patients developing a recurrence were treated with modified radical neck dissection (1),

posterolateral neck dissection (2), supraomohyoidal neck dissection (2), expanded supraomohyoidal

neck dissection (1) and selective neck dissection (1).

In patients with a pN+ neck, 19 of 184 (10,3%) developed a locoregional neck lymph node metastasis.

Likewise, there was no statistically significant difference between different types of neck dissections

performed.

73

Table 34) Percentage of locoregional recurrence free survival depending on type of neck dissection

3.12.3.1 Effect of extensive neck dissection versus selective neck dissection procedures on

locoregional recurrence (LRR) free survival:

Comparing extensive neck dissection (radical neck dissection, modified radical neck dissection and

posterolateral neck dissection) versus selective elective procedures (supraomohyoidal neck

dissection, suprahyoidal neck dissection, lateral neck dissection and selective neck dissection), there

was no statistically significant difference in LRR free survival. Even considering adjuvant therapy, no

statistically significant difference between treatment groups could be found in the Log-Rank test.

74

Figure 40) Kaplan-Meier curve illustrating similar run of curves between different types of neck dissection, considering adjuvant therapy

Further, comparing radical neck dissection versus modified radical neck dissection, run of curves

were hardly different from each other (Log-Rank = 0,884) implying that locoregional control can be

achieved without dissecting all non-lymphatic structures at risk in the neck.

75

Figure 41) Locoregional recurrence free survival considering type of neck dissection

3.12.4 Benefit of elective bilateral neck dissection in patients with a clinical negative

contralateral neck:

Number of patients presenting with a clinical negative contralateral neck were 284. 57 patients were

treated with bilateral neck dissection, 227 patients with unilateral neck dissection. Both disease free

survival and overall survival did not show any significant difference between those two groups in run

of Kaplan-Meier curves (Log-Rank = 0,709 and 0,973), percentage of recurrence (66% vs. 68%),

percentage of death (68% vs. 72%) or median disease free survival (91 months vs. 85 months).

Distribution of adjuvant therapy in patients with unilateral neck dissection and patients with bilateral

neck dissection was not significantly different.

Table 35) Percentage of adjuvant therapy in patients receiving unilateral or bilateral neck dissection

76

Figure 42) Overall survival of patients with clinical contralateral negative neck depending on unilateral or bilateral neck treatment (Log-Rank = 0,973)

77

3.13 Effect of excision of non-lymphatic structures on disease free and

overall survival: Effect of excision of jugular vein, accessoric nerve and sternocleidomastoid muscle could not be

evaluated because distribution of patients to different groups was not even.

Table 36) Chi-Square test did show a significant difference in distribution between patients and excision of non-lymphatic structures, and therefore could not be analyzed

3.14 Resection margin:

3.14.1 Disease free survival considering resection margin:

Postoperative, 230 patients had a negative resection margin (R0). At the end of follow-up, 69% of

patients were still disease free. Out of the other 63 patients, 58 had a histological positive resection

margin (R1) and 5 patients had a macroscopic positive resection margin (R2). 59% of R1 patients still

lived without a recurrence of disease at the end of follow-up, but only 1 of 5 patients with R2 (20%)

was disease free.

Median disease free survival time was 49 months and 20 months for R1 and R2, respectively. Patients

with a negative resection margin had a median disease free survival time of 93 month. Log-Rank test

showed the strong statistic impact of positive resection margin on disease free survival (Log-Rank =

0,002)

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Table 37) Statistical analysis of disease free survival considering resection margin

Figure 43) Kaplan-Meier curve of disease free survival considering resection margin

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3.14.2 Overall Survival considering Resection Margin:

At the end of follow-up of 250 patients with a negative resection margin, 72% were still alive. 32 0f

58 (55%) of R1 patients were still alive at the end of follow up, but only 1 of 5 patients with R2 (20%)

survived.

The Kaplan-Meier curve illustrated the strong prognostic factor of resection margin, and the Log-

Rank test demonstrated a strong statistical significance of resection margin for survival (Log-Rank =

0,000). Median survival for R1 was 49 months, for macroscopic positive resection margin only 20

months, the same amount of time that we experienced for disease free survival, implying the close

relationship between recurrence and death.

Table 38) Statistical analysis of overall survival considering resection margin

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Figure 44) Kaplan-Meier curve of overall survival considering resection margin

3.14.3 Influence of postoperative therapy in patients with resection margins R0, R1 or R2

on disease free survival:

Out of 293 patients, 114 did not receive adjuvant therapy: out of those 114 patients, 108 patients

were diagnosed with a negative resection margin, 6 patients had a R1 postoperative result. 36 of 108

patients (67%) with a negative resection margin did not experience a recurrence, while only 1 of 6

patients (17%) was disease free after follow up in the R1 group. Patients receiving postoperative

adjuvant therapy were 122 patients with a R0, 52 with a R1 and 5 with a R2 situation. Disease free

survival rate in those three groups were 86 of 122 (70%), 33 of 52 (63%), and 1 of 5 (20%),

respectively for R0, R1, and R2.

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Table 39) Number of patients being treated with or without postoperative adjuvant therapy and percentage of disease free survival (Event = recurrence)

Negative resection margin versus positive resection margin in patients not being treated with

adjuvant therapy was a strong prognostic factor (Log-Rank = 0,000) for disease free survival. R0 and

R1 patients receiving adjuvant therapy did not differ significantly in disease free survival. Patients

with a macroscopic positive resection margin (R2) had an unpromising prognosis (Log-Rank = 0,025

compared to R0 and 0,050 compared to R1).

Although there was no statistically significant difference in R0 and R1 patients receiving adjuvant

therapy, median disease free survival was reduced by 44 month; 105 month vs. 61 month in R0 and

R1 respectively.

Table 40) Statistical analysis for disease free survival considering resection margin and postoperative adjuvant therapy

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Figure 45) Kaplan-Meier curve illustrating the bad prognosis on disease free survival of patients with a R1 resection margin and no additional treatment compared to patients with negative resection margins (Log-Rank = 0,000)

Figure 46) Kaplan-Meier curve illustrating the effect of adjuvant therapy in positive resection margin (Log-Rank = 0.313 for R0 vs. R1)

83

Table 41) Patients at risk depending on adjuvant therapy and resection margin, after 1, 3 and 5 years

If administered adjuvant therapy was solely radiotherapy, Kaplan-Meier curve showed a similar run

of curve. Difference between disease free survival of R0 or R1 was not significant, whereas R2

remained prudent.

3.14.4 Influence of postoperative therapy in patients with resection margin R0, R1, or R2

on overall survival:

Among 114 patients receiving no adjuvant therapy, 108 had a negative resection margin, and 6

patients had a R1 resection margin. 80 of 108 patients with R0 were still alive at the end of follow-up

(74%) while 2 of 6 patients with R1 survived (33%)

Distribution of resection margin in the group receiving postoperative adjuvant therapy was 122

patients with R0, 52 with R1 and 5 with R2 resection margins. Overall survival in those three groups

was 70%, 58% and 20% for R0, R1 and R2, respectively.

Table 42) Number of patients being treated with or without postoperative adjuvant therapy and percentage of overall survival (Event = death)

Negative resection margin versus positive resection margin in patients not being treated with

adjuvant therapy was a strong prognostic factor (Log-Rank = 0,000) for overall survival. R0 and R1

patients receiving adjuvant therapy did not differ statistical significant in disease free survival;

nevertheless a border significance could be identified (Log-Rank = 0,088).

84

Patients with a R2 resection margin had the same unpromising prognosis in overall survival like they

had in disease free survival (Log-Rank = 0,25 compared to R0 and 0,50 compared to R1).

Figure 47) Kaplan-Meier curve illustrating the bad prognosis on overall survival of patients with a R1 resection margin and no additional treatment compared to patients with negative resection margins (Log-Rank = 0,000)

85

Figure 48) With adjuvant therapy, R1 and R0 did not show a statistical significant difference (Log-Rank = 0,088) in overall survival, while R2 remained a strong prognostic impact on overall survival (Log-Rank = 0,002 compared to R0 and 0,015 compared to R1)

Interestingly enough, looking at patients treated only with postoperative radiotherapy, there was a

significant difference in overall survival between patients with a R0 and R1 resection (Log-Rank =

0,045) compared to patients receiving postoperative radiochemotherapy in which difference

between R0 and R1 in overall survival was not statistical significant (Log-Rank = 0,088)

86

3.15 Adjuvant therapy:

3.15.1 Radiotherapy:

Most patients, 140 of 293 (47,7%), were treated with adjuvant radiotherapy. 114 patients did not

receive any additional therapy, 38 (12,9%) received radiochemotherapy, and only one patient (0,3%)

was additionally treated with cisplatin only.

Figure 49) Number of patients treated with postoperative adjuvant therapy

87

3.15.2 Chemotherapy:

Only 39 patients were treated with postoperative adjuvant chemotherapy. Most of those patients

received radiochemotherapy; only one patient received cisplatin solely (patient refused

radiotherapy).

Distribution between chemotherapeutics used was dominated by cisplatin with 33 patients, followed

by carboplatin/5FU with 5 patients, and one patient was treated with the epidermal growth factor

inhibitor Erbitux.

Figure 50) Number of patients treated with carboplatin/5FU, Cisplatin or Erbitux

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3.16 Impact and importance of adjuvant therapy:

Figure 51) Overall effect of adjuvant therapy

3.16.1 Impact of adjuvant therapy considering tumor classification:

3.16.1.1 Disease free survival:

Overall disease free survival in patients receiving adjuvant therapy was 67% versus 64% in patients

who did not receive postoperative treatment. Although percentage of disease free survival was

generally higher in patients receiving adjuvant therapy, only patients with a carcinoma of unknown

primary had a statistically significant benefit (Log-Rank = 0,000).

Run of the curves of disease free survival in patients without adjuvant therapy was statistical ly

significant depending on tumor classification. In patients with adjuvant therapy, only T4 tumors had a

statistically significant different run of the curves compared to T1 (Log-Rank = 0,040). There was a

borderline significance in run of the curves between T3 tumors and T2 tumors (Log-Rank = 0,053)

89

3.16.1.2 Overall survival:

Overall Survival rate of patients receiving adjuvant therapy was 69%, 54%, 80%, 54%, and 72% for T1,

T2, T3, T4, and Tx, respectively. Percentage of survival in patients receiving no adjuvant treatment

was 86%, 79%, 56%, 33%, and 75%, respectively for T1, T2, T3, T4, and Tx.

Looking at T2 and T3 separately, there was a statistically significant difference in overall survival

between patients with or without postoperative adjuvant treatment. While T3 did benefit from

adjuvant therapy, patients with a T2 stage did not – on the contrary, overall survival was worse in

patients with adjuvant therapy. Similarly, but not to a statistically significant degree, adjuvant

therapy in patients with T1 stage was rather a disadvantge.

Table 43) Percentage of overall survival in patients with or without adjuvant therapy considering tumor classification

90

Figure 52) Effect of postoperative adjuvant therapy in pT1 tumor patients (Log-Rank = 0,151)

Figure 53) Effect of postoperative adjuvant therapy in pT2 tumor patients (Log-Rank = 0,016)

91

Similar to disease free survival, run of curves for overall survival differed depending on tumor

classification and whether adjuvant postoperative therapy was applied or not. Patients with a T1, T2,

or Tx tumor stage not receiving adjuvant therapy showed a very similar run of curve. Curves of T3

and T4 patients differed significantly compared to T1,T2, and Tx.

Run of curves in patients receiving postoperative adjuvant therapy did not differ to a statistical ly

significant degree.

Table 44) Pairwise comparison of overall survival depending on postoperative adjuvant therapy and tumor classification

Figure 54) Kaplan-Meier curve illustrating overall survival depending on tumor classification of patients receiving no additional postoperative treatment

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Figure 55) Kaplan-Meier curve illustrating overall survival depending on tumor classification of patients receiving no additional postoperative treatment

3.16.2 Impact of adjuvant therapy considering Lymph Node Status:

3.16.2.1 Disease Free Survival:

In patients with a negative neck, disease free survival for patients with or without postoperative

adjuvant therapy was 76% and 75%, respectively. Only 10 of 30 patients (33%) with a pN+ stage

remained disease free if adjuvant therapy was not applied. Patients with a pN+ stage who did receive

adjuvant therapy had a percentage of disease free survival of 66%. Kaplan-Meier curve demonstrated

the statistical significant benefit of postoperative adjuvant therapy in patients with a pathological

lymph neck node status (Log-Rank = 0,004).

Difference in median disease free survival between patients receiving postoperative treatment

compared to those not receiving postoperative treatment was 85 months vs. 54 months.

Considering run of the curves of patients without adjuvant therapy, pN0 had a significantly better

disease free survival (Log-Rank = 0,000). But if patients were treated with postoperative adjuvant

therapy, run of the curves were not statistically significant (Log-Rank = 0,317).

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Table 45) Statistical analysis of disease free survival in patients with or without postoperative adjuvant therapy

Figure 56) Kaplan-Meier curve illustrating disease free survival without postoperative adjuvant therapy considering positive or negative lymph node status (Log-Rank = 0,000)

94

Figure 57) Kaplan-Meier curve illustrating disease free survival in patients receiving postoperative adjuvant therapy considering positive or negative lymph node status (Log-Rank = 0,317)

Figure 58) Kaplan-Meier curve illustrating the statistically significant impact on postoperative adjuvant therapy in patients with a positive lymph node status (Log-Rank = 0,004)

95

3.16.2.2 Overall survival:

Kaplan-Meier survival analysis in patients without adjuvant therapy demonstrated a statistically

significant difference in overall survival depending on lymph node status (negative vs. positive lymph

neck node), while patients receiving adjuvant therapy did not differ significantly (Log-Rank = 0,006 vs.

0.228, respectively).

Overall survival was 17 of 30 patients (57%) with pN+ stage, and 65 of 84 patients (77%) with a pN0

stage, if no adjuvant therapy was administered. In comparison to patients receiving additional

postoperative treatment, percentage in patients with a negative neck was similar, 19 of 25 patients

(76%), while 98 of 154 patients (64%) with a positive neck were still alive at the end of follow-up.

Median survival for patients with a positive neck was 66 months without adjuvant therapy versus 85

months in those receiving adjuvant treatment options. Median survival of pN0 patients could not be

calculated.

Table 46) Statistical analysis of overall survival depending on postoperative adjuvant therapy and lymph node status

Although patients with a pN+ neck did benefit significantly from postoperative adjuvant therapy as

far as disease free survival was concerned, this benefit could not be found in overall survival.

Prognosis for overall survival in both patients with a negative and patients with a positive lymph

node stage did not alter in any direction if adjuvant therapy was applied.

The difference of impact on disease free survival and overall survival might be explained by the high

toxicity coming along with adjuvant therapy, regardless of whether chemotherapy, radiotherapy, or

both was administered. Although recurrence was obviated, overall survival did not benefit.

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Figure 59) Difference in run of curves depending on postoperative adjuvant therapy in patients with a pathological positive neck (Log-Rank = 0,420)

3.17 Adjuvant therapy in early stage tumors (stage I and stage II) Most patients with early stage carcinoma had solely operative treatment. Only 7 of 70 patients

underwent adjuvant therapy in early stage tumors. Adjuvant therapy in all those cases was adjuvant

radiotherapy.

Table 47) Adjuvant therapy applied in early stage carcinoma

Percentage of overall survival was similar. Looking at the Kaplan-Meier curve, patients receiving

adjuvant therapy did not have an event within 5 years. However, Log-Rank test was not significant at

Log-Rank = 0,771

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Figure 60) Kaplan-Meier curve illustrating impact of adjuvant therapy in early stage cancer on overall survival

3.18 Adjuvant therapy in advanced tumors (stage III and stage IV): A total of 222 patients were staged with a stage III or stage IV tumor. One patient declined

radiotherapy and received postoperative chemotherapy only. Because of this small number, patient

was not included in statistical analysis.

Disease free survival in this group of patients was 62%; 84 patients suffered a recurrence. 133

patients were treated with a postoperative radiotherapy. 50 of those 133 patients experienced a

recurrence (62,4%). Recurrence rate of patients without adjuvant therapy and with combined

postoperative radiochemotherapy was 44% and 84% respectively. Chi square test was highly

significant (Chi-square = 0,001). Log-Rank test could demonstrate a significance (Log-Rank = 0,004).

Table 48) Number of recurrence in patients with a stage III or stage IV disease

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Figure 61) Disease free survival of patients with stage III or stage IV disease considering adjuvant therapy (Log-Rank = 0,004)

Impact of adjuvant therapy on overall survival showed a similar effect. 22 patients without

postoperative adjuvant treatment died (44%). Overall survival in patients with postoperative

radiotherapy was 57,9%, and 86,8% in patients with postoperative adjuvant radio-, and

chemotherapy. Chi-Square test was significant at p = 0,003. Likewise to disease free survival, Kaplan-

Meier curve demonstrated different run of curves depending on adjuvant therapy, however, Log-

Rank test was not significant at Log-Rank = 0,245.

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Table 49) Statistical analysis of disease free and overall survival in stage III/IV patients considering adjuvant therapy

Figure 62) Kaplan-Meier curve illustrating different run of curves considering adjuvant therapy in stage III and stage IV disease, however, Log-Rank test did not reach statistical significance (Log-Rank = 0,245)

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3.19 Multivariate data analysis: After univariate data analysis, multivariate data analysis was performed, using every covariable with

a significance level below p-value of 0,2. Size of tumor, conglomerate lymph nodes, and perineural

invasion remained as the leading covariables for recurrence free survival. In disease free survival,

most powerful effect for an event were tumor size, conglomerate lymph nodes and lymph node ratio

(using threshold at 7%). Stage, lymph node ratio, conglomerate lymph nodes, resection margin, and

adjuvant therapy are most important covariables for overall survival.

3.19.1 Recurrence free survival:

Number of stderr of

observations estimate

Gender 265 1,163 0,286 (0.664, 1.039) 0,5974

Localization (hypopharynx vs. other tumor

sites)265 1,294 0,273 (0.758, 2.209) 0,3455

Staging (1,2 vs. 3,4) 265 2,203 0,303 (1.216, 3.994) 0,0092

pT1/2 vs. 3/4 265 2,07 0,225 (1.331, 3.219) 0,0012

pN0 vs. pN+ 265 1,758 0,241 (1.096, 2.820) 0,0192

Positive Lymph Nodes (1 vs. 0) 265 1,408 0,3 (0.782, 2.536) 0,2538

Positive Lymph Nodes (2-5 vs. 0) 265 1,777 0,29 (1.007, 3.137) 0,0473

Positive Lymph Nodes (>5 vs. 0) 265 2,586 0,343 (1.322, 5.061) 0,0055

Lymph Node Ratio (<7 vs. >7) 265 1,855 0,225 (1.193, 2.886) 0,0061

Grade (high vs. low) 265 1,205 0,224 (0.777, 1.871) 0,405

Perineural Invasion 265 2,274 0,325 (1.201, 4.303) 0,0116

Lymphangiosis 265 1,952 0,354 (0.975, 3.908) 0,0588

Haemangiosis 265 3,573 0,464 (1.438, 8.876) 0,0061

Capsule Penetration 265 2,357 0,244 (1.461, 3.804) 0,0004

Conglomerat Lymph Nodes 265 2,961 0,287 (1.687, 5.195) 0,0002

R0 vs. R+ 265 1,8 0,239 (1.128, 2.873) 0,0138

Radical Neck Dissection 265 2,21 0,28 (1.276, 3.827) 0,0047

Neck Dissection (functional vs.

comprehensive)265 1,395 0,247 (0.860, 2.261) 0,1776

Levels (Level 1-3 vs. 4-5) 265 1,663 0,31 (0.906, 3.051) 0,1005

Levels (Level 1-3 vs. >5) 265 1,625 0,379 (0.773, 3.418) 0,2005

Excision of M. Sternocleidomastoideus 265 1,279 0,229 (0.817, 2.003) 0,2816

Excision of Jugular Vein 265 1,69 0,234 (1.068, 2.676) 0,0251

Excision of Accessoric Nerve 265 1,499 0,223 (0.968, 2.322) 0,0697

Adjuvant Therapy 265 0,917 0,226 (0.589, 1.429) 0,7025

Recurrence Free Survival

p-valuehazard ratio CI

Table 50) Multivariate data analysis for recurrence free survival

101

Number of stderr of

observations estimate

pT1/2 vs. 3/4 265 1,886 0,229 (1.204, 2.953) 0,0056

Perineural Invasion 265 2,28 0,336 (1.179, 4.407) 0,0143

Conglomerat Lymph Nodes 265 3,165 0,293 (1.782, 5.621) < 0.0001

p-valueCIhazard ratio

Multivariate Model with Univariate Significant Covariables (p-Wert < 0.2)

Table 51) Multivariate model for recurrence free survival including univariate significant covariables

3.19.2 Disease free survival:

Number of stderr of

observations estimate

Gender 265 1,086 0,253 (0.662, 1.783) 0,7428

Localization (hypopharynx vs. other

tumor sites)265 1,446 0,228 (0.925, 2.261) 0,1057

Staging (1,2 vs. 3,4) 265 2,306 0,265 (1.372, 3.874) 0,0016

pT1/2 vs. 3/4 265 1,942 0,194 (1.329, 2.838) 0,0006

pN0 vs. pN+ 265 1,669 0,206 (1.115, 2.497) 0,0128

Positive Lymph Nodes (1 vs. 0) 265 1,215 0,265 (0.723, 2.043) 0,4624

Positive Lymph Nodes (2-5 vs. 0) 265 1,892 0,242 (1.178, 3.039) 0,0084

Positive Lymph Nodes (>5 vs. 0) 265 2,289 0,302 (1.266, 4.140) 0,0062

Lymph Node Ratio (<7 vs. >7) 265 2,08 0,193 (1.424, 3.038) 0,0002

Grade (high vs. low) 265 1,126 0,193 (0.772, 1.642) 0,5386

Perineural Invasion 265 1,788 0,307 (0.980, 3.264) 0,0583

Lymphangiosis 265 1,935 0,307 (1.061, 3.529) 0,0312

Haemangiosis 265 2,64 0,46 (1.072, 6.502) 0,0348

Capsule Penetration 265 2,239 0,213 (1.474, 3.401) 0,0002

Conglomerat Lymph Nodes 265 2,754 0,253 (1.676, 4.524) < 0.0001

R0 vs. R+ 265 1,958 0,202 (1.316, 2.914) 0,0009

Radical Neck Dissection 265 1,776 0,259 (1.069, 2.951) 0,0265

Neck Dissection (functional vs.

comprehensive)265 1,399 0,213 (0.922, 2.122) 0,1141

Levels (Level 1-3 vs. 4-5) 265 1,516 0,259 (0.913, 2.518) 0,1081

Levels (Level 1-3 vs. >5) 265 1,5 0,321 (0.800, 2.813) 0,2061

Excision of M. Sternocleidomastoideus 265 1,224 0,196 (0.833, 1.798) 0,3029

Excision of Jugular Vein 265 1,587 0,204 (1.063, 2.369) 0,0238

Excision of Accessoric Nerve 265 1,465 0,193 (1.004, 2.137) 0,0477

Adjuvant Therapy 265 0,904 0,195 (0.617, 1.324) 0,6036

Disease Free Survival

hazard ratio CI p-value

Table 52) Covariables used for multivariate data analysis for overall survival

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Number of stderr of

observations estimate

pT1/2 vs. 3/4 265 1,838 0,194 (1.256, 2.689) 0,0017

Lymph Node Ratio (<7 vs. >7) 265 1,649 0,214 (1.083, 2.510) 0,0196

Conglomerat Lymph Nodes 265 1,981 0,28 (1.144, 3.431) 0,0147

hazard ratio CI p-value

Multivariate Model with Univariate Significant Covariables (p-Wert < 0.2)

Table 53) Multivariate model for disease free survival including univariat significant covariables

3.19.3 Overall survival:

Number of hazard ratio stderr of CI p-value

observations estimate

Gender 265 0,795 0,34 (0.408, 1.548) 0,4995

Localization (hypoharynx vs. other tumor

sites)265 1,888 0,258 (1.138, 3.130) 0,0138

Staging (1,2 vs. 3,4) 265 5,154 0,427 (2.233, 11.893) 0,0001

pT1/2 vs. 3/4 265 2,02 0,235 (1.274, 3.201) 0,0028

pN0 vs. pN+ 265 2,396 0,267 (1.420, 4.042) 0,0011

Positive Lymph Nodes (1 vs. 0) 265 1,563 0,34 (0.804, 3.041) 0,1883

Positive Lymph Nodes (2-5 vs. 0) 265 2,819 0,303 (1.556, 5.111) 0,0006

Positive Lymph Nodes (>5 vs. 0) 265 3,602 0,361 (1.776, 7.305) 0,0004

Lymph Node Ratio (<7 vs. >7) 265 3,001 0,235 (1.893, 4.756) < 0.0001

Grade (high vs. low) 265 1,392 0,237 (0.875, 2.215) 0,1623

Perineural Invasion 265 1,918 0,357 (0.952, 3.863) 0,0684

Lymphangiosis 265 2,165 0,356 (1.077, 4.352) 0,0302

Haemangiosis 265 2,657 0,594 (0.829, 8.515) 0,1001

Capsule Penetration 265 2,744 0,25 (1.682, 4.475) < 0.0001

Conglomerat Lymph Nodes 265 4,025 0,278 (2.334, 6.941) < 0.0001

R0 vs. R+ 265 2,464 0,241 (1.537, 3.951) 0,0002

Radical Neck Dissection 265 2,204 0,298 (1.228, 3.955) 0,0081

Neck Dissection (functional vs.

comprehensive)265 2,523 0,297 (1.409, 4.517) 0,0018

Levels (Level 1-3 vs. 4-5) 265 2,458 0,361 (1.211, 4.992) 0,0128

Levels (Level 1-3 vs. >5) 265 2,209 0,434 (0.944, 5.174) 0,0678

Excision of M. Sternocleidomastoideus 265 1,726 0,249 (1.060, 2.810) 0,0283

Excision of Jugular Vein 265 2,187 0,24 (1.367, 3.498) 0,0011

Excision of Accessoric Nerve 265 2,275 0,234 (1.439, 3.597) 0,0004

Adjuvant Therapy 265 1,408 0,246 (0.869, 2.282) 0,1649

Overall Survival

Table 54) Covariables used for multivariate data analysis for overall survival

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Number of stderr of

observations estimate

Staging (1,2 vs. 3,4) 265 5,305 0,47 (2.111, 13.332) 0,0004

Lymph Node Ratio (<7 vs. >7) 265 1,861 0,281 (1.073, 3.229) 0,0271

Conglomerat Lymph Nodes 265 2,442 0,315 (1.317, 4.527) 0,0046

R0 vs. R+ 265 2,069 0,272 (1.215, 3.522) 0,0074

Adjuvant Therapy 265 0,358 0,301 (0.198, 0.646) 0,0007

hazard ratio CI p-value

Multivariate Model with Univariate Significant Covariables (p-Wert < 0.2)

Table 55) Multivariate model for overall survival including univariat significant covariables

3.20 Recurrence: One-third of the patients, 99 of 293 (34%) suffered a recurrence. Highest percentage of recurrence

rate was carcinoma of unknown primary (42%); in 5 out of 11 patients with recurrence in this group

of carcinomas, recurrence equaled the finding of the primary tumor. Lowest percentage of

recurrence rate was found in patients with a laryngeal cancer (29%). No tumor localization was

statistically more at risk to develop a recurrence.

If a recurrence occurred, most patients suffered a local recurrence (13% of patients), followed by

distant metastasis (9%) and lymph node recurrence (12%). Patients with laryngeal cancer had a very

low percentage of local recurrence (4,5%). All other tumor regions aside from nasopharyngeal cancer

had a local recurrence rate of about 15%. Lymph node recurrence happened most often in

nasopharyngeal cancer and cancer of unknown primary, 17% and 15%, respectively. In every 5th

patient with a hypopharyngeal cancer, distant metastasis occurred.

Contralateral recurrence only occurred in 4 of 293 patients (1%):

• 2 patients with a tumor of the oral cavity:

• One patient with a tumor of the tongue, pT1N2b, experienced a local recurrence as

well as a bilateral recurrence after modified radical neck dissection and

postoperative adjuvant radiotherapy.

• Another patient with a tumor of the floor of the mouth, pT2N2c, developed a

submental lymph node recurrence on the contralateral side after extended (Va)

supraomohyoidale neck dissection and selective neck dissection (II and III) on the

contralateral side and postoperative adjuvant radiotherapy.

• One patient with a hypopharyngeal tumor of the sinus piriformis, pT4N2b, developed after

lateral neck dissection a lymph node recurrence at level II on the contralateral side.

• One patient with a laryngeal tumor, pT4, and a pathological negative neck developed a

contralateral lymph node recurrence at level III.

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Table 56) Percentage of recurrence depending on tumor localization

Percentage of overall survival in patients that remained disease free was 79,9% (155 of 194 patients).

Every second patient with a local recurrence died (19 of 38 patients) and 57,7% of patients with

lymph node recurrence did not survive (15 of 26 patients).

As expected, the worst outcome was experienced by patients with distant metastasis. 28,6% (10 of

25 patients) died during follow-up; the remaining 10 patients received palliative treatment onwards.

Since at some point they did not show up for follow up any more, they are supposed to have died of

the disease as well. Therefore, all patients experiencing distant metastasis died of the disease.

If loco-regional lymph neck node recurrence occurred, in most cases, it happened in the region of the

former neck dissection. In 20 of 26 patients with a lymph node recurrence, recurrence was in the

field of neck dissection (76,9%); in 2 of 26 patients it was in the region of neck dissection and in

another not dissected region; and 4 patients suffered a lymph node recurrence outside the region of

dissection.

According to the statistical analysis, distant metastasis has the worst outcome, with a median overall

survival of 29 months (only patients receiving palliative treatment at our department). Median

overall survival for lymph node recurrence was 84 months and for local recurrence 47 months. One

must keep in mind that those numbers of months are considered from the point of first diagnosis.

105

Table 57) Statistical analysis of overall survival depending on type of recurrence

Kaplan-Meier curves showed the same result: the bad overall survival of patients suffering distant

metastasis, local recurrence and lymph node recurrence showing a better prognosis but still not

comparable if patient remained disease free. Log-Rank test was highly significant at Log-Rank =

0,000.

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Figure 63) Kaplan-Meier curve illustrating overall survival depending on type of recurrence (Log-Rank = 0,000)

Figure 64) Number of patients dying after recurrence depending on type of recurrence

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3.21 Cause of death: A total of 94 patients (32%) died during follow-up. In 60 of 94 patients (64%), cause of death was

tumor associated. 6 patients (6%) died therapy associated, and 28 patients (30%) died due to other

reasons.

Reason for therapy associated death was as follows:

One Patient with oropharyngeal cancer: major bleeding in operation field, one week after

operation

One patient with hypopharyngeal cancer died due to infection of the port-a-cath

Three patients with laryngeal cancer died therapy associated: one patient suffered a cardial

decompensation after operation, one died due to an ulcus bleeding in the hypopharyngeal

anastomosis region, and one patient suffered a postoperative ileus, leading to a necrosis of

the gut and furtheron died because of sepsis

One patient with a carcinoma of unknown primary died because of a postoperative ileus

leading to a lethal sepsis.

Table 58) Number and cause of death depending on tumor localization

Table 59) Number and cause of death depending on tumor classification

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Table 60) Number and cause of death depending on lymph node status

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4 Discussion:

4.1 Tumor Stage: Yeole et al(49) investigated on the 5 year overall survival of more than 5000 patients in Mumbai,

India. He classified tumor stages of patients as localized, if no neck involvement was found, regionally

spread, if neck lymph nodes were positive, and distant metastasis. 5 year overall survivals of those

patients were 63%, 22%, and 9%, respectively.

In carcinoma of the oral cancer, Shah et al experienced a cause specific survival of 94%, 80%, 66% ,

and 58% for Stage I, II, III and IV, respectively. Overall Survival for Stage III and IV cancer was 68%(50).

Compared to a retrospective study in Taiwan conducted on 703 patients by Chen et al(51), a much

better prognosis. In our patients, overall survival depending on stage, was comparable with the result

of the Memorial Sloan Kettering Center described by Shah. Especially stage I and stage II tumors offer

a very good prognosis(52). The good prognosis in early stage cancer was also described by

Mendenhall et al(53). He could demonstrate the high cause specific 5 year survival rate of early stage

laryngeal cancer: 98% in T1a and 90% in T2b patients and a 5 year overall survival between 82% for

T1a cancer and 77% for T2b.

Other study groups could not obtain such high survival rates(54). Hinerman et al(55) experienced a

stage III and stage IV overall survival of less than 50 percent.

4.2 Tumor Grade: In our patients we only had a very small number of patients with grade I or grade IV disease. Those

with undifferentiated carcinoma included into this study (5 patients), were described as squamous

cell carcinoma by more differentiated parts of the tumor mass. Due to the small numbers of GI and

GIV tumors, tumor grade was confounded into two groups: high differentiated (GI,GII) and low

differentiated (GIII,GIV)

Between those two groups we could not demonstrate a statistically significant difference in

recurrence free and overall survival depending on differentiation of primary tumor. In our tumor

board, decision for adjuvant therapy was not based upon tumor grade. However, lower

differentiation grade correlated with higher pN-status and therefore also with higher tumor stage.

Hence assessment of the impact of tumor grade on disease free and overall survival is difficult to

make, since low differentiated tumors were treated statistically more often with adjuvant therapy

compared to highly differentiated tumors.

In the literature, subjectivity of evaluation(56) into different grading groups is mentioned. In our

patients, pathological reports were made by one experienced examiner, therefore inter-examiner

variability was not an issue. This might be a very important factor considering the inconclusive

literature of the impact of grading on overall survival. Since differentiation of tumor is based on

microscopically conducted pathological evaluation, in which borderlines between well differentiated,

110

moderately differentiated and poorly differentiated tumors are set by the pathologist individually,

comparison and effect of tumor grade on outcome might be difficult if more than one pathologist

was responsible for evaluation.

As mentioned, literature on tumor grade is inconclusive. Janot et al(56) described the risk of early

and more frequently metastases in poorly differentiated tumors, concluding that patients with

poorly differentiated tumors and clinical nodal involvements are at high risk for recurrence and

therefore have a poorer overall survival. Likewise, Jerjes et al(57) could demonstrate in a recent

study the same effect of tumor differentiation in early stage oral squamous cell carcinoma on loco-

regional neck lymph node metastasis and overall survival. Even the relationship between histological

differentiation and perineural invasion is debated in the literature(58).

On the other side, other authors support the thesis of less important effects of tumor differentiation

on outcome. Li et al(59) investigated retrospectively on 391 patients with head and neck squamous

cell carcinoma; similar to our study setting, he investigated on patients primarily treated with surgical

tumor therapy and optional adjuvant therapy. In his patients, tumor grade did not have an impact on

distant metastasis and therefore survival. Kane et al(60), investigating prospectively on patients with

early stage oral carcinoma, could also find no impact of tumor grade on survival.

Trying to merge those two different views, our results to some extent support both theses at the

same time: we also experienced the correlation of tumor grade with lymph node metastases, as

described by Janot and Jerjes. Nevertheless, looking at the outcome, both overall and disease free

survival were not altered just as described by Kane and Li. The unchanged outcome might be

explained due to the adjuvant therapy administered. Looking at our patients treated solely with

surgical therapy, low grade and high grade tumors differed, although statistical significance was

missing. On the other side, run of curves of patients receiving adjuvant therapy did not differ at all.

We did not see the correlation of differentiation of tumor and perineural invasion as proposed by

Rahima. Although expecting the lower differentiated tumors to be more aggressive or more invasive,

we could not see a correlation of tumor grade not only on perineural invasion but also on capsule

penetration, haemangiosis, lymphangiosis, and congolemerate tumors.

4.3 Histological aspects: In our patients, perineural invasion, extracapsular spread, lymphangiosis carcinomatosa,

haemangiosis carcinomatosa and conglomerate tumors played an important role for disease free and

overall survival.

Perineural invasion is a strong predictor for local and locoregional recurrence and has to be looked

for and is requested to be reported in pathological examination(61) and treated with adjuvant

therapy(55). Also in cutaneous cancer of head and neck, perineural invasion is known as a predictive

factor for survival, nevertheless importance of adjuvant radiotherapy is still under debate in this

entity(62) - on a wide basis of discussion. Liao et al(63) did not see a statistically significant difference

in disease free survival and overall survival if patients with perineural invasion received adjuvant

radiotherapy or not. He therefore concluded that surgical resection alone is a sufficient treatment

even for patients with perineural invasion. This is in complete contrast to our patient data, showing

the importance of adjuvant therapy in patients with perineural invasion. Le Tourneau et al(64)

111

supports the importance of adjuvant therapy while he did not find a poorer survival in patients with

perineural invasion after primary surgical treatment and adjuvant radiotherapy. Nevertheless,

prospective trials for impact of adjuvant radiotherapy on patients with perineural invasion should be

realized.

The impact of extracapsular spread on locoregional and overall survival is well documented

throughout the literature(65,66). Even in patients with clinical negative neck, occult metastases with

capsule penetration occur(67), putting the patient at high risk of undertreatment. This disproves the

former thought of extracapsular spread being associated with larger lymph node metastasis and

fixed lymph nodes(68).

Investigating on 266 patients with squamous cell carcinoma of the oral tongue, Myers et al(69)

experienced a 5 year overall survival rate for patients with pathological node-negative neck, node-

positive neck without extracapsular spread, and node-positive neck with extracapsular spread, of

75%, 50%, and 30%, respectively. With 89% of postoperative radiotherapy in patients with

extracapsular spread in this study, nevertheless regional failure rate was 29%, therefore he

concluded that further adjuvant therapy is needed to affect regional and distant control and improve

survival. Our data suggests the significant importance of extracapsular spread on disease free and

overall survival. 6 out of 7 (85,7%) patients with extracapsular spread receiving no adjuvant therapy

died during follow-up. With adjuvant therapy, overall survival was significantly higher in patients with

extracapsular spread. Overall survival in all patients with extracapsular spread was 48% (29 of 56

patients died during follow-up).

Aside from capsule penetration and perineural invasion, further important tumor factors associated

with prognosis are local invasion, angioinvasion, lymphogenic dissemination and soft tissue

extension(57,70). In our patients, conglomerate tumors and haemangiosis carcinomatosa was a

strong predictive factor for distant metastasis. Patients with lymphangiosis carcinomatosa suffered

significantly more often ipsilateral and contralateral recurrence. All of these factors were strong

predictive factors for poor outcome. Both, disease free survival and overall survival were reduced

significantly if angioinvasion, lymphogenic dissemination, or conglomerate tumors were present.

In the literature, reports of haemangiosis carcinomatosa is rare as far as head and neck squamous

cell carcinoma is concerned, but the impact of haemangiosis on survival is documented in other

topics such as breast cancer(71). Likewise, impact of conglomerate lymph nodes – so called bulky

lymph nodes – is not documented in the literature for head and neck surgery. However, bulky

disease plays an important role for overall survival for example in penile cancer(72).

Similar to our results McMahon et al demonstrated in a prospective audit of patients in 1999 until

2001 with oral and oropharyngeal cancer, the bad prognostic impact of perineural invasion,

extracapsular spread, and vascular invasion(54).

4.4 Tumor Localization:

4.4.1 Hypopharynx:

In our data, patients with a hypopharyngeal tumor had a significantly lower recurrence free and

overall survival compared to other tumor localizations. Overall survival was 49% in patients with a

112

hypopharyngeal cancer compared to 71,7% of patients with cancer in other localizations. The poor

outcome in hypopharyngeal tumors is also described in the literature(73,74). In a study by Johansen

et al(75), an overall survival of 21% in hypopharyngeal cancer was described. Hypopharyngeal cancer

tends to present with advanced primary disease, and nodal metastasis is highly likely(76). Although

advanced stage of disease at time of diagnosis seems to be mainly responsible for poor outcome, and

T1 and T2 hypopharyngeal tumors have satisfying disease free survival and local control according to

Karatzanis et al(77), we have to contradict this statement, since results of our patient data showed

the bad prognosis of T1 and T2 hypopharyngeal tumors compared to other tumor localizations.

4.4.2 Tongue Cancer:

Looking at the literature, it seems as if within the oral cavity tumors, tongue cancer plays a

substantially different role(78). Looking at the outcome of our patients, we did not see a significant

difference in disease free and overall survival compared to other localizations of the oral cavity, but

similar to Yao et al(79), tongue cancer was always the one behind. Of course, statistic always faces

the problem of small numbers as seen in oral cavity cancer. However, Rusthoven et al(80) could

demonstrate in a study on more than 6700 patients, the bad prognostic factor of tongue cancer.

4.5 Lymph Node Status: Importance of lymph node status for disease free and overall survival is well documented throughout

the literature. Hahn et al(81) described the statistical significance between N0 or N1 versus N2 and

N3 status, finding no difference between N0 and N1. Li et al(59) demonstrated the statistically

significant impact of N-stage and numbers of positive lymph node levels on distant metastasis and

therefore overall survival. In our patients, we experienced the importance of negative lymph node

versus positive lymph node status. As soon as neck lymph node was involved, overall survival was

diminished by 15%. The effect of lymph node status on overall survival remains significant even in

patients with locally advanced (T4) disease(82). In a large retrospective publication by Layland et

al(83) on 3887 patients, he could demonstrate the negative prognostic factor of positive lymph node

status for each tumor site: oral cavity, oropharynx, hypopharynx and larynx, separately.

4.6 Lymph Node Ratio: In certain tumor entities such as gastric cancer(84-86), endometrial cancer(87), colorectal cancer(88-

90) and pancreatic cancer(91,92), lymph node ratio is a very important diagnostic tool.

Based upon those findings in other cancer entities, Shrime et al(47,93) postulated that lymph node

ratio between number of excised lymph nodes and number of positive lymph nodes is a predictive

factor for outcome. Investigating on 386 patients with an oral squamous cell carcinoma, Gil et al(94)

came to the same conclusion. While Shrime et al used two cut off points (6% and 13%) Gil only

compared the lymph node ratio below and above 6%. In both studies, results were similar showing a

statistically significant difference in disease free and overall survival depending on the lymph node

ratio. Süslü et al(95) also came to the conclusion of the importance of lymph node ratio; however,

this group used 4% as the cutoff point for different outcomes.

113

Comparing our data with the literature, we had a very similar result compared to the study

conducted by Gil. As suggested by Shrime, we also used two cutoff points, finding out that there was

no significant difference between patients with a lymph node ratio between 7-13% and patients with

a lymph node ratio higher than 13%. But patients with a lymph node ratio of 6% or lower had a

better disease free and overall survival.

4.7 Resection Margin: As expected, resection margin played a very important role in disease free and overall survival in our

patients. While macroscopic positive resection margin offered a crucial prognosis, microscopic

positive resection margins had a significant better prognosis. However, if microscopic positive

resection margin was not treated with adjuvant therapy (radiotherapy or radiochemotherapy),

prognosis was bleak.

If adjuvant therapy was administered in case of microscopic positive resection margin, Kaplan-Meier

curve could be converged to run of curve of negative resection margin. Still, median overall survival

differed by many months, indicating the importance of tumor free resection margins.

The importance of resection margin on disease free and overall survival is well documented

throughout the literature. Patel et al(96) concluded that, aside fromT-stage, N-stage, extracapsular

spread and tumor thickness, resection margin is a very important predictive factor for disease free

survival. Karatzanis et al(77) emphasized the importance of negative resection margin. Similar to

Patel, McMahon et al filtered resection margin, among other predictive factors, as a very important

statistically significant factor for outcome(54).

114

4.8 Neck Dissection:

4.8.1 Preserving non lymphatic tissue:

In the mid-20th century, it became evident that radical neck dissection was too aggressive in a large

number of situations. The group of surgeons aiming for preservation of non-lymphatic tissue was led

by Osvaldo Suarez and his pupils Ettore Bocca and Cesar Gavilan(97). Kokemueller et al(98) however

disagreed with the idea of preserving non-lymphatics. At least as far as advanced stages were

concerned, because curves for actuarial neck control demonstrated a remarkable divergence.

Nevertheless, he could not find a statistically significant influence on prognosis for different types of

comprehensive neck dissections, but explained the missing significance by the usually more extensive

disease when radical procedure was performed.

In our patients, we did not see a difference in disease free survival or overall survival comparing

whether non-lymphatic tissues were excised or not. For all three (sternocleidomastoid muscle,

accessoric nerve and jugular vein), Kaplan-Meier curves had a similar run. However, likewise with

Kokemueller, groups were not eligible for comparison, because distribution of disease stage was not

even, and therefore validity of evidence was missing.

4.8.2 Preserving lymphatic tissue:

With the discussion on preserving non-lymphatic tissue at debate at the end of the 20th century, also

discussion about whether selective neck dissection could be a sufficient treatment option for some

patients or whether the need of radical neck dissection remained, was coming up and was

investigated by some study groups(99-102). All of those investigations are based on distribution of

neck lymph node metastases described by earlier studies of Lindberg(103) and Shah(104). In oral

cancer, most commonly, lymph nodes at levels I-III are involved while positive lymph nodes in level IV

are rare. In oropharyngeal and hypopharyngeal cancer, Candela et al(105) described the likelihood of

level II to level IV metastasis, while involvement of level I and level V was seen very randomly (less

than 1 percent). It appears that the pattern of metastasis in laryngeal cancer is very similar to

hypopharyngeal cancer(106,107).

In 1998, Clayman et al(108) reviewed existing literature, confounding lymph node levels at highest

risk for lymph node metastasis and set recommendations of selective procedures for every tumor

site:

Oral cavity: lymph node levels I-III, in case of tongue carcinoma also IV are at risk for lymph

node metastasis and therefore, the recommended neck procedure is a supraomohyoidal

neck dissection, in case of tongue carcinomas recommendation includes extension to region

IV.

Oropharynx: regions at risk are the lymph node levels I-III, also lymph nodes in the

retropharyngeal and parapharyngeal regions should be looked for in a supraomohyoidal neck

dissection.

115

Hypopharynx: levels at risk are especially levels II-IV, but also retropharyngeal and

parapharyngeal lymph nodes. Recommended neck procedure in hypopharyngeal cancer is a

lateral neck dissection with inclusion of retro-, and parapharyngeal basins.

Larynx: most common lymph node metastasis in laryngeal tumors are levels II-IV, in case of

advanced carcinomas also regio VI. Lateral neck dissection or in case of advanced disease,

anterolateral neck dissection should be performed.

In our patient data, we could not find a statistical significant benefit in patients receiving a more

extensive type of neck dissection compared to patients receiving only selective procedures. Looking

at the number of lymph node levels excised, we could demonstrate that with an increasing number

of lymph nodes resected, disease free and overall survival did not increase in the same way but

rather showed a very similar outcome; regardless the benefit of morbidity in patients with neck

dissections of only I-III lymph node levels (especially prevention of shoulder dysfunction(109,110))

Nevertheless, overall survival in patients with neck dissection of 1-3 lymph node levels in patients

with a positive neck did have a very low median overall survival compared to patients being dissected

with more than 3 nodes. But looking at the Kaplan-Meier curve together with the Log-Rank test,

small number of median overall survival (34 months) can be explained by the small number of

patients in this group (11 patients).

As far as radical neck dissection is concerned, we could demonstrate that radical neck dissection does

not provide a better outcome in patients with a stage IV disease, patients with a positive neck, and

also patients with different number of positive neck lymph nodes affected. In every setting, radical

neck dissection did not offer an advantage compared to other types of neck dissections. Kohler et

al(111), comparing radical neck dissection versus modified radical neck dissection, came to the same

conclusion: radical neck dissection, with all its sequels, did not show a better outcome.

Looking at the locoregional recurrence free survival, comparing extensive neck dissection (radical

neck dissection, modified radical neck dissection, and posterolateral neck dissection) with the more

or less elective selective procedures of selective neck dissections (supraomohyoidal neck dissection,

suprahyoidal neck dissection and lateral neck dissection), lymph node recurrence was even. Even if

adjuvant therapy was considered, there was not benefit in any neck procedure on locoregional

recurrence free survival. In our patients, we experienced a locoregional recurrence (LRR) free survival

of 91 percent. Patel et al(99) experienced a LRR free survival of 87 percent, Shepard et al(112) a LRR

free survival of 90 percent. Both could not find a statistically significant benefit of comprehensive

neck dissection versus selective neck dissection for LRR free survival. This is even more remarkable

considering the fact that patients receiving comprehensive neck dissection usually have a higher

disease stage.

Therefore, with the great support of the literature, we would vote for a selective neck procedure,

especially in elective neck dissections, rather than a comprehensive radical, or modified radical neck

dissection.

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4.8.3 Clinical Node Negative Neck – is there a need of elective contralateral Neck

Dissection?

Knowing the good prognosis of patients with a negative lymph neck node status, and the bad effect

of lymph node metastasis on overall survival, especially in patients receiving no adjuvant therapy,

physicians are faced with the problem of patients with clinical negative lymph nodes but occult neck

metastasis. Is there a need of elective procedure and what is the indication for elective neck

dissection? Today there are at least 4 prospective studies available questioning whether elective

neck dissection or observation and therapeutically treating the clinically negative neck is the best

decision. But still, the issue remains unresolved since answers are inconclusive:

Fakih et al(113,114) showed in 70 patients with a squamous cell carcinoma (SCC) of the oral tongue

that there is no significant difference in disease free survival between patients treated with elective

ipsilateral radical neck dissection versus observation. Similar to Fakih, Vandenbrouck et al(115)

investigated in 75 patients on T1-T3 SCC of mixed oral tongue and floor of mouth carcinomas

showing that there is no benefit if elective radical neck dissection was performed.

Based on their earlier conducted retrospective study(116), showing a significant reduction of node

related mortality from 23% of observation to 3% after selective neck dissection Yuen et al(117)

investigated prospectively on the same issue in 71 patients, trying to confirm their retrospective

study. The 5 year disease-specific survival rate was 87% for the observation arm and 89% for the

elective neck dissection arm showing once again no significant difference. These 3 studies indicate

that if close follow-up is assured, both observation as well as elective neck dissection offers similar

treatment results.

On the other hand, Kligerman et al(118) prospectively analyzed T1-T2 SCC of the oral cavity in 67

patients finding recurrences in 42% of patients of the observation group and 24% of the elective

omohyoidale neck dissection group. The disease-free survival rates at 3,5 years were 49%, and 72%,

respectively, leading to the conclusion that neck dissection remains mandatory.

In 1997 Pillsbury and Clark concluded that considering the high percentage of occult metastases in

oral cavity SCC, observation of the n0 neck with oral cavity primary is ill advised(119). Other

retrospective studies and reviews demonstrated the high incidence of occult metastases in the oral

cavity(46,120-122). In case of oropharyngeal and hypopharyngeal primary tumor, bilateral elective

treatment should be strived for, since probability of occult metastases is – depending on

literature(105,123-125) – between 17% and 55% But even though the rich lymphatic network in this

region puts the patient at higher risk of occult metastases bilaterally, the discussion whether bilateral

neck dissection should be performed in every case is questioned(126)(126).

Therefore it is essential to filter out those patients who might benefit of a bilateral treatment and

those who would not.

Interestingly enough, facing a high number of occult lymph node metastastis in the ipsilateral and

contralateral neck in oral cavity and oropharyngeal cancer, locoregional recurrence rate seems to be

much lower. Moncrieff et al(52) experienced a locoregional lymph node recurrence in 8 % and only

2% in the contralateral neck in T1/T2 tumors of the oropharynx – any N was included. Considering

that only 1 patient was treated bilaterally and 22 out of 92 did not receive lymphadenectomy, a very

small number. 10 out of 155 patients experienced a lymph node recurrence in a recent study by

Sklenicka et al(127) similar to a Korean study(128), finding 25 out of 230 patients with a recurrence in

117

the neck. Unfortunately number and type of lymphadenectomy in those patients with lymph node

recurrence was not described in those studies. Garcia et al(129) investigated in a retrospective study

on 315 patients with oral cavity cancer: 9% developed ipsilateral and only 5% contralateral neck

relapse. 101 patients did not receive any lymphadenectomy, only 2 of them experienced

contralateral lymph node relapse.

Weiss et al(130) calculated a treatment threshold for elective neck dissection if the probability of

occult metastases being higher than 20%. Okura et al(131) calculated the threshold point being at

44%, suggesting an elective treatment of the neck if the probability of occult metastases being above

this threshold percentage.

The literature available exposes two main arguments: 1) how high is the risk of occult metastases to

the neck in different tumor types considering grading and other histopathological subgroups, and 2)

if the risk of occult metastases is known, at what point is prophylactic treatment indicated?

However, we could not find a statistical significant benefit of elective treatment of the contralateral

neck, but rather a very similar result in both groups. Considering the high morbidity of bilateral neck

dissection, we would not suggest such a therapy approach in clinical negative contralateral necks,

except when the tumor is crossing the midline.

4.9 Adjuvant therapy in advanced disease: Throughout the literature, debate about best treatment strategies in head and neck cancer are going

on. Carvalho et al(132) came to the conclusion that surgery should be the first option for initial

clinical stage oral and oropharyngeal cancers. For advanced cases, independently of the site of the

tumor, surgery and postoperative radiotherapy should be the standard of care because it is

associated with the lowest rates of locoregional recurrence. Further discussion on advantage or

disadvantage of surgical procedure (i.e. organ preservation(133)) will not be conducted, since our

patients were included into this study, if primary treatment plan consisted of surgical resection of

primary tumor with additional neck dissection and, if administered, adjuvant therapy. Patients

receiving induction chemotherapy, definitive radiotherapy, et cetera, were not included and

therefore any advantage of those treatment options will not be included into discussion.

Adjuvant therapy is an integral part of treating locally advanced head and neck cancer. In a

comparative analysis of the EORTC 22931(134) and the RTOG 9501(135) studies, Bernier et al(136)

confounded the importance of postoperative adjuvant radiochemotherapy especially in patients with

microscopically positive resection margins and extracaspular rupture outside lymph nodes. Although

detectable, the contribution of adjuvant chemoradiation in the group of patients who have stage III-

IV disease, perineural infiltration, vascular embolisms, and/or level IV-V lymph nodes secondary to

tumors of the oral cavitiy or oropharynx seems to be less important in this combined analysis.

Comparing combined radiochemotherapy with single modality treatment options in advanced

oropharyngeal cancer, Kader et al(137) could demonstrate the superiority of combined

radiochemotherapy in disease free and overall survival.

Reviewing more than 25 papers on the effect of additional adjuvant chemotherapy versus

radiotherapy solely after primary surgery, Furness et al(138) calculated a 16% increase in overall

118

survival if postoperative radiochemotherapy was administered. Oliver et al(139) came to the same

conclusion finding a statistically significant difference in patients being treated with surgery plus

radiochemotherapy compared to patients undergoing surgery plus radiotherapy solely; large

European(134) as well as American(135) studies were included. However, it has to be said, that

overall survival did not differ statistically significant in the American study by Cooper. Comparing the

literature with our results, we could see the benefit of combined postoperative radiochemotherapy

compared to surgery and surgery with postoperative radiotherapy. Percentage of overall and disease

free survival was significantly higher in patients treated with postoperative radiochemotherapy.

However, Log-Rank test in the Kaplan-Meier analysis did not show up to be significant.

Furthermore, in our results, overall survival of patients with stage III and stage IV disease was very

high compared to literature. Bernier et al(134) experienced in 334 patients with stage III and stage IV

disease an overall survival of 40% and 52% respectively for patients with adjuvant radiotherapy and

adjuvant radiochemotherapy. In our patient cohort, with 221 patients, overall survival for the same

group was 58% and 87%. Investigating on the high percentage of overall survival in our patients, we

found out that long time follow-up in patients with radiotherapy could be achieved: after 3 years we

still had 58 patients at risk, 34 patients after 5 years. In patients treated with postoperative adjuvant

radiochemotherapy, only 6 of 37 patients were still at risk after three years, and only 1 patient was

followed up for more than 5 years. This could be responsible for the very high number of percentage

of overall survival in this specific group.

However, one has to keep in mind that with increasing aggressiveness of treatment modalities, side

effects as well as morbidity rises as well. The Radiation Therapy Oncology Group investigated

together with the Eastern Cooperative Oncology Group and the Southwest Oncology Group in 459

patients with high risk squamous cell carcinoma of head and neck (positive mucosal resection

margin, more than 2 positive lymph nodes and extracapsular spread) the effect of postoperative

adjuvant radiotherapy versus postoperative adjuvant chemoradiation. Although local and regional

control was increased significantly in the combined adjuvant therapy group, overall survival did not

benefit of combined postoperative chemoradiation. Adverse side effects of grade 3 or higher were

seen in 34 percent of radiotherapy patients, but 77 percent in patients with chemoradiation(135).

Especially in older age and high T-status, as well as tumors of the hypopharynx and larynx are

associated with severe late toxicity after concurrent chemoradiation(140).

In a meta-analysis by Pignon et al(34), investigating on 17354 patients with advanced disease and

impact of chemotherapy together with locoregional therapy, he could not find a higher percentage of

patients dying of other causes than the cancer between patients receiving chemotherapy to those

patients without chemotherapy. Furthermore, he confounded the positive impact of chemotherapy

especially if applied concomitant with radiotherapy. Considering the different chemotherapeutics, he

identified platin based chemotherapeutics as being the most effective agents considering overall

survival – especially if chemotherapy was a mono-chemotherapy.

In a recent study by Tobias et al(141), investigating on the effect of timing of chemotherapy in a large

cohort of patients with advanced head and neck cancer (966 patients) he agreed with Pignon that

concurrent chemoradiotherapy has the best effect on disease free and overall survival. However,

since he also included patients with inoperable cancer, this conclusion was not right for patients who

were operable and had undergone surgery. Looking at those patients separately, additional

concurrent chemoradiation did not offer a better recurrence free survival or overall survival

119

compared to patients with postoperative radiotherapy. In addition, late toxicity was doubled and

therefore not suggested. Nevertheless, he used non-platinum chemotherapeutics in his study design.

This might explain the missing effect of chemotherapeutics in patients undergoing surgery and

postoperative radiotherapy.

Nevertheless, one has to keep in mind the high toxicity of platinum based chemotherapeutics. Newer

agents, such as taxanes and targeted therapies might improve on the longer established cisplatin. In

this context, a large study on 424 patients with advanced head and neck cancer by Bonner et al(142)

investigating on effect of adjuvant radioimmunotherapy with cetuximab as immunotherapeutic, has

to be mentioned. Bonner came to the conclusion that patients treated with postoperative

radiotherapy and additional cetuximab experienced a significantly better overall survival. However,

validity of this study is doubted, since he did not compare cetuximab with the gold-standard in

advanced carcinomas but with radiotherapy solely. Discussion is on-going, whether all patients would

benefit of concurrent radiotherapy and cetuximab(143), and explanation of the connection between

cetuximab induced rash and overall survival is demanded(144).

Two phase III randomized trials (RTOG 0522 and GORTEC 2007-01) might resolve the question

whether combining cetuximab with chemoradiotherapy is better than chemoradiotherapy alone or

cetuximab and radiotherapy in locally advanced head and neck cancers(145).

Looking at the literature, the issue of treatment associated morbidity and mortality is getting more

into focus of therapists. With all the effective treatment choices available, and with the rise of

combined therapy modalities, one has to weigh the aggressive treatment for cancer control on the

one side with the high therapy associated morbidity on the other side. To oversimplify a bit, cancer

might be controlled by today’s treatment options, but does the patient survive our treatment? And

that should be the most important factor: what is best for the patient, not what is best to treat the

cancer.

120

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Tables

Table 1) Ranking of age-standardized incidence rate of lip, oral cavity, oropharyngeal and laryngeal

cancer in Europe according to GLOBOCAN (2008) ................................................................................ 12

Table 2) Ranking of age-standardized mortality rate for lip, oral cavity, pharyngeal and laryngeal

cancer worldwide according to GLOBOCAN (2008) .............................................................................. 13

Table 3) Ranking of age-standardized mortality rate of lip, oral cavity, oropharyngeal and laryngeal

cancer in Europe according to GLOBOCAN (2008) ................................................................................ 14

Table 4) Staging system of the oral cavity and lip cancers, according to the sixth-edition of the TNM-

Staging System of the International Union Against Cancer (UICC) and the American Joint Committee

on Cancer (AJCC) ................................................................................................................................... 16

Table 5) Staging system of pharyngeal cancers, according to the sixth-edition of the TNM-Staging

System of the UICC and AJCC, *parapharyngeal extension denotes posterolateral infiltration

beyond the pharyngobasilar fascia .................................................................................................. 17

Table 6) Staging system of laryngeal cancers, according to the sixth-edition of the TNM-Staging

System of the UICC and AJCC ................................................................................................................ 18

Table 7) Staging system for lymph nodes of all head and neck sites except nasopharynx, according to

the sixth-edition of the TNM-Staging System of the UICC and AJCC .................................................... 19

Table 8) Staging system for lymph nodes of nasopharyngeal tumor, according to the sixth-edition of

the TNM-Staging System of the UICC and AJCC, *midline nodes are considered to be ipsilateral nodes

............................................................................................................................................................... 19

Table 9) Tumor staging of squamous cell carcinomas in oral cavity, oropharynx, hypopharynx and

larynx ..................................................................................................................................................... 20

Table 10) Tumor staging of nasopharyngeal tumors ............................................................................ 20

Table 11) Borders of neck lymph node regions(10) .............................................................................. 21

Table 12) Classification and terminology of neck dissection(12) .......................................................... 24

Table 13) Distribution of cancer staging in patients ............................................................................. 40

Table 14) Test of normality proving there is no normal dispersion ...................................................... 42

Table 15) Statistic for survival of male, female and overall survival ..................................................... 42

Table 16) Log-Rank test for the impact of tumor localization on overall survival ................................ 44

Table 17) Test of equality of distribution depending on hypopharyngeal cancer or cancer of other

localization ............................................................................................................................................ 45

Table 18) Overall survival depending on localization of oral cavity carcinoma .................................... 46

131

Table 19) Distribution of recurrence, localization of recurrence and number of death according to

localization ............................................................................................................................................ 46

Table 20) Comparison of hypopharyngeal cancer and cancer of other tumor sites in recurrence,

localization of recurrence and number of deaths ................................................................................. 47

Table 21) Percentage of patients suffering a recurrence considering tumor classification ................. 48

Table 22) Percentag of patients dying considering tumor classification .............................................. 49

Table 23) Statistical analysis of disease free survival depending on lymph node status ...................... 50

Table 24) Percentage of patients being alive at the end of follow up considering positive or negative

lymph node status ................................................................................................................................. 51

Table 25) Statistical analysis of median overall survival considering lymph node status ..................... 52

Table 26) Percentage of disease free survival depending on number of positive lymph nodes. ......... 53

Table 27) Statistic of overall survival depending on number of positive lymph nodes (Event = death)

............................................................................................................................................................... 55

Table 28) Statistical analysis for disease free survival depending on lymph node ratio....................... 58

Table 29) Statistical analysis for overall survival depending on lymph node ratio ............................... 58

Table 30) Statistical analysis of conglomerate lymph nodes as prognostic factor for overall survival;

median disease free survival was reduced from 108 months to 29 months ........................................ 63

Table 31) Statistical analysis of histological aspects and occurrence and localization of recurrence .. 64

Table 32) Log-Rank test on effect of radical neck dissection considering number of positive lymph

nodes ..................................................................................................................................................... 70

Table 33) Distribution of tumor classification and lymph node status within stage IV disease treated

with or without radical neck dissection ................................................................................................ 71

Table 34) Percentage of locoregional recurrence free survival depending on type of neck dissection 73

Table 35) Percentage of adjuvant therapy in patients receiving unilateral or bilateral neck dissection

............................................................................................................................................................... 75

Table 36) Chi-Square test did show a significant difference in distribution between patients and

excision of non-lymphatic structures, and therefore could not be analyzed ....................................... 77

Table 37) Statistical analysis of disease free survival considering resection margin ............................ 78

Table 38) Statistical analysis of overall survival considering resection margin..................................... 79

Table 39) Number of patients being treated with or without postoperative adjuvant therapy and

percentage of disease free survival (Event = recurrence) ..................................................................... 81

132

Table 40) Statistical analysis for disease free survival considering resection margin and postoperative

adjuvant therapy ................................................................................................................................... 81

Table 41) Patients at risk depending on adjuvant therapy and resection margin, after 1, 3 and 5 years

............................................................................................................................................................... 83

Table 42) Number of patients being treated with or without postoperative adjuvant therapy and

percentage of overall survival (Event = death) ..................................................................................... 83

Table 43) Percentage of overall survival in patients with or without adjuvant therapy considering

tumor classification ............................................................................................................................... 89

Table 44) Pairwise comparison of overall survival depending on postoperative adjuvant therapy and

tumor classification ............................................................................................................................... 91

Table 45) Statistical analysis of disease free survival in patients with or without postoperative

adjuvant therapy ................................................................................................................................... 93

Table 46) Statistical analysis of overall survival depending on postoperative adjuvant therapy and

lymph node status ................................................................................................................................. 95

Table 47) Adjuvant therapy applied in early stage carcinoma .............................................................. 96

Table 48) Number of recurrence in patients with a stage III or stage IV disease ................................. 97

Table 49) Statistical analysis of disease free and overall survival in stage III/IV patients considering

adjuvant therapy ................................................................................................................................... 99

Table 50) Multivariate data analysis for recurrence free survival ...................................................... 100

Table 51) Multivariate model for recurrence free survival including univariate significant covariables

............................................................................................................................................................. 101

Table 52) Covariables used for multivariate data analysis for overall survival ................................... 101

Table 53) Multivariate model for disease free survival including univariat significant covariables ... 102

Table 54) Covariables used for multivariate data analysis for overall survival ................................... 102

Table 55) Multivariate model for overall survival including univariat significant covariables ............ 103

Table 56) Percentage of recurrence depending on tumor localization ............................................. 104

Table 57) Statistical analysis of overall survival depending on type of recurrence ............................ 105

Table 58) Number and cause of death depending on tumor localization .......................................... 107

Table 59) Number and cause of death depending on tumor classification ........................................ 107

Table 60) Number and cause of death depending on lymph node status .......................................... 108

133

Figures

Figure 1) Worldwide incidence for lip, oral cavity, pharyngeal and laryngeal cancer according to

GLOBOCAN (2008) ................................................................................................................................. 12

Figure 2) Worldwide incidence for lip, oral cavity, pharyngeal and laryngeal cancer according to

GLOBOCAN (2008) ................................................................................................................................. 13

Figure 3) Mortality crude rate from lip, oral cavity and pharynx in Australia, Austria, Canada,

Germany, United Kingdom and United States of America(5) ............................................................... 15

Figure 4) Anatomical subsites of the head and neck region(11) ........................................................... 22

Figure 5) First layer of database with basic information ....................................................................... 28

Figure 6) Second layer of database with tumor specific information ................................................... 29

Figure 7) Third layer of database with information on tumor excision ................................................ 30

Figure 8) Fourth layer of database, holding information on neck dissection ....................................... 31

Figure 9) Fifth layer of database holding information of adjuvant therapy, recurrence and death ..... 32

Figure 10) Sixth layer of database holding additional information ....................................................... 33

Figure 11) Distribution of patients who were neck dissected and included into the study during the

years 1999-2009 .................................................................................................................................... 38

Figure 12) Distribution of sublocalizations: floor of the mouth 26, tongue 40, cheek mucosa 2, lip 6,

soft palate 6, root of tongue 19, lateral pharyngeal wall 2, tonsils 67, nasopharynx 6, sinus piriformis

38, postcricoidal region 1, epiglottis 7, lateral laryngopharyngeal wall 1, supraglottic 15, glottis 27,

transglottic 2, unknown primary 26 ...................................................................................................... 39

Figure 13) Time of follow up in months ................................................................................................ 41

Figure 14) Test of normality .................................................................................................................. 41

Figure 15) 5 year overall survival........................................................................................................... 43

Figure 16) 5 year overall survival considering gender ........................................................................... 43

Figure 17) Kaplan-Meier curve illustrating the overall survival considering tumor localization .......... 44

Figure 18) Small hypopharyngeal cancer compared to small cancer of all other tumor localizations

combined showing a significant difference in outcome (Log Rank = 0.011) ......................................... 45

Figure 19) Kaplan Meier curve illustrating disease free survival considering tumor classification ...... 48

Figure 20) Kaplan Meier curve illustrating overall survival considering tumor classification ............... 49

Figure 21) Kaplan Meier curve illustrating disease free survival considering lymph node status ........ 51

134

Figure 22) Kaplan-Meier curve demonstrating the high impact of positive lymph node status on

overall survival ....................................................................................................................................... 52

Figure 23) Kaplan Meier curve illustrating overall survival considering lymph node status (Log-Rank =

0,001) ..................................................................................................................................................... 53

Figure 24) Kaplan-Meier curve illustrating disease free survival considering number of positive lymph

nodes ..................................................................................................................................................... 54

Figure 25) Kaplan-Meier curve illustrating overall survival considering number of positive lymph

nodes ..................................................................................................................................................... 55

Figure 26) Number of positive lymph nodes excised ............................................................................ 56

Figure 27) Scatter plot of lymph node status and number of lymph nodes excised ............................ 57

Figure 28) Disease free survival and overall survival considering lymph node ratio (Log-Rank = 0,000

for both disease free and overall survival) ............................................................................................ 59

Figure 29) Kaplan-Meier curve illustrating 5 year overall survival depending on stage ....................... 60

Figure 30) Kaplan Meier curve illustrating no impact of tumor grade on disease free survival ........... 61

Figure 31) Kaplan Meier curve illustrating no impact of tumor grade on overall survival (well-

differentiated and undifferentiated tumor grades were excluded out of the graphic on behalf of small

patient number) .................................................................................................................................... 61

Figure 32) Impact of conglomerate lymph nodes on disease free survival .......................................... 62

Figure 33) Impact of conglomerate lymph nodes on 5 year overall survival ........................................ 63

Figure 34) Distribution of types of neck dissections performed (according to the recommendations of

the American Head and Neck Society 2008) ......................................................................................... 65

Figure 35) Kaplan-Meier curve, showing no statistically significant difference in disease free or overall

survival depending on number of excised lymph node levels in patients with a pN0 status. .............. 68

Figure 36) Kaplan-Meier curve, showing no statistically significant difference in disease free or overall

survival depending on number of excised lymph node levels in patients with a pN+ status. .............. 69

Figure 37) Impact of radical neck dissection on overall survival in patients with a positive lymph node

status (Log-Rank = 0,74) ........................................................................................................................ 70

Figure 38) Kaplan-Meier curve illustrating the negative effect of radical neck dissection on disease

free survival (Log-Rank = 0,002) ............................................................................................................ 71

Figure 39) Overall survival of patients with stage IV disease depending on type of neck dissection

(Log-Rank = 0,115) ................................................................................................................................. 72

Figure 40) Kaplan-Meier curve illustrating similar run of curves between different types of neck

dissection, considering adjuvant therapy ............................................................................................. 74

135

Figure 41) Locoregional recurrence free survival considering type of neck dissection ........................ 75

Figure 42) Overall survival of patients with clinical contralateral negative neck depending on

unilateral or bilateral neck treatment (Log-Rank = 0,973) .................................................................... 76

Figure 43) Kaplan-Meier curve of disease free survival considering resection margin ........................ 78

Figure 44) Kaplan-Meier curve of overall survival considering resection margin ................................. 80

Figure 45) Kaplan-Meier curve illustrating the bad prognosis on disease free survival of patients with

a R1 resection margin and no additional treatment compared to patients with negative resection

margins (Log-Rank = 0,000) ................................................................................................................... 82

Figure 46) Kaplan-Meier curve illustrating the effect of adjuvant therapy in positive resection margin

(Log-Rank = 0.313 for R0 vs. R1) ............................................................................................................ 82

Figure 47) Kaplan-Meier curve illustrating the bad prognosis on overall survival of patients with a R1

resection margin and no additional treatment compared to patients with negative resection margins

(Log-Rank = 0,000) ................................................................................................................................. 84

Figure 48) With adjuvant therapy, R1 and R0 did not show a statistical significant difference (Log-

Rank = 0,088) in overall survival, while R2 remained a strong prognostic impact on overall survival

(Log-Rank = 0,002 compared to R0 and 0,015 compared to R1) .......................................................... 85

Figure 49) Number of patients treated with postoperative adjuvant therapy ..................................... 86

Figure 50) Number of patients treated with carboplatin/5FU, Cisplatin or Erbitux ............................. 87

Figure 51) Overall effect of adjuvant therapy ....................................................................................... 88

Figure 52) Effect of postoperative adjuvant therapy in pT1 tumor patients (Log-Rank = 0,151) ......... 90

Figure 53) Effect of postoperative adjuvant therapy in pT2 tumor patients (Log-Rank = 0,016) ......... 90

Figure 54) Kaplan-Meier curve illustrating overall survival depending on tumor classification of

patients receiving no additional postoperative treatment ................................................................... 91

Figure 55) Kaplan-Meier curve illustrating overall survival depending on tumor classification of

patients receiving no additional postoperative treatment ................................................................... 92

Figure 56) Kaplan-Meier curve illustrating disease free survival without postoperative adjuvant

therapy considering positive or negative lymph node status (Log-Rank = 0,000) ................................ 93

Figure 57) Kaplan-Meier curve illustrating disease free survival in patients receiving postoperative

adjuvant therapy considering positive or negative lymph node status (Log-Rank = 0,317) ................. 94

Figure 58) Kaplan-Meier curve illustrating the statistically significant impact on postoperative

adjuvant therapy in patients with a positive lymph node status (Log-Rank = 0,004) ........................... 94

Figure 59) Difference in run of curves depending on postoperative adjuvant therapy in patients with a

pathological positive neck (Log-Rank = 0,420) ...................................................................................... 96

136

Figure 60) Kaplan-Meier curve illustrating impact of adjuvant therapy in early stage cancer on overall

survival .................................................................................................................................................. 97

Figure 61) Disease free survival of patients with stage III or stage IV disease considering adjuvant

therapy (Log-Rank = 0,004) ................................................................................................................... 98

Figure 62) Kaplan-Meier curve illustrating different run of curves considering adjuvant therapy in

stage III and stage IV disease, however, Log-Rank test did not reach statistical significance (Log-Rank

= 0,245) .................................................................................................................................................. 99

Figure 63) Kaplan-Meier curve illustrating overall survival depending on type of recurrence (Log-Rank

= 0,000) ................................................................................................................................................ 106

Figure 64) Number of patients dying after recurrence depending on type of recurrence ................. 106